International Journal of Cardiology 172 (2014) 297–298

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Screening for atrial fibrillation in patients with obstructive sleep apnoea to reduce ischaemic strokes☆ D. Wilson a,b,⁎,1,2, A. Frontera a,1,2, G. Thomas a,2, E. Duncan a,2 a b

Bristol Heart Institute, University Hospitals Bristol NHS Foundation Trust, Bristol Royal Infirmary, Bristol BS2 8HW, United Kingdom Southampton General Hospital, University Hospitals Southampton NHS Foundation Trust, Tremona Road, SO16 6YD, United Kingdom

a r t i c l e

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Article history: Received 4 September 2013 Received in revised form 9 January 2014 Accepted 11 January 2014 Available online 18 January 2014 Keywords: Atrial fibrillation Obstructive sleep apnoea Stroke Screening

a b s t r a c t Obstructive sleep apnoea is an independent risk factor for stroke. A number of different mechanisms have been identified which link OSA and stroke including hypertension and oxidative stress. Atrial fibrillation (AF) is likely to play a role in the development of stroke in patients with OSA. Indeed, patients with OSA have a higher incidence of AF than the general population. Given the higher constellation of cardiovascular co-morbidities seen in patients with OSA, we believe that a strategy of actively screening for the presence of AF in patients with OSA and initiating oral anticoagulation therapy when appropriate may reduce the burden of stroke in this population. This is a question that needs to be addressed in a clinical trial. © 2014 Elsevier Ireland Ltd. All rights reserved.

1. Introduction

2. Scope of the problem

Obstructive sleep apnoea (OSA) is common, under-diagnosed, and increasing in prevalence and has been shown to be an independent risk factor for stroke. It has also been associated with a number of cardiovascular disorders such as heart failure, hypertension and atrial fibrillation (AF) that are also associated with stroke. As a consequence, there is increased interest in OSA as a potential treatable risk factor in stroke. Whilst OSA is treatable with dietary and lifestyle changes to achieve weight loss and nocturnal continuous positive airway pressure (CPAP), there is a paucity of randomised trial data supporting the efficacy of these treatments in stroke reduction. In this article we aim to discuss the complex interplay between OSA, stroke and AF. We would like to highlight the need to not only actively screen patients with OSA and stroke for AF in order to initiate oral anticoagulant (OAC) therapy to prevent future strokes (secondary prevention), but also, perhaps more importantly, screen for AF in otherwise healthy patients with OSA and initiate OAC if appropriate to prevent future strokes (primary prevention).

The prevalence of OSA in the general population is high and it is estimated that 12–18 million adults may have untreated OSA in the United States alone [1]. Sleep apnoea is associated with hypertension, heart failure, stroke, arrhythmias, pulmonary arterial hypertension and advanced kidney disease [2]. Patients with OSA and stroke also have an increased likelihood of early death than controls (adjusted hazard ratio, 1.76; 95% confidence interval, 1.05–2.95; P = .03) and this is independent of age, sex, body mass index, smoking, hypertension, diabetes mellitus, atrial fibrillation, Mini-Mental State Examination score, and Barthel index of activities of daily living [3]. AF is the most common sustained cardiac arrhythmia and is associated with increased risk of morbidity including cognitive decline, heart failure, stroke and even death. AF is an extremely expensive public health problem with direct costs related to managing AF in various health care environments, and indirect costs relating to managing vascular complications of AF such as stroke. The prevalence of atrial fibrillation in the general population increases with age with age-specific rates of 3.6% among patients 66 to 69 years and 16.3% among patients 85 to 89 years identified in Medicare beneficiaries in 2005 [4]. The risk of AF in patients with OSA in the Sleep Heart study is about four times greater than that of those with no sleep-disordered breathing (adjusted OR 4.02; 95% CI 1.03–15.74) [5]. As the severity of OSA worsens, the risk of AF increases. The use of clinical risk stratification tools such as the CHA2DS2 VASc score to predict stroke and thromboembolism in AF has been recommended. Guidelines recommend the initiation of oral anticoagulant (OAC) therapy for patients with AF with a score of ≥ 1 [6]. There are

☆ No financial support was received in connection with the preparation of this manuscript. ⁎ Corresponding author at: Southampton General Hospital, University Hospitals of Southampton NHS Trust, United Kingdom. E-mail address: [email protected] (D. Wilson). 1 Equal contribution. 2 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

0167-5273/$ – see front matter © 2014 Elsevier Ireland Ltd. All rights reserved.



currently no data on the distribution of CHA2DS2 VASc scores in patients with OSA. However, in an epidemiological study of 4991 subjects who were free of self-reported cardiovascular disease at the start of the study but who were found to have evidence of sleep disordered breathing, the mean age of patients with a respiratory disturbance index (RDI N10.7) was 64.1 years and hypertension was present in 50.3% of males and 60.6% of females over the age of 65 years [7]. It is therefore likely that given the constellation of co-morbidities associated with OSA, the majority of patients with OSA who have AF would score at least one on the CHA2DS2 VASc score and thus benefit from OAC for stroke prophylaxis. 3. OSA and stroke OSA has been shown to increase the risk of stroke particularly among males in the highest quartile of OSA severity (Apnoea– Hypopnoea Index, AHI N19) (P = 0.016), with an adjusted hazard ratio of 2.86 (1.1, 7.4 CI). This is independent of other traditional risk factors for stroke such as hypertension, diabetes and atrial fibrillation [8]. A number of different mechanisms linking OSA with stroke have been proposed [9] including changes to the autonomic nervous system, haemodynamic disturbances, abnormal vascular function, association with a procoagulant state and increased oxidative stress. It appears that many of these mechanisms are interlinked. 4. Atrial fibrillation Approximately 20% of ischaemic strokes are considered cardioembolic. Of these 80% are due to atrial fibrillation. Blood stasis in a poorly contractile left atrial appendage coupled with a pro-coagulant environment results in thrombus formation. The presence of AF provides a unique environment for the development of thrombi that can subsequently embolise to the cerebral circulation and cause a stroke. OSA has been found to be strongly associated with atrial fibrillation but the presence of multiple confounding co-morbidities found in both populations has prevented it being an independent risk factor for its development. Nevertheless, the supporting evidence is persuasive. The mechanisms involved appear to be similar to the mechanisms linking OSA and stroke described above. A combination of large negative intra-thoracic pressures, hypoxaemia, hypercapnia, autonomic system activation, systemic inflammation, hypertension, cardiac structural remodelling and atrial electromechanical remodelling conspires to promote AF [10]. Furthermore, there is evidence that outcomes following catheter ablation for AF are worse in patients with untreated OSA compared with patients with OSA treated with CPAP suggesting that OSA has a role to play in perpetuation of AF [11]. Is the presence of un-diagnosed AF a significant factor in stroke in patients with OSA? The diagnosis of AF in patients with stroke is often made on admission to hospital following palpation of the radial artery or on the resting electrocardiogram (ECG). However, if AF is not found, ambulatory monitoring with 24 hour ECG or in-hospital telemetry can be carried out to identify the presence of AF as part of the workup following stroke. This is important as OAC reduces recurrence of stroke in this population. Unfortunately, the diagnosis of AF is often made at the time of it's major complication, stroke. Early detection of AF is therefore desirable so that patients can be appropriately risk stratified and OAC be initiated for the prevention of future strokes. Ambulatory monitoring allows us to do this. Prolonged ECG recordings increase the yield in diagnosing occult atrial fibrillation as well as other arrhythmias in a range of clinical settings. Indeed, ECG recording may have a role in the investigation of stroke of unknown cause, whether by 2-week Holter or implantable loop recorders. The advent of telemonitoring offers an additional avenue to screen for asymptomatic arrhythmias. Whilst this technology is principally being used to detect changes in physiological parameters in order to identify early deterioration in heart failure status, it is likely to have more mainstream applications. The detection of short runs of asymptomatic yet clinically significant (typically N 6 min) AF by either

Table 1 cEstimated number of strokes avoided in the US if all OSA patients aged N65 with AF are given OAC. Estimated number of untreated patients with OSA [1] Proportion of patients with OSA aged N65 years [7] Estimated number of patients with OSA aged N65 years Odds ratio for presence of AF in OSA [5] Prevalence of AF in patients aged N65 years [7] Estimated prevalence of AF in OSA patients N65 years Estimated number of patients with OSA aged N65 years and AF Estimated mean CHA2DS2 VASc score in OSA patients aged N65 years Annual risk of stroke with CHA2DS2 VASc Estimated number of strokes in OSA patients N65 years with AF if no OAC is given Estimated number of strokes avoided if all OSA patients aged N65 with AF are given OAC (using OR 0.39 for OAC in primary prevention of stroke in non-valvular AF)_ENREF_29 [12]

12–18,000,000 50% 7,500,000 4.0 5% 20% 1,500,000 2 2.2% 33,000 20,130

ILR or an incumbent intra-cardiac lead (e.g., permanent pacemaker or implantable cardioverter–defibrillator) is relatively common and if OAC is started in a timely fashion can result in reductions in stroke risk. It is therefore logical to assume that diagnosing AF in patients with OSA and subsequently initiating OAC where appropriate may help reduce the burden of stroke in this population. It is conceivable that this strategy has the potential to avoid many thousands of strokes each year in the United States alone (Table 1). A clinical trial is required to prove whether this is feasible, safe and true. In summary, stroke is a devastating but potentially avoidable consequence of AF. The risk of stroke is increased in OSA patients. The precise mechanisms linking all three common conditions are currently unknown but appear to be mediated by changes including autonomic tone, blood pressure, endothelial function and oxidative stress. Early identification of AF in patients with OSA and appropriate treatment with OAC provide a common sense approach to reducing stroke in these conditions. References [1] Young T, Palta M, Dempsey J, Peppard PE, Nieto FJ, Hla KM. Burden of sleep apnea: rationale, design, and major findings of the Wisconsin Sleep Cohort study. Wis Med J 2009;108(5). [2] Somers VK, White DP, Amin R, et al. Sleep apnea and cardiovascular disease: an American Heart Association/American College Of Cardiology Foundation Scientific Statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council on Cardiovascular Nursing. In collaboration with the National Heart, Lung, and Blood Institute National Center on Sleep Disorders Research (National Institutes of Health). Circulation 2008;118(10):1080–111. [3] Sahlin C, Sandberg O, Gustafson Y, et al. Obstructive sleep apnea is a risk factor for death in patients with stroke: a 10-year follow-up. Arch Intern Med 2008;168(3):297–301. [4] Piccini JP, Hammill BG, Sinner MF, et al. Incidence and prevalence of atrial fibrillation and associated mortality among Medicare beneficiaries, 1993–2007. Circ Cardiovasc Qual Outcomes 2012;5(1):85–93. [5] Mehra R, Benjamin EJ, Shahar E, et al. Association of nocturnal arrhythmias with sleep-disordered breathing: the Sleep Heart Health Study. Am J Respir Crit Care Med 2006;173(8):910–6. [6] 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. Europace 2012;14(10):1385–413. [7] Newman AB, Nieto FJ, Guidry U, et al. Relation of sleep-disordered breathing to cardiovascular disease risk factors: the Sleep Heart Health Study. Am J Epidemiol 2001;154(1):50–9. [8] Redline S, Yenokyan G, Gottlieb DJ, et al. Obstructive sleep apnea–hypopnea and incident stroke: the Sleep Heart Health Study. Am J Respir Crit Care Med 2010;182(2): 269–77. [9] Barone DA, Krieger AC. Stroke and obstructive sleep apnea: a review. Curr Atheroscler Rep 2013;15(7):334. [10] Latina JM, Estes III NA, Garlitski AC. The relationship between obstructive sleep apnea and atrial fibrillation: a complex interplay. Pulm Med 2013;2013:621736. [11] Naruse Y, Tada H, Satoh M, et al. Concomitant obstructive sleep apnea increases the recurrence of atrial fibrillation following radiofrequency catheter ablation of atrial fibrillation: clinical impact of continuous positive airway pressure therapy. Heart Rhythm 2013;10(3):331–7. [12] Aguilar MI, Hart R. Oral anticoagulants for preventing stroke in patients with nonvalvular atrial fibrillation and no previous history of stroke or transient ischemic attacks. Cochrane Database Syst Rev 2005;3:CD001927.

Screening for atrial fibrillation in patients with obstructive sleep apnoea to reduce ischaemic strokes.

Obstructive sleep apnoea is an independent risk factor for stroke. A number of different mechanisms have been identified which link OSA and stroke inc...
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