Atrial Fibrillation and Cardioembolic Stroke

Atrial fibrillation and the need for antithrombotic therapy

Atrial fibrillation (AF) is the most common sustained arrhythmia seen in clinical practice, affecting more than 6 million people in Europe, up to 5.1 million people in the US and more than 800,000 people in Japan.^{289, 290, 291} Atrial fibrillation is associated with a major risk of stroke, caused by a thrombus that forms within the left atrium and embolises to block a cerebral artery. The degree of stroke risk and the need for anticoagulant therapy to lower this risk varies among patients with AF.

AF — the most common arrhythmia

AF, the most common type of sustained cardiac arrhythmia, is primarily a problem of the elderly. The prevalence is less than 1% in those under 60 and almost 10% in those over 80.⁷⁹

AF is often classified based on the temporal pattern of presentation⁴:

Recurrent AF: two or more episodes of AF
Paroxysmal AF: episodes end spontaneously within seven days
Persistent AF: pharmacologic or electrical cardioversion is required to terminate the arrhythmia
Permanent AF: sustained AF despite treatment to end the arrhythmia or when cardioversion is inappropriate

Paroxysmal and persistent AF are referred to as recurrent AF based on the pattern of the arrhythmia.

AF — rhythm control vs rate control

The objectives of treating AF are to relieve symptoms (when present) and to optimise cardiac function. This can be accomplished with either a rhythm-control or a rate-control approach. Rhythm control involves efforts — electrical cardioversion or drug therapy, or both — to restore and maintain normal sinus rhythm. In addition, interventional approaches designed to ablate the source of the abnormal rhythm — known as catheter ablation procedures — have proven successful in some patients with paroxysmal AF.⁴

Rate control involves using medications to maintain a ventricular rate under 100 beats per minute without attempting to terminate the arrhythmia.⁴ Generally, studies have shown that there is no survival advantage with rhythm control as opposed to rate control.⁸⁰

AF — the role of antithrombotic therapy

Regardless of which treatment approach is pursued, antithrombotic therapy is essential, according to AF guidelines. This is because cardioembolic stroke is one of the main complications of AF.⁴ Cardioembolic stroke (or thromboembolic stroke) occurs when stagnant blood in the fibrillating atrium forms a thrombus that then embolises to the cerebral circulation, blocking arterial blood flow and causing ischaemic injury.

The incidence of stroke in patients with nonvalvular AF (ie, AF not caused by damage to the mitral valve) is between two- and seven-fold greater than in the general population. For patients with AF caused by valvular disease, the risk of stroke increases 17-fold.²²

Thrombus in right atrial appendage

AF — the risk of stroke

The risk of stroke is age-dependent. In the Framingham study, the annual risk was 1.5% in those 50 to 59 years old and 23.5% in those 80 to 89 years old.²² A systematic review of six cohorts of AF patients identified three other independent risk factors in addition to age: prior history of stroke or transient ischaemic attack (TIA), history of hypertension, and diabetes.⁸¹

Several scoring systems are available to help clinicians estimate the stroke risk in AF. One popular, well-validated risk assessment tool is the "CHADS₂". This system assigns single points for Congestive heart failure, Hypertension, Age ≥75, and Diabetes and prior Stroke or/transient ischemic attack”. The scale assigns 2 points if there is a history of prior stroke or TIA and 1 point for each of the other factors.⁸² This scoring system is a commonly used schema for stroke risk assessment. Patients with a CHADS₂ score of ≥2 have a high risk and merit anticoagulation therapy.²²⁶

The CHADS₂ score, however, has limitations, as it does not incorporate a number of documented stroke risk factors. To expand the CHADS₂ score — especially where patients have a CHADS₂ score of 0-1 or where a more comprehensive stroke risk assessment is needed — the CHA₂DS₂-VASc score has been developed. This score identifies “major” risk factors, including stroke/TIA/thromboembolism and age ≥75, and “clinically relevant non-major” risk factors, which are congestive heart failure, hypertension, diabetes, age 65-74, female gender and vascular disease (see table below). Single points are assigned for all risk factors, with the exception of age ≥75 and stroke/TIA/systemic thromboembolism, which are assigned 2 points each. Patients with a CHA₂DS₂-VASc score of ≥2 are considered at high risk and should receive oral anticoagulation therapy. Those with a score of 1 can be offered antithrombotic therapy with oral anticoagulation or aspirin, although oral anticoagulation is preferred. Subjects with a score of 0 are truly at low risk, and while they can be offered antithrombotic therapy or aspirin, no therapy would generally be needed.²³⁰

Stroke Risk Assessment: The CHA₂DS₂-VASc Score
	Risk Factor	Points
C	Congestive heart failre/LV dysfunction	1
H	Hypertension	1
A	Age ≥ 75	2
D	Diabetes mellitus	1
S	Stroke/TIA/thromboembolism	2
V	Vascular disease (prior myocardial infarction, peripheral artery disease, aortic plaque)	1
A	Age 65-74	1
Sc	Sex category (ie, female gender)	1

Adapted from Lip and Halperin, AM J Med, 2010.²²⁶

AF — the role of new anticoagulants in stroke prevention

New oral anticoagulants such as direct Factor Xa inhibitors (eg, rivaroxaban, apixaban, edoxaban, betrixaban) and direct thrombin inhibitors (eg, dabigatran) with stable pharmacokinetics and pharmacodynamics have the potential to advance antithrombotic therapy in stroke prevention.^{17, 89, 156, 201}

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Article references

289 - Kannel WB, Benjamin EJ. Status of the epidemiology of atrial fibrillation. Med Clin North Am. 2008 Jan;92(1):17-40
290 - Myasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation. 2006;114(2):119-125.
291 - Inoue H, Fujiki A, Origasa H, Ogawa S, et al., Prevalence of atrial fibrillation in the general population of Japan: an analysis based on periodic health examination. Int J Cardiol. 2009 Oct 2;137(2):102-7. Epub 2008 Aug 8.
79 - Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA. 2001; 285(18):2370-2375.
4 - Lip GY, Tse HF. Management of atrial fibrillation. Lancet. 2007;370(9587):604-618.
80 - Wyse DG, Waldo AL, DiMarco JP, et al; Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002;347(23):1825-1833.
22 - Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines 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 European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114(7):e257-e354.
81 - Stroke Risk in Atrial Fibrillation Working Group. Independent predictors of stroke in patients with atrial fibrillation: a systematic review. Neurology. 2007;69(6):546-554.
82 - Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285(22):2864-2870.
226 - Lip GY, Halperin JL. Improving stroke risk stratification in atrial fibrillation. Am J Med. 2010;123(6):484-488.
230 - 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(2):263-272.
17 - Turpie AG. Oral, direct factor Xa inhibitors in development for the prevention and treatment of thromboembolic diseases. Arterioscler Thromb Vasc Biol. 2007;27(6):1238-1247.
89 - Haas S. New oral Xa and IIa inhibitors: updates on clinical trial results. J Thromb Thrombolysis. 2008;25(1):52-60.
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Arrhythmia: Any variation from the normal rhythm of the heart beat (e.g., sinus arrhythmia, premature beat, heart block, atrial fibrillation, atrial flutter, pulsus alternans, and paroxysmal tachycardia).
Hypertension: Persistently high arterial blood pressure. Hypertension may have no known cause (essential or idiopathic hypertension) or be associated with other primary diseases (secondary hypertension). This condition is considered a risk factor for the development of heart disease, peripheral vascular disease, stroke, and kidney disease.
Aspirin: The brand name of acetylsalicylic acid (ASA), an antithrombotic medication that prevents thrombosis by inhibiting the activity of platelets – a component of blood that helps to prevent blood loss.
Congestive heart failure: Congestive heart failure (CHF) is a condition with impaired ability of the heart to fill with or pump a sufficient amount of blood through the body. Typical symptoms include shortness of breath with exertion, difficulty breathing when lying flat and leg or ankle swelling.
Factor Xa: The activated form of Factor X. It catalyses the conversion of prothrombin to thrombin in conjunction with other cofactors.
Rivaroxaban: Oral, direct Factor Xa inhibitor.
Thrombin: Also called Factor IIa, thrombin performs two functions in the coagulation cascade: activating platelets, and catalysing the conversion of soluble fibrinogen into insoluble fibrin. It is formed from prothrombin by a reaction that is catalysed by Factor Xa.