Stroke Prevention in AF

Reducing the risk of thromboembolism with anticoagulation

Atrial fibrillation (AF) is the most common sustained form of cardiac arrhythmia. Because of improvements in the care of conditions such as myocardial infarction and heart failure, as well as the aging of the population, the prevalence of AF is increasing.⁴

Irrespective of a rate-control or rhythm-control strategy, stroke prevention with appropriate thromboprophylaxis still remains central to the management of atrial fibrillation.

Professor Gregory YH Lip

Professor of Cardiovascular Medicine at the University of Birmingham, United Kingdom Director of the Haemostasis Thrombosis and Vascular Biology Unit, University Department of Medicine at City Hospital, Birmingham

AF is associated with a markedly increased long-term risk of thromboembolism. Cardiac emboli that lodge in the cerebral circulation to cause an ischaemic stroke are a major complication of AF; approximately 1 in every 5 strokes occurs in a patient with AF.¹⁶⁹ Anticoagulation is indicated to reduce the risk of thromboembolism in all patients with AF except in those with lone AF (those under 60 years of age with no evidence of cardiopulmonary disease) or in patients with contraindications to this therapy.²²

Many patients require lifelong anticoagulation therapy

The risk of stroke in AF varies depending on cardiovascular status, coronary anatomy, and age.¹²⁶ In nonvalvular AF, the stroke risk is between 4 and 6 times as great as in people with sinus rhythm.^{287, 150} In patients with rheumatic heart disease and AF, the stroke risk is increased 17-fold.²² It is important to note that treatments intended to restore normal sinus rhythm do not necessarily reduce stroke risk in AF. Therefore, even for patients who have undergone successful cardioversion, lifelong anticoagulation is appropriate when the risk of recurrent AF is high.⁴ Data compiled in meta-analyses of stroke prevention in AF provide strong support for the use of vitamin K antagonists (VKAs) (eg, warfarin, adjusted to maintain the INR in the range of 2.0 to 3.0).^{125, 127} Pooled data from six trials, involving 2900 patients, showed that adjusted-dose warfarin decreased stroke risk by 64%, compared with a 22% decrease in risk in patients taking antiplatelet agents (eight studies, N=4876).

There is widespread underutilisation of anticoagulant therapy to prevent stroke in patients with AF. The reasons are multifactorial. Some patients refuse treatment because of the inconvenience of treatment with VKAs, which require frequent blood tests to monitor therapy and dosage adjustments, as well as food restrictions. Others may choose to forgo treatment because their fear of bleeding complications may outweigh their perception of likely benefits. Improved physician-patient communication may be required to ensure that all patients are educated adequately about the risk/benefit ratio of anticoagulation in AF.4 Novel approaches to anticoagulant therapy may one day alleviate some of the issues and challenges associated with VKA use.

In 2010, the first oral direct thrombin inhibitor, dabigatran etexilate, was approved for stroke prevention in patients with nonvalvular AF.²⁵¹ Other new drugs are being studied for stroke prevention in AF, including anticoagulants that target Factor Xa (eg, rivaroxaban, apixaban, edoxaban, betrixaban and YM150).¹⁶⁹ The newer agents have the potential to decrease the risk of stroke without requiring therapeutic drug monitoring.¹⁶⁹

Balancing risks and benefits of therapy

Bleeding is the major complication associated with VKA use in stroke prevention in AF. This risk varies with age, being substantially higher in those 80 years of age or older (13.1 per 100 patient-years) compared with younger patients (4.7 per 100 patient-years).¹²⁸ As in all situations involving anticoagulant use, clinicians must balance the risk of haemorrhage against the benefits of preventing thrombosis.

A “user-friendly” score to assess an AF patient’s 1-year risk of major bleeding has recently been proposed. The HAS-BLED score predicts bleeding risk based on a combination of risk factors, as outline in the table below.

HAS-BLED Bleeding Risk Score

	Risk Factor	Description	Points
H	Hypertension	Uncontrolled, >160 mm Hg systolic	1
A	Abnormal renal or liver function (1 point each)	Abnormal renal function: chronic dialysis or renal transplantation or serum creatinine =200µmol/L Abnormal liver function: chronic hepatic disease or biochemical evidence of significant hepatic derangement	1 or 2
S	Stroke	Previous history, particularly lacunar	1
B	Bleeding history or predisposition	Predisposition could include bleeding diathesis or anaemia	1
L	Liable INR	Therapeutic time in range < 60%	1
E	Elderly	Age > 65 years	1
D	Drugs or alcohol (1 point each)	Drugs include antiplatelet agents and nonsteroidal anti-inflammatory medications	1 or 2
			Maximum: 9 points

Adapted from Pisters et al, Chest, 2010.²⁵⁰

Studies of the HAS-BLED score indicate that the annual bleeding rate increases with the addition of each risk factor up to 5 risk factors. HAS-BLED has demonstrated good predictive accuracy, with a c-statistic of 0.72.²⁵⁰

Warfarin: more effective than antiplatelet therapy in AF stroke prevention

Clinical research continues to clarify the role of intensive antiplatelet therapy. In 2003, 2 interrelated trials, ACTIVE W and ACTIVE A, were conducted concurrently in AF populations with a high risk of stroke and without major risk factors for bleeding. All subjects were receiving some sort of antithrombotic treatment at the start of the trials. ACTIVE W patients were appropriate candidates for VKA therapy, while VKA therapy was contraindicated in patients in the ACTIVE A trial. ^{175, 176}

The ACTIVE W study demonstrated that warfarin was significantly more effective than a combination of clopidogrel plus Aspirin in preventing vascular events such as stroke, and furthermore carried a similar risk of bleeding. Due to this evidence, the Data Safety Monitoring Board terminated the study early in September 2005.¹⁷⁶

The ACTIVE A trial found that the combination of clopidogrel plus Aspirin, compared with Aspirin alone, significantly reduced the rate of major vascular events, especially stroke, in patients unsuitable for VKA therapy. However, this combination increased the risk of major haemorrhage to rates seen with warfarin.¹⁷⁵

Increasing evidence reveals the efficacy and safety of using warfarin in older people with AF. In 2007, the BAFTA (Birmingham Atrial Fibrillation Treatment of the Aged) study demonstrated that warfarin is more effective than Aspirin in the prevention of stroke in people with AF aged 75 or over.²³⁸ Warfarin and Aspirin displayed no significant differences in major bleeding.²³⁸ The safety of warfarin compared to Aspirin in older people with AF was established in the WASPO (Warfarin versus Aspirin for Stroke Prevention in Octogenarians) study. Results from WASPO indicated that dose-adjusted warfarin was significantly better tolerated, with fewer adverse events, than Aspirin 300 mg in patients aged 80 to 90.²⁵³

The use of Aspirin monotherapy to prevent stroke in AF has come into question, even for low-risk “lone AF” patients at any age.¹⁶⁹ A study by Sato and colleagues, published in 2006, reported that the use of Aspirin (150 to 200 mg per day) did not effectively reduce stroke risk and was associated with a higher risk of major bleeding (1.2%) compared with patients receiving no treatment.²⁵⁹

The direct thrombin inhibitor dabigatran has been approved in the United States for stroke prevention in AF, and the new Factor Xa inhibitors rivaroxaban, apixaban and betrixaban, with stable pharmacokinetics and pharmacodynamics, have the potential to advance antithrombotic therapy in stroke prevention. ^{89, 201, 251}

Stroke prevention therapy based on level of risk

The use of anticoagulants to reduce the risk of stroke must be balanced against safety, dosing and (in the case of VKAs) coagulation monitoring issues. A scoring system widely used to assess individual patient risk for stroke is known by the acronym “CHADS₂”. Points are assigned based on Cardiac failure, Hypertension, Age, Diabetes, and Stroke (doubled).⁸² This simple, well-validated schema has recently been updated in an effort to improve its predictive value.²²⁶ Components of the revised score, known as CHA₂DS₂-VASc, are outlined in the table below.

Stroke Risk Assessment: The CHA₂DS₂-VASc Score

	Risk Factor	Points
C	Congestive heart failure/LV dysfunction	1
H	Hypertension	1 or 2
A	Age > 75	2
D	Diabetes mellitus	1
S	Stroke/transient ischaemic attack/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

Using this system, patients with a CHA₂DS₂-VASc score of 1 or more could be considered for anticoagulation, whereas patients with a score of 0 are at low risk and could be managed without anticoagulants.²²⁶

Stopping anticoagulants after successful ablation

When ablative therapy is successful and a patient with AF is restored to sinus rhythm, the clinician must decide on whether or not to continue treatment with an anticoagulant (to inhibit formation of intracardiac clots should AF recur). In this situation, the risk/benefit ratio favours stopping anticoagulation treatment. Guidelines published in 2010 by the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology recommend that after ablation patients at high risk for stroke should continue to receive oral anticoagulation, as AF is a chronically progressive arrhythmia.¹⁶⁹

A nonrandomized study by Themistoclakis and colleagues evaluated safety outcomes in 3355 patients who stopped oral anticoagulation following a successful isolation of the anatomic source of their arrhythmia. Of these patients, 2692 discontinued therapy 3 to 6 months after ablation, while 663 remained on treatment. The researchers found that stopping treatment was associated with a significantly lower risk of suffering an ischaemic stroke. This result occurred even in those patients with a moderate to high risk of thromboembolic events based on their CHADS₂ score.²⁷¹ Further clinical trial data are needed to confirm these findings.

Medical registries are expanding the knowledge base

Since 2001, several major medical registries have been launched to assess real-world outcomes in patients with AF. These registries include:

GARFIELD
ORBIT-AF
RecordAF
Stroke Prevention in Atrial Fibrillation (SPAF)

GARFIELD

In August 2009, GARFIELD (Global Anticoagulant Registry in the FIELD), involving 50,000 newly diagnosed patients with AF, was launched by the Thrombosis Research Institute (TRI). TRI is a charitable research foundation based in London. The largest study of its kind to date, GARFIELD will prospectively follow patients from 50 countries worldwide for up to 6 years to assess the global burden of AF.²⁷⁴

RecordAF and ORBIT-AF

RecordAF is the first international, prospective, observational survey established to assess the burden of AF by investigating how it is managed in clinical cardiology settings around the world. This 12-month survey showed that a rhythm-control strategy was more effective at keeping patients in a sinus rhythm than a rate-control strategy. The benefit of rhythm control, however, did not translate into a reduction in the occurrence of AF-related clinical events at 1 year.²⁵⁴

A similar registry, ORBIT-AF, was launched in the United States in 2009. The ORBIT-AF registry will collect information about the effects of AF on patient outcomes, costs and quality of life. The registry will prospectively follow 10,000 patients and will include information on the use of both antiplatelet and anticoagulant agents in this population.¹⁸³

SPAF

In 2001, the US Congress set up the Paul Coverdell National Acute Stroke Registry, which has funded the Stroke Prevention in Atrial Fibrillation (SPAF) trials I, II, and III. Overall, SPAF results have shown that antithrombotic prophylaxis should be individualised based on the patient’s risk for stroke and bleeding associated with drug therapy.²⁴⁹

Print page

Email page

Acute Treatment and Prevention of ACS >

Article references

4 - Lip GY, Tse HF. Management of atrial fibrillation. Lancet. 2007;370(9587):604-618.
169 - Camm AJ, Kirchhof P, Lip GY, et al; European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery. 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;31(19):2369-2429.
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.
126 - Lip GY, Lim HS. Atrial fibrillation and stroke prevention. Lancet Neurol. 2007;6(11):981-993.
287 - Wolf PA, Dawber TR, Thomas HE Jr, Kannel WB. Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: the Framingham Study. Neurology. 1978;28(10):973-977.
150 - Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22:983– 988.
125 - Hart RG, Halperin JL. Atrial fibrillation and thromboembolism: a decade of progress in stroke prevention. Ann Intern Med.1999;131(9):688-695.
127 - 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(12):857-867.
251 - Pradaxa [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals; 2010.
128 - Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation. 2007;115(21):2689-2696.
250 - 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(5):1093-1100.
175 - Connolly SJ, Pogue J, Hart RG, et al; ACTIVE Investigators. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med. 2009;360(20):2066–2078.
176 - Connolly S, Pogue J, Hart R, et al; ACTIVE Writing Group on behalf of the ACTIVE Investigators. 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(9526):1903-1912.
238 - Mant J, Hobbs FD, Fletcher K, et al; Midland Research Practices Network (MidReC). 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(9586):493-503.
253 - Rash A, Downes T, Portner R, Yeo WW, Morgan N, Channer KS. A randomized controlled trial of warfarin versus aspirin for stroke prevention in octogenarians with atrial fibrillation (WASPO). Age Ageing. 2007;36(2):151-156.
259 - Sato H, Ishikawa K, Kitabatake A, et al; Japan Atrial Fibrillation Stroke Trial Group. Low-dose aspirin for prevention of stroke in low-risk patients with atrial fibrillation: Japan Atrial Fibrillation Stroke Trial. Stroke. 2006;37(2):447-451.
89 - Haas S. New oral Xa and IIa inhibitors: updates on clinical trial results. J Thromb Thrombolysis. 2008;25(1):52-60.
201 - Haas S. New anticoagulants - towards the development of an "ideal" anticoagulant. Vasa. 2009;38(1):13-29.
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.
271 - Themistoclakis S, Corrado A, Marchlinski FE, et al. The risk of thromboembolism and need for oral anticoagulation after successful atrial fibrillation ablation. J Am Coll Cardiol. 2010;55(8):735-743.
274 - Thrombosis Research Institute website. www.tri-london.ac.uk/research-Garfield.asp. Accessed May 19, 2010.
254 - RecordAF registry. www.recordaf.org. Accessed May 11, 2010.
183 - Duke Clinical Research Institute website. ORBIT-A registry 2010. www.dukehealth.org. Accessed May 21, 2010.
249 - Paul Coverdell National Acute Stroke Registry. http://www.cdc.gov/dhdsp/programs/stroke_registry.htm. Accessed December 10, 2010.

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).
Myocardial infarction: Destruction of heart tissue due to reduced blood flow to the heart. Also known as a heart attack. It usually results from coronary artery disease and is more severe than angina.
Ischaemic stroke: Potentially fatal brain damage due to interrupted blood supply to the brain caused by thrombosis or an embolism.
Vitamin K antagonists: Vitamin K antagonists block the regeneration of the reduced form of vitamin K.
Warfarin: A vitamin K antagonist. Most commonly used oral anticoagulant in chronic prevention or treatment of VTE.
International Normalised Ratio: A system for standardising the reports of blood clotting tests and used to monitor the effects of warfarin. INR values should remain within 2.0–3.0 to ensure optimal safety and efficacy in patients with atrial fibrillation.
Dabigatran: The active form of the prodrug dabigatran etexilate, an oral direct thrombin inhibitor.
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.
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.
Clopidogrel: Oral antiplatelet agent used in the treatment of coronary artery disease, peripheral vascular disease and cerebrovascular disease.
Coagulation monitoring: Coagulation monitoring is practice of checking a specific coagulation parameter in order to adjust the dose. A precise adjustment of the drug intake allows the patient to stay within a defined therapeutic range, which is measured by prothrombin time or International Normalized Ratio (INR).
Prophylaxis: The prevention of a disease or pathological condition.