The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

December 2, 2009 — AF affects up to 1% of the population with an increasing prevalence with age with up to 10% of persons 80 years of age or older having AF. [2] The risk of stroke with AF is very much reflective of coexistent disease and the patientapos;s age. For example, patients less than 65 years or age with a structurally normal heart and no risk factors, such as hypertension, diabetes mellitus, or prior embolism, have a stroke risk similar to an age-matched control without AF. This has been termed “lone atrial fibrillation.” AF in combination with rheumatic valvular heart disease, however, is associated with up to a 17-fold increased risk of cardioembolic events. In a systemic review of independent predictors of stroke in AF, [3] the most consistent independent risk factors were prior stroke or transient ischemic attack (TIA), advancing age, hypertension, and diabetes. The most reliable risk factor, conferring a stroke risk of approximately 10% per year, was prior stroke or TIA.  (Click for more details)

Other risk factors cited have included heart failure or significant left ventricular systolic dysfunction by echocardiography. This is more of a relative issue, however, and is dependent on the impaired level of the EF and whether or not there is associated left ventricular thrombus formation. There has also been some information identifying female gender and age greater than 75 years as enhancing the risk of stroke with AF. Coronary artery disease and AF that is paroxysmal, however, have not been identified as particularly important contributors to higher risk stratification in AF. Risk stratification is very important in terms of the decision about whether to initiate long-term anticoagulation versus antiplatelet therapy, usually with aspirin, in patients at higher risk of stroke with AF (Box 1).

Box 1. Risk Stratification for NVAF

1. Low risk of stroke (roughly 1% risk per year of stroke without therapy)
2. Age <65 years with structurally normal heart
3. No other risk factors for stroke
4. Moderate risk of stroke (roughly 2% risk per year of stroke without therapy)
5. Patients =65 years of age with no high-risk coexistent disease
6. High risk (roughly 6% or greater per year risk of stroke without therapy)
7. History of hypertension
8. History of diabetes mellitus
9. Prior embolic event or TIA
10. Women >75 years of age
11. Recent, less than 3 months, decompensation of CHF or cardiac EF =25% or presence of mural wall thrombus

Data from Report of the Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: stroke prevention in patients with nonvalvular atrial fibrillation. Neurology 1998;51:671–3.

With recognition that duration and severity of associated risk factors most likely play a role in the level of contribution to the risk.

In the Practice Parameter of the American Academy of Neurology, [4] published in 1998, three categories were identified: (1) high-risk with a stroke risk with aspirin of approximately 8% or greater per year, (2) moderate-risk with a stroke rate of approximately 3.5% per year with aspirin, and (3) low-risk with a stroke rate of approximately 1% per year with aspirin. Higher-risk patients are those with hypertension, diabetes mellitus, and coronary artery disease, but as mentioned previously, cumulative information raises questions about the contribution of coronary artery disease. Furthermore, when citing either hypertension or diabetes mellitus as contributing factors to risk, one should also include duration and level of control. They cite an EF less than or equal to 25% and recent decompensation of CHF and the recognized prior stroke or TIA to help identify higher risk. Mention is also made of women greater than 75 years of age. Moderate risk includes age greater than or equal to 65 years with either no higher-risk features or with a history of hypertension. Low risk is lone AF in patients less than 65 years of age. Higher-risk patients should be assigned to warfarin therapy with an INR range of 2 to 3 and INR target of around 2.5 being perhaps optimal for younger higher-risk patients and closer to 2 for patients greater than 75 years of age because of the enhanced risk of bleeding complications.

Some have advocated an international normalization ratio  (INR) range of 1.5 to 2.1 for older patients at considerable risk for bleeding complications. [5] Hylek and colleagues, [6] however, reported a greater risk of stroke and a greater severity and increased risk of death from stroke with an INR less than 2 in a study of 13,559 patients with NVAF treated either with warfarin, aspirin, or untreated. In a meta-analysis of oral anticoagulants versus aspirin in NVAF, [7] the authors reported that treating 1000 patients with AF with oral anticoagulant instead of aspirin, for 1 year, prevents 23 ischemic strokes, but causes nine additional major bleeds. In an updated meta-analysis, [8] the relative risk reduction for stroke in NVAF was 64% with vitamin K antagonists and 22% with antiplatelet therapy. This reinforces the selection process as recently outlined by American College of Chest Physicians Evidence-Based Clinical Practice Guidelines for Antithrombotic Therapy in Atrial Fibrillation. [1] They recommend aspirin at a dose of 75 to 325 mg per day for patients less than or equal to 75 years of age with NVAF, but no other risk factors. With higher-risk patients, warfarin is generally recommended both for AF and atrial flutter as long as the risk of bleeding is judged acceptable on clinical grounds.

Combination therapy, either combining an oral anticoagulant with an antiplatelet agent, or combining two antiplatelet agents, has also been addressed to some degree. In the Stroke Prevention in Atrial Fibrillation III study, [9] which looked at the combination of low-intensity fixed-dose warfarin (mean INR, 1.3) plus 325 mg of aspirin per day versus adjusted dose warfarin with a mean INR of 2.4. This study did not find that the combination of low-intensity warfarin with aspirin provided adequate stroke prevention in patients with NVAF who were at higher risk for thromboembolism. It is recognized, however, that some AF patients have symptoms of stroke while taking warfarin with the INR in a desirable range or who are believed have a need for both warfarin and an antiplatelet agent for coronary artery disease. Shireman and colleagues [10] looked at such a combination in elderly patients with AF. They reported that antiplatelet agents increased major bleeding rates from 1.3% to 1.9% with factors associated with an enhanced risk of bleeding in the multivariate analysis reported to be age, anemia, and history of bleeding along with concurrent therapy. In a randomized study of clopidogrel or placebo added to aspirin at 75 to 100 mg a day for patients with AF who were not believed to be suitable for anticoagulant therapy, [11] the risk of stroke was 2.4% per year in the clopidogrel group compared with 3.3% per year with placebo. This was a relative risk reduction of 0.72 (P <0.001). There was a trade off, however, because major bleeding was 2% per year in patients receiving clopidogrel and 1.3% per year in patients receiving placebo (relative risk, 1.57; P <0.001). Careful patient selection for such an approach is mandatory.

1. Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2008;133(Suppl 6):593S–629S.
2. 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;285:2370–2375.
3. The Stroke Risk in Atrial Fibrillation Working Group. Independent predictors of stroke in patients with atrial fibrillation: a systematic review. Neurology. 2007;69:546–554.
4. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: stroke prevention in patients with nonvalvular atrial fibrillation. Neurology. 1998;51:671–673.
5. Yamaguchi Japanese Nonvalvular Atrial Fibrillation-Embolism Secondary Prevention Cooperative Study Group T. Optimal intensity of warfarin therapy for stroke prevention in patient with nonvalvular atrial fibrillation: a multicenter, prospective, randomized trial. Stroke. 2000;31:817–821.
6. Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oral anticoagulation on stroke severity and mortality in atrial fibrillation. N Engl J Med. 2003;349:1019–1026.
7. van Walraven C, Hart RG, Singer DE, et al. Oral anticoagulants vs aspirin in nonvalvular atrial fibrillation: an individual patient meta-analysis. JAMA. 2002;288:2441–2448.
8. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146:857–867.
9. Stroke Prevention in Atrial Fibrillation Investigators. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet. 1996;348:633–638.
10. Shireman TI, Howard PA, Kresowik TF, et al. Combined anticoagulant-antiplatelet use and major bleeding events in elderly atrial fibrillation patients. Stroke. 2004;35:2362–2367.
11. The ACTIVE Investigators. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med. 2009;360:2066–2078.
12. Primary prevention of stroke [Click to download in PDF format]
13. Secondary prevention of stroke [Full text]