Stroke in atrial fibrillation: a need for effective anticoagulation.

Atrial fibrillation (AF) occurs in 2 to 4% of the population aged 60 years and older and in up to 10% of the population above the age of 80 years. In the Framingham study, AF was found to be responsible for approximately one-sixth of all ischemic strokes in people older than 60 years of age. (1) In addition to causing clinical stroke with major deficits, AF is also associated with silent cerebral infarctions. (2,3) Paroxysmal AF, which usually lasts less than 7 days and is usually asymptomatic, can also cause embolization with almost the same risk as persistent AF. (4,5) Furthermore embolic events can even occur in patients with acute AF for as little as 72 hours. The AFFIRM and RACE trials have demonstrated that embolic events occur with equal frequency regardless of whether a rate control or rhythm control strategy is pursued in the management of AF. Hence most patients with AF, regardless of whether a rate control or rhythm control strategy is chosen, should be on long-term anticoagulants with an international normalized ratio (INR) in the therapeutic range.

Primary Prevention

The goal of primary prevention in AF is to prevent the occurrence of a first embolic event. However, the absolute embolic risk varies among patients from 1% in those at low risk to 16% in those at high risk. As a result, risk stratification is essential for making decisions about treatment to maximize the benefit and minimize the risk of bleeding. Five randomized, primary stroke prevention trials in patients with AF (Veteran Affairs SPAF, (4) BAATAF, (5) AFASAK, (6) CAFA, (7) and SPINAF (8)) used their own risk stratification schemes. Analyzing the pooled data from these trials, the ACCP Consensus Conference, and the ACC/AHA/ESC guidelines, the following independent risk factors for embolism in AF are identified:

    Previous history of stroke or transient ischemic attack (TIA)
    Diabetes mellitus
    History of hypertension
    Older age
    Valvular heart disease, especially mitral stenosis

The ACCP Consensus Conference and the ACC/AHA/ESC guidelines also considered coronary artery disease and thyrotoxicosis to be risk factors. Patients with none of these risk factors (15% of the group) comprised a low-risk group with an annual stroke risk less than 1%. Pooled analysis from the three trials that incorporated echocardiography into their risk stratification scheme (BAATAF, SPINAF, and SPAF) found that left ventricular (LV) dysfunction diagnosed by transthoracic echocardiography (TTE) was a risk factor for stroke in patients with AF. Left atrial (LA) diameter was not a predictor of stroke in the pooled analysis. In contrast, the SPAF investigators found that an LA anteroposterior diameter >2.5 cm/[m.sup.2] was an independent predictor of thromboembolism in addition to global LV dysfunction.

The five studies cited above addressed the issue of primary prevention of stroke in patients with AF. Together these trials randomly assigned more than 4,000 patients to aspirin, warfarin, or placebo and clearly demonstrated that anticoagulation with adjusted-dose warfarin significantly reduced stroke risk in patients with AF when compared with aspirin or placebo. (4-6,8) Overall, adjusted-dose warfarin reduced the risk of stroke by 62 to 68% with an absolute annual reduction of 2.7 to 3.1%. (9,10) Several trials have evaluated the role of aspirin for the primary prevention of thromboembolism in AF with conflicting results. (5,6,9) However, the benefit of aspirin is mainly in reducing the rate of minor strokes, which account for 30 to 50% of all strokes. In patients over the age of 75 years, the risk of intracranial hemorrhage with aspirin is much lower than with warfarin. In this age group, the benefit of warfarin in reducing embolic stroke is largely offset by the increased incidence of hemorrhagic stroke. (11) However, the efficacy of aspirin varies with risk. In a pooled analysis, aspirin was of particular benefit in patients between the ages of 65 and 75 years who had no other risk factors (eg, hypertension, diabetes mellitus, previous TIA or stroke, poor LV function). (12) Although there is modest benefit from aspirin, randomized trials have shown that it is consistently and substantially less effective than warfarin (except in low-risk patients). Although the risk of any bleeding is significantly higher with adjusted-dose warfarin compared with aspirin or placebo, the incidence of major hemorrhage may be similar.

Secondary Prevention

Patients who had a prior stroke are stratified as high risk because the incidence of recurrent stroke is high, and they have an annual stroke risk of at least 4.9% for those younger than age 65 and at least 5.7% for those older than 65 years of age. (9) Warfarin seems to be the most effective antithrombotic therapy for prevention of recurrent stroke in patients with AF. The International Stroke Trial (IST) (13) and the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) (14) suggested that early treatment with heparin in patients with acute stroke and AF may not be beneficial. Warfarin (goal INR 2.0-3.0) can be initiated with minimal risk in normotensive patients with no evidence of intracranial hemorrhage and small infarct size (or no evidence of infarction). In patients with large infarcts, the initiation of warfarin therapy should be delayed for 2 weeks due to the potential risk of hemorrhagic transformation. A similar delay is recommended in hypertensive patients. Patients are likely to benefit from aspirin until warfarin is begun.

An INR between 2.0 and 3.0 has been generally recommended for most patients with AF who receive warfarin anticoagulation. However, somewhat higher values may be more effective in patients at increased risk. On the other hand, lower values may be desirable in patients over the age of 75 years, including those with a previous ischemic event, given the uncertainty about the safety of INR above 2.5 in these patients. A target INR of 2.0 may be a reasonable compromise between risk and efficacy for this age group. Despite the compelling evidence that anticoagulation with warfarin reduces the risk of stroke in most patients with AF, this therapy continues to be underutilized.

Several studies have shown that only 50 to 60% of the patients with AF in whom anticoagulation is indicated may actually be administered warfarin. (15,16) Even when warfarin is prescribed, maintaining the target INR is achieved in only one-half of these patients. (17) In this issue, Rahimi et al, (18) in their retrospective study, report that they have found inadequate anticoagulation in patients with AF in a community in-hospital setting. This may be even truer in the ambulatory patients. Various factors seem to be responsible for inadequate anticoagulation. Apprehension of bleeding with warfarin seems to be the biggest culprit, both among the physicians and the patients. Busy physician practices may have inadequate time for optimum patient follow-up and monitoring. The introduction of kits and nomograms for home monitoring of INR and warfarin dose adjustment by patients themselves can be a big step forward, if proven safe and effective in large studies. As warfarin therapy imposes a variety of lifestyle constraints, including frequent blood test monitoring and possibly dietary modification, patient compliance becomes a limiting factor in an ambulatory setting. There is a need for both patient and physician education for promoting effective and adequate anticoagulation in AF.

The introduction of newer more predictable drugs such as ximelegatran may alleviate the fear of bleeding and improve compliance and hence the final outcome.

Accepted August 29, 2003.

Please see "Clinical Correlation Between Effective Anticoagulants and Risk of Stroke: Are We Using Evidence-based Strategies?" on page 924 of this issue.

References

1. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22:983-988.

2. Ezekowitz MD, James KE, Nazarian SM, et al. Silent cerebral infarction in patients with nonrheumatic atrial fibrillation: the Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. Circulation 1995;92:2178-2182.

3. Kempster PA, Gerraty RP, Gates PC. Asymptomatic cerebral infarction in patients with chronic atrial fibrillation. Stroke 1988;19:955-957.

4. Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation 1991;84:527-539.

5. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation. N Engl J Med 1990;323:1505-1511.

6. Petersen P, Boysen G, Godtfredsen J, et al. Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation: the Copenhagen AFASAK study. Lancet 1989;1:175-179.

7. Connolly SJ, Laupacis A, Gent M, et al. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol 1991;18:349-355.

8. Ezekowitz MD, Bridgers SL, James KE, et al: Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. N Engl J Med 1992;327:1406-1412.

9. Anonymous. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: Analysis of pooled data from five randomized controlled trials. Arch Intern Med 1994;154:1449-1457.

10. Hart RG, Benavente O, McBride R, et al. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: A meta-analysis. Ann Intern Med 1999;131:492-501.

11. The Stroke Prevention in Atrial Fibrillation Investigators. Bleeding during antithrombotic therapy in patients with atrial fibrillation. Arch Intern Med 1996;156:409-416.

12. Ezekowitz MD, Levine JA. Preventing stroke in patients with atrial fibrillation. JAMA 1999;281:1830-1835.

13. Saxena R, Lewis S, Berge E, et al; the International Stroke Trial Collaborative Group. Risk of early death and recurrent stroke and effect of heparin in 3169 patients with acute ischemic stroke and atrial fibrillation in the International Stroke Trial. Stroke 2001;32:2333-2337.

14. The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. Low molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute ischemic stroke: A randomized controlled trial. JAMA 1998;279:1265-1272.

15. Go AS, Hylek EM, Borowsky LH, et al. Warfarin use among ambulatory patients with nonvalvular atrial fibrillation: The anticoagulation and risk factors in atrial fibrillation (ATRIA) study. Ann Intern Med 1999;131:927-934.

16. Gage BF, Boechler M, Doggette AL, et al. Adverse outcomes and predictors of underuse of antithrombotic therapy in medicare beneficiaries with chronic atrial fibrillation. Stroke 2000;31:822-827.

17. Anonymous. 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.

18. Rahimi AR, Wrights B, Akhondi H, et al. Clinical correlation between effective anticoagulants and risk of stroke: Are we using evidence-based strategies? South Med J 2004;97(1):924-931.

Vishal Bhatia, MD

From the Department of Medicine, School of Medicine and Biomedical Sciences, State University of New York, Buffalo, NY.

Reprint requests to Vishal Bhatia, MD, Department of Medicine, School of Medicine and Biomedical Sciences, State University of New York, 808 Potomac Avenue, Buffalo, NY 14209. Email: [e-mail]