6 - Atrial Fibrillation
Editors: Norris, John W.; Hachinski, Vladimir
Title: Stroke Prevention, 1st Edition
Copyright 2001 Oxford University Press
> Table of Contents > I - Primary Prevention > 6 - Atrial Fibrillation
6
Atrial Fibrillation
David Sherman
Atrial fibrillation (AF) is an important cause of ischemic stroke. It represents the most common arrhythmia in the general population and is particularly relevant as a focus for stroke prevention considering its growing prevalence and the effectiveness of strategies for stroke prevention. About 15% of patients suffering ischemic stroke have associated AF, but the percentage rises with age, so that by age 80 more than 30% of ischemic stroke patients have associated AF.1 The evidence is overwhelming that more than two-thirds of these strokes can be prevented with appropriate preventive therapy.
Accurate estimates of the number individuals in population with AF are difficult to obtain. In the United States almost certainly three million people have AF. Estimates must be continually increased because of the striking association of AF with advancing age. The median age of the population with documented AF is 75 years. Because the elderly population is increasing each year, number of individuals with AF and exposed to its attendant stroke risk is also increasing. The contention that estimates are low is supported by the observation that many patients with AF are unaware of their arrhythmia until it is documented in a medical evaluation. Many patients have paroxysmal AF, especially early in the course of the arrhythmia, and most bouts AF in patients with paroxysmal AF are unrecognized by the patient. Symptoms of palpitations, lightheadedness, or dyspnea may be absent in some patients with AF, making them oblivious to
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the presence of this potentially devastating cardiac irregularity. This fact is painfully apparent when one finds that more than one-third of patients with stroke and AF were unaware of the arrhythmia until the occurrence a major cardioembolic stroke.2,3 Thus, population screening for AF before the occurrence of a stroke is an important public health priority, especially in the elderly but otherwise healthy population at greatest risk for development of this arrhythmia.
Epidemiologic evidence of the importance AF as a risk factor for stroke led to the formulation of hypotheses as to potential prevention strategies. The Framingham study, for example, showed that the risk of stroke in a population with AF is five to six times that of a comparable population without AF. Patients with AF and associated mitral stenosis had a seventeen-fold increase in risk of stroke or embolus.4 This difference in risk observed AF subpopulations illustrates an important principle in the management of patients with AF, namely, that the risk of stroke can vary widely depending on associated cardiovascular conditions.
The clinical and radiologic features of a cardioembolic stroke due to AF are not highly specific. Unfortunately, most strokes associated with AF are unheralded by more benign cerebrovascular events, such as transient ischemic attacks (TIA). Quite the opposite is the case, in that strokes from a left atrial embolus tend to be large and disabling with a higher mortality than strokes from other sources.5,6,7 Stroke onset is more often sudden, with maximal deficit immediately. Any arterial territory can be involved, but the middle cerebral artery is the commonest site of embolization. Cortical strokes from middle cerebral artery branch embolic occlusions are suggestive of a cardioembolic source. In the vertebrobasilar territory, posterior cerebral artery occlusions and top of the basilar strokes should raise suspicion of a potential cardiac source embolus.8 Large subcortical strokes, lagoons rather than lacunes, may be due to embolic occlusion of the small penetrating arteries arising from the proximal middle cerebral artery and demand investigation for a cardiac source of embolus rather than assuming their location dictates a small artery occlusive mechanism. As noted, antecedent TIAs in the same arterial territory are uncommon with cardiogenic emboli. A somewhat increased probability of a seizure or transient loss consciousness exists at stroke onset with a cardiogenic embolus.9,10 The lack of specificity of these clinical features dictates that appropriate diagnostic studies be done to explore other etiologic possibilities, such as significant carotid atherosclerotic disease that might warrant consideration of endarterectomy.
The radiological features of a stroke related to cardiogenic embolus from AF are generally what one might expect based on the anatomic observations outlined above. Characteristic findings with computerized tomography (CT) or magnetic resonance imaging (MRI) are cortical or large subcortical infarcts in the middle or posterior cerebral artery territories. Also suggestive are multiple cortical infarcts in different arterial territories. The dense middle cerebral artery sign is indicative of an occlusion, usually embolic, the middle cerebral artery.11 Hemorrhagic
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transformation of the infarct is somewhat more common with large embolic strokes, presumably because lysis of the embolus and reperfusion of a large, severely ischemic region of brain allows blood to infuse the infarct. Using the more sensitive imaging technique of MRI, hemorrhagic transformation can be demonstrated in more than two-thirds of cardioembolic infarcts.12
Most hemorrhagic transformations are not associated with neurologic deterioration unless the patient is anticoagulated at the time of transformation. This observation is the basis for the recommendation of this author and others to avoid immediate anticoagulation of patients with stroke cardioembolic source until a CT done 36 hours from stroke onset confirms the absence of hemorrhagic transformation. At this time, small- or medium-sized infarcts may be anticoagulated if the patient is considered a safe candidate for anticoagulation. Large infarcts are particularly prone to hemorrhagic transformation, and anticoagulation should be withheld if possible for 7 to 10 days. Of course, each case must be considered individually, weighing the estimated risk of recurrent embolus against risk of intracerebral hemorrhage aggravated by full anticoagulation.
Uncertainty about the utility and risk of long-term warfarin therapy led to the design of five randomized clinical treatment trials anticoagulation in individuals with AF.13,20 All trials compared various intensities of anticoagulation to a non-anticoagulated control population. Two trials, AFASAK and SPAF I, included an aspirin-treated group.15,16,18 Two of the trials, CAFA and SPINAF, were designed with a double-blind comparison of warfarin and placebo.14,20 The remaining trials managed the warfarin-treated patients in an open-label design.13,15,16-18
The benefit of warfarin for prevention of stroke was proven consistently and conclusively by these randomized clinical trials. Warfarin-assigned AF patients had the risk of ischemic stroke or systemic embolus reduced by about two-thirds in each of the trials. On average, the annual rate stroke was reduced from 4.5% to 1.5% (Figure 6.1). The true efficacy of warfarin is undoubtedly greater when the outcomes in these trials are viewed with an on-treatment analysis. Most patients suffering an ischemic stroke had no or inadequate anticoagulation at the time of the stroke.21,22 Patients willing and able to continue warfarin treatment experienced an 80% or greater reduction in stroke risk.
The prospective randomized treatment trials of patients with AF have defined a number of coexistent conditions that influence the risk stroke. Multivariate analyses have consistently shown that hypertension, prior TIA or stroke, and left ventricular systolic dysfunction are independently predictive of stroke in AF patients.21,23,24,25,26 In other studies, additional risks were coronary artery disease, diabetes, and age.21,22,23,24,26
The condition of greatest predictive value for risk stroke in patients with AF is a prior stroke or TIA. This fact was well established by the European Atrial Fibrillation Trial (EAFT).27 In this trial, 669 patients with AF and a recent TIA
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or minor stroke considered candidates for anticoagulation were randomized to open anticoagulation or double-blind treatment with either 300 ing. aspirin per day or placebo. An additional 338 patients considered not candidates for anticoagulation were randomized to either aspirin or placebo. After a mean follow-up of 2.3 years, the risk of stroke in the placebo-treated group was 12% per year, compared to 4% per year in the anticoagulated group (Figure 6.2). Major bleeds occurred in 2.8% of the anticoagulated patients each year, compared to 0.9% per year in the aspirin-treated patients.
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FIGURE 6.1. Stroke rate (percent per patient-year [pt-y]. in patients randomized to warfarin and in control subjects (intention-to-treat analysis). Strokes represent all strokes, regardless of suspected cause. Transient ischemic attacks, systemic emboli, and intracranial hemorrhages are not included. Control subjects received placebo in all studies except BAATAF. (In BAATAF, 46% of the control patients took aspirin and 54% received no treatment .) P values by chi square analysis. Reprinted permission.22 |
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FIGURE 6.2. Survival analysis for primary outcome event: group 1. Vascular death, nonfatal stroke, nonfatal myocardial infarction, or nonfatal systemic embolism, whichever came first: anticoagulation (AC), aspirin, and placebo. Reprinted by permission.27 |
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The practical clinical management decision is often whether a patient with AF has a stroke risk that justifies the bleeding risk and inconvenience of warfarin anticoagulation or can be managed with aspirin alone some simpler treatment regimen. The SPAF III study was designed to determine whether patients with increased stroke risk could be treated with a low fixed dose of warfarin (1 3 mg) and aspirin effectively and safely. This study was stopped early when, after a mean follow-up of only 1.1 years, the rate ischemic stroke and systemic embolus was 7.9% per year in the patients on the low-dose combination therapy and only 1.9% per year in the patients treated with warfarin adjusted to an INR of 2.0 3.0 (Figure 6.3).28
The predictors of stroke risk in patients treated only with aspirin was addressed in the SPAF I-III studies. More than 2000 participants were treated with aspirin or the above-noted low-dose warfarin combination with aspirin. A multivariate logistic regression analysis of predictors yielded a number significant factors.29 The predictors were age with a relative risk (RR) of 1.8 per decade, history hypertension (RR = 2.0), female gender 1.6), systolic blood pressure > 160 torr (RR = 2.3), and prior stroke or TIA 2.9). These predictors were significant at the/? = <0.001 level. Consumption of >14 alcohol drinks per week reduced stroke risk (RR = 0.4, p = 0.04). Estrogen hormone replacement in women in the SPAF studies was associated with an increased risk of stroke (RR = 3.2, p = 0.007).
Echocardiography is a commonly applied diagnostic tool in the assessment of patients for a potential cardiac source of embolus, including patients with AF.
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FIGURE 6.3. Cumulative rate of ischemic stroke or systemic embolism (primary events, in adjusted-dose warfarin group (n = 523) and combination therapy group (n = 521). The relative risk reduction by adjusted-dose warfarin was 74% (95% CI 50,87, p < 0.0001).28 |
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Transthoracic echocardiography (TTE) fails to adequately visualize the left atrium. The ability of transesophageal echocardiography (TEE) to outline the atrial anatomy and contents has made it the favored technique for evaluation of the heart in patients with AF. TEE is consistently superior to TTE in detecting left atrial thrombi. In the SPAF cohort of patients undergoing TEE, 13% had left atrial thrombi detected.30 Nineteen percent had dense spontaneous echo contrast, a finding predictive of thrombus formation and stroke. A reduced flow velocity (<20 cm/sec.) in the left atrium also predicted the presence of thrombus. Spontaneous echo contrast is presumed to be a consequence of reduced flow of blood, allowing the clumping together of red blood cells that slowly swirl and reflect the echocardiographic signals to yield a smoke-like illusion. The SPAF TEE studies also found that complex aortic atherosclerotic plaque was more common in patients with prior stroke.
The optimal intensity of anticoagulation has been evaluated directly and indirectly by a number of investigators. SPAF III demonstrated that low doses warfarin, even with aspirin, were ineffective in preventing thromboembolism in high-risk AF patients. Other investigators have addressed the optimal range of international normalized ratio (INR) to prevent stroke and minimize the risk for major bleeding, especially intracerebral bleed. An analysis of the 214 patients who received anticoagulant therapy in the European Atrial Fibrillation Trial calculated incidence rates for both ischemic and major hemorrhagic events as they related to the patients' INR. The optimal intensity of anticoagulation was found to lie between an INR of 2.0 and 3.9. No treatment effect was apparent with anticoagulation below an INR of 2.0. The rate of thromboembolic events was lowest at INRs from 2.0 to 3.9, and most major bleeding complications occurred with treatment at INRs of 5.0 and above.31
TABLE 6.1. Primary Prevention of Ischemic Stroke: Source of Potential Cardiogenic Emboli | ||||||||||
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Another case control study concluded that the optimal INR range was 2.0 3.0, although some effect in prevention of thromboembolism was noted with INRs below 2.O.26 Given the difficulties in maintaining a consistent INR level over time, it seems most prudent to target an INR of 2.5 (range 2.0 3.0). Randomized trials have observed that about 20% of INR levels over an extended period of time will fall below the target range. Thus, practice of targeting a low INR in an attempt to avoid bleeding complications may cause periods of inadequate anticoagulation, placing the patient at risk for stroke. The major predictor of intracerebral hemorrhage seems to be advanced age. Poorly controlled hypertension is also considered to increase the risk of intracerebral bleed. Based on the available information about the predictors of stroke risk, the value warfarin and aspirin therapy, and the bleeding risks of warfarin therapy, a recommendation can be made for the management of these patients as outlined in Table 6.1 and Figure 6.4.
The potential for stroke prevention in patients with AF is great. The number of individuals with this common arrhythmia is increasing as a consequence of an aging population. The evidence is overwhelming as to the risk of thromboembolism without treatment and the risks reduction with appropriate therapy. Information is available to allow identification of patients at highest risk for stroke and to reduce their stroke risk by a remarkable 65% 80%. The greatest challenge is to identify these patients at risk and to manage them with the appropriate therapy, thereby preventing the devastating consequences of unheralded stroke.
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FIGURE 6.4. A treatment algorithm for patients with atrial fibrillation. |
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References
1. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation: a major contributor to stroke in the elderly The Framingham Study. Arch Intern Med 1987;147:1561 1564.
2. Sherman DG, Goldman L, Whiting RB, Jurgensen K, Kaste M, Easton JD. Thromboembolism in patients with atrial fibrillation. Arch Neurol 1984;41:708 710.
3. Wolf PA, Kannel WB, McGee DL, Meeks SL, Bharucha NE, McNamara PM. Duration of atrial fibrillation and imminence stroke: The Framingham study. Stroke 1983;14:664 667.
4. Wolf PA, Dawber TR, Thomas HE, Jr., Kannel WB. Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: Fhe Framingham study. Neurology 1978; 28:973 977.
5. Censori B, Camerlingo M, Casto L, Ferraro Gazzaniga GC, Cesana Mamoli A. Prognostic factors in first-ever stroke the carotid artery territory seen within 6 hours after onset. Stroke 1993;24:532 535.
6. Lin HJ, Wolf PA, Kelly-Hayes M, Beiser AS, Kase CS, Benjamin EJ, D'Agostino RB. Stroke severity in atrial fibrillation. The Framingham Study. Stroke 1996;27(10): 1760 1764.
7. Sandercock P, Bamford J, Dennis M, Burn Slattery Jones L, Boonyakarnkul S, Warlow C. Atrial fibrillation and stroke: Prevalence in different types of stroke influence on early and long term prognosis (Oxfordshire Community Stroke Project). BMJ 1992;305:1460 1465.
8. Caplan LR, Hier DB, D'Cruz I. Cerebral embolism in the Michael Reese Stroke Registry. Stroke 1983; 14:530 536.
9. Bogousslavsky J, Hachinski VC, Boughner DR, Fox AJ, Vi:nuela F, Barnett HJ. Clinical predictors of cardiac and arterial lesions in carotid transient ischemic attacks. Arch Neurol 1986;43:229 233.
10. Bogousslavsky J, Cachin C, Regli F, Despland PA, Van Melle G, Kappenberger L. Cardiac sources of embolism and cerebral infarction clinical consequences vascular concomitants: The Lausanne Stroke Registry. Neurology 1991;41:855 859.
11. Tomsick TA, Brott TG, Chambers AA, Fox AJ, Gaskill MFLR, Pleatman CW, Wiot JG, Bourekas E. Hyperdense middle cerebral artery sign on CT: Efficacy in detecting middle cerebral artery thrombosis. Am J Neuroradiol 1990;ll(3):473 477.
12. Hornig CR, Dorndorf W, Agnoli AL. Hemorrhagic cerebral infarction a prospective study. Stroke 1986;17:179 185.
13. The Boston Area Anticoagulation Trial for Atrila 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.
14. Ezekowitz MD, Bridgerws SL, James KE, Carliner NH, Colling CL, Gornick CC, Krause-Steinrouf H, Kurtzke JK, Nazarian SM, Radford MJ, et al. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. N Engl J Med 1992;327:1406 1412.
15. Petersen P, Boysen G, Godtfredsen J, Andersen ED, B. Placebo-controlled, randomised trial of warfarin and aspirin for prevention thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK Study. Lancet 1989;: 175 179.
16. Petersen P, Kastrup J, Helweg-Larsen S, Boysen G, Godtfredsen J. Risk factors for thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK Study. Arch Intern Med 1990; 150:819 821.
P.115
17. Stroke Prevention in Atrial Fibrillation Investigators. Preliminary report of the Stroke Prevention in Atrial Fibrillation Study. N Engl J Med 1990;322:863 868.
18. Stroke Prevention in Atrial Fibrillation Investigators. Stroke Prevention Fibrillation Study: Final results. Circulation 1991;84:527 539.
19. Stroke Prevention in Atrial Fibrillation Investigators. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention Atrial Fibrillation II Study. Lancet 1994;343:687 691.
20. Connolly SJ, Laupacis A, Gent M, Roberts RS, Caims JA, Joyner C. Canadian Atrial Fibrillation Anticoagulation (CAFA. Study. J Am Coll Cardiol 1991;18:349 355.
21. Atrial Fibrillation Investigators. 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.
22. Albers GW. Choice of antithrombotic therapy for stroke prevention in atrial fibrillation: warfarin, aspirin, or both? Arch Intern Med 1998;158(14):1487 1491.
23. Atrial Fibrillation Investigators. Echocardiographic predictors of stroke in patients with atrial fibrillation: A prospective study of 1066 patients from 3 clinical trials. Arch Intern Med 1998;158(12):1316 1320.
24. The Stroke Prevention in Atrial Fibrillatin Investigators. Predictors of thromboembolism in atrial fibrillation: I. Clinical features of patients at risk. Ann Intern Med 1992; 116:1 5.
25. The Stroke Prevention in Atrial Fibrillation Investigators. Predictors of thromboembolism in atrial fibrillation: II. Echocardiographic features of patients at risk. Ann Intern Med 1992; 16:6 12.
26. Hylek EM, Skates SJ, Sheehan MA, Singer DE. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. Engl J Med 1996;335:540 546.
27. European Atrial Fibrillation Trial Study Group. Secondary prevention in nonrheumatic atrial fibrillation after transient ischaemic attack or minor stroke. EAFT (European Atrial Fibrillation Trial. Study Group. Lancet 1993;342(8882): 1255 1262.
28. 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(9028):633 638.
29. Hart RG, Pearce LA, McBride R, Roghbart RM, Asinger RW, for the Stroke Prevention in Atrial Fibrillation Investigators. Factors associated with ischemic stroke during aspirin therapy in atrial fibrillation: Analysis of 2012 participants the SPAF I-III clinical trials. Stroke 1999;30:1223 1229.
30. The Stroke Prevention in Atrial Fibrillation Investigators Committee on Echocardiography. Transesophageal echocardiographic correlates of thromboembolism in highrisk patients with nonvalvular atrial fibrillation. The Stroke Prevention in Atrial Fibrillation Investigators Committee on Echocardiography. Ann Intern Med 1998; 128(8):639 647.
31. European Atrial Fibrillation Trial Study Group. Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia. N Engl J Med 1995;333(1):5 10.
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