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
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
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
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
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
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
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.
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
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
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.
FIGURE 6.4. A treatment algorithm for patients with atrial fibrillation.
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