Clinical and Diagnosis

## **Chapter 3** Atrial Fibrillation and Stroke

*Francesca Spagnolo, Vincenza Pinto and Augusto Maria Rini*

## **Abstract**

Atrial fibrillation (AF) represents a major cause of morbidity and mortality in adults, especially for its strong association with thromboembolism and stroke. In this chapter, we aim to provide an overview on this cardiac arrhythmia, addressing several important questions. Particularly, we faced the possible mechanisms leading to an increased risk of embolism in AF, emphasizing how Virchow's triad for thrombogenesis is unable to fully explain this risk. Disentangling the risk of stroke caused by AF and by other associated vascular conditions is extremely challenging, and risk stratification of patients with AF into those at high and low risk of thromboembolism has become a crucial determinant of optimal antithrombotic prophylaxis. Moreover, we discuss the typical clinical and radiological characteristics of cardioembolic strokes, addressing acute, time-dependent reperfusional therapies in case of ischemic stroke. The role of anticoagulation in AF is also fully analyzed; the benefit of oral anticoagulation generally outweighs the risk of bleeding in AF patients, and a variety of scoring systems have been developed to improve clinical decision-making when initiating anticoagulation. With their predictable pharmacokinetic profiles, wide therapeutic windows, fewer drug–drug and drug-food interactions, and the non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) have changed the landscape of thromboprophylaxis for AF patients, offering the opportunity to use effective anticoagulants without the need for intensive therapeutic drug monitoring.

**Keywords:** atrial fibrillation, stroke, ischemic, NAOS, prevention

## **1. Introduction**

Thirty-three million people worldwide suffer from atrial fibrillation (AF), a common cardiac arrhythmia considered a major cause of morbidity and mortality in adults for its strong association with thromboembolism and stroke, which represents its most devastating complication [1].

AF is present in 3% of the general population above 20 years of age, and its prevalence increases substantially in people older than 65 years of age [2]. As expected, AF prevalence will increase as population get older [3].

Numerous cardiac pathologies, other than AF, have among their complications cardioembolic stroke. The cardiological substrate that is most frequently associated with embolism, especially in the elderly population, is represented by AF which is able to explain from 50% to 75% of all cerebral cardioembolic phenomena,

in the West. AF may be caused by valvular, typically rheumatic, disease, but the vast majority of cases are of nonvalvular etiology. In this chapter, we will focus on nonvalvular AF.

The ischemic stroke rate among people with AF is about six times that of people without AF and varies greatly with coexisting cardiovascular disease. It is estimated that at least 15–20% of all ischemic strokes have a cardioembolic origin, carrying a mortality rate of 25% at 30 days and 50% at 1 year [4]. Strokes due to AF are often devastating: between 70% and 80% of patients die or have permanent disability [5, 6], but also largely preventable through anticoagulation, that guarantees a 64% reduction in stroke risk and a 25% reduction in mortality [7]. AF also increases the risk of cognitive impairment and dementia [8]. For these reasons, prevention of AF-related thromboembolic events must be a public health priority. However, since AF is often intermittent and asymptomatic, it can be easily undiagnosed [9, 10]. On the other hand, even dysrhythmic episodes of short duration seem to significantly increase the thromboembolic risk [11, 12] and deserve to be identified in order to be appropriately treated.

Therefore, risk stratification of patients with AF into those at high and low risk of thromboembolism has become a crucial determinant of optimal antithrombotic prophylaxis. This chapter will focus on discussing the deep association between this dysrhythmia and cerebrovascular accidents and identifying which patients with AF require long-term oral anticoagulation with either vitamin K antagonist (VKA; e.g. warfarin) or novel direct oral anticoagulants (DOAC).

### **2. Possible stroke mechanisms in AF**

Only in 2% of patients with AF, no cardiac or extracardiac predisposing factor is detected, while 70% of AF cases are associated with organic heart diseases [13]. Risks factors associated with the development of AF are shown in **Table 1**.

The association between AF and ischemic stroke is strong and has been consistently confirmed in different cohorts [14–16]. After adjustment for risk factors, patients with AF face a three- to fivefold higher stroke risk than people without AF [14]. Therefore, a causal association between AF and stroke is biologically plausible, based on the assumption that in AF uncoordinated myocyte activity would lead to an impaired atrial contraction, stasis of blood and, as a result, to an increased thromboembolic risk. However, several other data do not support this straightforward relationship. For example, a clear biological gradient between the burden of AF and the risk of stroke is lacking: young and otherwise healthy patients with AF do not face a significantly increased stroke risk [17], while in older patients with vascular risk factors, a single brief episode of subclinical AF is associated with a twofold higher risk of stroke [9].

Moreover, the connection between AF and stroke also fails to respect the criterion of specificity: if AF causes thromboembolism, it should be specifically associated with embolic stroke. This is not the case, as for example 10% of patients with lacunar strokes have AF [18], and large-artery atherosclerosis is twice as common in patients with AF as those without [19].

Additionally, the criterion of temporality necessary to explain a causal relationship between AF and stroke is often not satisfied, and two recent studies found that approximately one-third of patients with both AF and stroke do not manifest any AF until after their stroke, despite undergoing continuous heart-rhythm monitoring before the cerebrovascular event [20, 21]. These data suggest that the mechanisms of stroke in AF have still to be fully elucidated and other factors are surely involved. Understanding the deep link between AF and stroke risk does

#### Major


#### Minors


#### **Table 1.**

#### *Risk factors for atrial fibrillation.*

not represent a pure academic exercise but has crucial therapeutic implications: if assuming that AF is the only cause of thromboembolism, maintaining normal rhythm should eliminate stroke risk. However, a recent meta-analysis of eight randomized clinical trials showed that a rhythm control strategy had no effect on stroke risk [22].

As in AF stroke risk cannot be entirely explained by the dysrhythmia itself, other factors are probably involved. Almost 150 years ago, Virchow hypothesized that development of thrombosis depends on three factors: abnormalities in blood flow, abnormalities in the blood vessel wall, and interaction with blood constituents [23]. Each of these elements may contribute to thromboembolism in AF [24, 25]. Dilated, poorly contracting atria, valvular heart disease (particularly mitral stenosis), and congestive heart failure represent abnormalities in blood flow and vessels, commonly associated with stroke and thromboembolism in patients with AF [24]. Independent clinical risk factors for stroke in nonvalvular AF also include a history of hypertension and diabetes, dilated left atrium, impaired left atrial function, and impaired left ventricular systolic function [26]. Aging and systemic vascular risk factors probably determine an abnormal atrial tissue substrate, or atrial cardiopathy, that can result in AF and/or thromboembolism [27]. Once AF develops, over time a structural remodeling of the atrium takes place, worsening atrial cardiopathy and further increasing the risk of thromboembolism, thereby propagating itself [28]. This mechanism can clarify why a brief period of AF is associated with stroke months later [9]. An *atrial substrate hypothesis* also explains the lack of specificity between AF and embolic stroke, as well as the fail of rhythm control strategies to eliminate thrombogenic potential. In this model, atrial cardiopathy alongside AF can cause thromboembolic stroke, explaining why one-third of strokes have no known cause [29], as well as why in many cryptogenic, cardioembolic, stroke only one-third of patients manifest AF even after 3 years of continuous heart-rhythm monitoring [30]. Supporting this hypothesis, a dilated left atrium and reduced left atrial and left atrial appendage (LAA) blood flow on echocardiography are independent risk factors for thromboembolism; the presence of spontaneous echo contrast or "smoke" on transesophageal echocardiography (TEE) is often observed in these patients. Spontaneous echo contrast has been related to hemodynamic and hemostatic abnormalities determining an increased risk of thromboembolism and

stroke [31–36]. The presence of both left atrial spontaneous echo contrast and atrial enlargement in AF patients confer a very high risk of cerebral ischemic events (odds ratio 33.7) [34]. In this context, a greater emphasis on the atrial cardiopathy that led to AF may reinforce the importance of continuing proven anticoagulant treatments even after reoccurrence of normal rhythm.

Local epicardial fat and obesity-induced obstructive sleep apnea are increasingly recognized risk factors for atrial cardiopathy, contributing to local inflammation in the atrium, and raising intra-atrial pressures, respectively [37]. Intensive vascular risk factor management after AF ablation appears to improve the underlying atrial pathology [38].

Moreover, several observations indicate that AF is associated with a hypercoagulable state [39]. Fibrin D-dimer levels are increased in patients with AF. In one study, fibrin D-dimer levels were highest in patients who were not receiving any antithrombotic therapy, intermediate in those onaspirin, and lowest in those treated with warfarin [40]. High-fibrin D-dimer levels have been associated with an increased rate of embolic events in patients with AF on oral anticoagulant (OAC) therapy [41, 42]. Endothelial damage and dysfunction in AF are also described [43–46]. Moreover, other data suggest that inflammation may contribute to the hypercoagulable state in AF [47]. As an example, high plasma levels of C-reactive protein (CRP) and interleukin-6 (IL-6) among patients with AF are independently related to indices of the prothrombotic state in AF (e.g. CRP to fibrinogen and IL-6 to tissue factor) [48]. In a larger series of 880 AF patients, CRP was positively correlated with stroke risk and prognosis, particularly mortality and vascular events [49]. Activation of the coagulation system has been identified by other authors in both paroxysmal [50, 51] and chronic AF [52, 53]. Cardioversion to sinus rhythm seems to result in normalization of hemostatic markers within 2–4 weeks [54]. Thereby, the mechanisms leading to an increased risk of stroke, thrombus, and embolism in AF are multiple, complex, and closely interact with each other. Many of these factors can be explained by Virchow's triad for thrombogenesis.

### **3. Factors increasing stroke risk in AF patients**

Several conditions represent risk factors for both AF and stroke: age, gender (male sex), hypertension, diabetes mellitus, tobacco smoke, valvular hearth disease, heart failure, coronary heart disease, chronic kidney disease, inflammatory disorders, and sleep apnea confer higher risk of AF itself and stroke; disentangling the risk of stroke caused by AF and by these other associated conditions is challenging.

However, as we already said, AF remains independently associated with stroke even after adjusting for shared risk factors. Among conditions predisposing to thromboembolism in AF patients, particular attention has to be reserved to **cardioversion**. Cardioversion of AF leads to an increased risk of thromboembolism, particularly if patients are not anticoagulated before, during, and after cardioversion. In addition to dislodgement of preexisting thrombi, embolization may result from de novo thrombus formation induced by atrial contractile dysfunction after cardioversion, a transient condition known as atrial "stunning." This transient dysfunction has been described after spontaneous as well as drug or electrical restoration of normal rhythm, and its duration is at least partially related to the duration of AF, ranging from 24 hours to 1 week for AF duration lasting less than 2 weeks, and 2 to 6 weeks of AF, respectively. For longer periods of dysrhythmia, atrial stunning may last 1 month [55]. This long time of atrial dysfunction could explain why the great

#### *Atrial Fibrillation and Stroke DOI: http://dx.doi.org/10.5772/intechopen.104619*

majority of embolic events in patients who remain in sinus rhythm occur within the first 10 days after cardioversion [56, 57].

Moreover, the presence of a poorly contracting, dilated left ventricle is likely to promote stasis of blood and lead to an increased risk of intracardiac thrombus formation and subsequent embolism. In fact, left ventricular dysfunction, i.e., heart failure, confers an additive risk of stroke to AF patients [58]. This risk is indirectly correlated with left ventricular ejection fraction (LVEF): every 5% point decrease in LVEF is associated with an 18% increase in the risk of stroke during a 42-month follow-up in patients with left ventricular dysfunction [58]. This risk was significantly reduced with the use of warfarin (relative risk 0.19) and oraspirin (relative risk 0.44).

As and probably more than in patients with AF, patients suffering from heart failure also demonstrate the presence of a prothrombotic or hypercoagulable state. As an example, both plasma fibrinogen and von Willebrand factor concentrations are often increased in heart failure, and platelet abnormalities are evident [59]. These blood dysfunctions may be additive to the hemodynamic and hemostatic abnormalities conferred by AF, further increasing the risk of thromboembolism [60].

Among valvular dysfunctions, mitral stenosis increases the risk of stroke in AF 17-fold [14]. On the other hand, the presence of mitral regurgitation seems to be protective against the development of intracardiac thrombi in chronic AF, presumably due to decreased stasis within the left atrium [24]. To support this hypothesis, the Stroke Prevention in Atrial Fibrillation (SPAF) study reported a decreased annual rate of clinical thromboembolism in patients with an enlarged left atrium and abnormal left ventricular wall motion if they also had mitral regurgitation (7.2% versus 15.4%) [61].

## **4. Characteristics of stroke in AF**

AF is associated not just with stroke in general, but most strongly with strokes whose neuroimaging patterns resemble that of cardiac embolism [62]. Stroke associated with AF tends to be more extensive/larger than stroke related to carotid artery disease. This is probably due to embolization of larger thrombi with AF, which also explains "longer" transient ischemic attacks (TIAs) than emboli from carotid disease [63, 64].

Typical characteristics of cardioembolic strokes are the extension, bilaterality, the wedge-shaped appearance of the lesions, the presence of multiple vascular territories involved (particularly the lower division of the middle cerebral artery), and the rapid hemorrhagic transformation. Ischemic strokes with probable embolic pathophysiology cannot be clinically differentiated from ischemic strokes by other causes, although generally symptoms such as Wernicke's aphasia, homonymous lateral hemianopia without hemiparesis, and/or contralateral sensory deficit or an ideomotor apraxia are more suggestive of a cardioembolic origin [65]. Cardioembolic lesions generally present on MR images as multiple, narrow areas in DWI or CT scan involving several vascular districts and are generally bilateral. When a pattern with these characteristics is identified, an accurate evaluation of the heart becomes critical, taking into account all the possible sources of thromboembolism. At the same time when an isolated lesion in the territory of the anterior cerebral artery is documented on neuroimaging, a cardioembolic source should be considered, although the possibility of an atherosclerotic process involving the anterior cerebral artery itself (frequent in the Asian population, for example) is debated.

Patients with AF who suffer an ischemic stroke appear to have a worse outcome (the more the disability, the greater the mortality) than patients without AF [66, 67]. AF is also associated with silent cerebral infarctions and TIAs [68, 69] with an estimated rate

of new silent cerebral infarcts of about 1.3% per year at up to 3 years of follow-up with a similar "silent" event rate for placebo and warfarin [68].

AF is asymptomatic in less than 40% of patients; unfortunately the absence of symptoms does not suggest a benign course [70], and stroke is the first manifestation of AF in at least 2–5% of patients [71]. In a hospital-based series, around 20% of stroke patients had previously unidentified or underrecognized AF [72]. Identifying AF and reducing stroke risk in patients with AF before stroke occurs is, therefore, an important goal.

### **5. Treatment and evalutation of acute ischemic stroke in AF patients**

As we already said, the presence of AF in a stroke patient does not always mean that there is a causal relationship, and cerebral injuries, such as ischemic stroke affecting the autonomic nervous system can play an important role in the pathogenesis of AF itself [73]. In fact, several clinical observations support the hypothesis that stroke may trigger AF. For example, new-onset AF in stroke patients without left atrial enlargement may belong to this category [74]. However, even if stroke can trigger AF, this pathway cannot explain the well-documented association between AF and future stroke [14, 16], and one-third of patients with AF and stroke do not manifest AF until after their stroke [20]. For this reason, evaluation and treatment of stroke patients with AF is the same as the evaluation in other patients with acute stroke, including brain and neurovascular imaging, cardiac monitoring during the acute phase, and echocardiography. Patients with acute ischemic stroke should then be evaluated for possible reperfusion therapy even in the setting of AF, considering that international normalized ratio (INR) >1.7 or PT >15 s or evidence of intracranial hemorrhage (ICH) on neuroimaging are **absolute contraindications** to treatment with intravenous alteplase.

Current European guidelines [75] recommend that:


Specific data on the risk/effectiveness balance of thrombolytic therapy in ischemic stroke patients suffering from AF are limited mainly to data coming from clinical trials [76, 77]. It seems to be no evidence of a treatment interaction between a history of AF and benefit from alteplase. The large size and worse prognosis of AF-associated acute ischemic stroke accentuates both the risks and the benefits of fibrinolysis [77]. In AF patients, mechanical thrombectomy is indicated as well, as in stroke without AF, when acute ischemic stroke is caused by an intracranial largeartery occlusion.

The detection of AF after stroke is important to delineate the mechanism of stroke itself and generally leads to a change in antithrombotic strategy. Long-term searching for AF allows to diagnose AF in 25% of patients with stroke or TIA [78];

#### *Atrial Fibrillation and Stroke DOI: http://dx.doi.org/10.5772/intechopen.104619*

most guidelines, therefore, recommend screening patients for the presence of AF, but the exact timing and duration of screening are undefined [79–82].

As a result of what we have said so far, if AF is a downstream marker of vascular risk factors that separately produce non-atrial stroke mechanisms, a comprehensive approach to the patient, with full consideration of other causes of stroke, is desirable. Moreover emphasizing intensive management of all risk factor is a crucial point to stroke secondary prevention.

## **6. Role of anticoagulation in AF**

Thromboprophylaxis is critical for stroke prevention in AF patients. Despite overwhelming evidence that oral anticoagulation is superior to aspirin for primary stroke prevention in patients with AF, aspirin remains overused; notwithstanding, it is only minimally effective and confers a bleeding risk that is similar to that of well-controlled warfarin [7, 83–85]. This evidence is underlined in the recent National Institute for Health and Care Excellence (NICE) [86] and European Society of Cardiology guidelines [87]. Ischemic stroke can occur with either paroxysmal (intermittent) or chronic (permanent) AF. Long-term anticoagulation is recommended to reduce the risk of thromboembolism for most patients with AF, but its use is associated with and increased risk of bleeding. However, the benefit generally outweighs the risk, and randomized trials have shown that therapeutic oral anticoagulant (OAC) reduces the risk of ischemic stroke and other embolic events by approximately two-thirds compared with placebo, irrespective of baseline risk [84, 88–95]. Moreover anticoagulated AF patients who experience ischemic stroke typically have smaller infarcts and lower mortality rates compared with not anticoagulated AF patients [96]. A variety of scoring systems have been developed to evaluate the risks of thrombosis and bleeding, thus aiding clinical decisionmaking when initiating anticoagulation [97, 98].

With their predictable pharmacokinetic profiles, wide therapeutic windows, and fewer drug–drug and drug-food interactions, the non-VKA oral anticoagulants (NOACs) have changed the landscape of thromboprophylaxis for ischemic stroke, offering physicians and patients the opportunity to use effective anticoagulants without the need for intensive therapeutic drug monitoring. The NOACs have been shown to be noninferior to warfarin for stroke prevention in patients with AF, although each has various properties that may favor use in particular patients, allowing physicians to fit the drug to patient's profile [99–102]. As the therapeutic armamentarium for the management of ischemic stroke risk in AF has expanded, clinical decision-making in terms of the choice of anticoagulant has become more complex.

**Warfarin.** Slow onset, drug–drug and drug-food interactions [103], genetic polymorphisms in CYP2C9 [104], and the vitamin K epoxide reductase complex subunit [105], all affect the anticoagulant effect of warfarin, making it monitoring of the international normalized ratio (INR) sometimes very difficult. Even when an optimal control of anticoagulation is achieved, adverse hemorrhagic events can still occur in patients treated with VKAs. However, warfarin is the most studied antithrombotic therapy for the prevention of recurrent stroke in patients with AF. A meta-analysis including six randomized trials comparing warfarin with placebo or no treatment in a total of 2900 participants with AF showed that the overall rate of stroke was 2.2%/patient year in the warfarin group and 6.0%/patient year in the control group (relative risk reduction 0.64; 95% CI 0.49–0.74) [7]. With warfarin therapy, all-cause mortality was reduced by 1.6%/year (relative risk reduction 0.26; 95% CI 0.03–0.43). Compared with aspirin, treatment with adjusted-dose warfarin (INR between 2 and 3) reduced stroke risk in AF patients from 10% to 4% per year in a pooled analysis of several randomized trials [84].

**Direct oral anticoagulants (DOACs),** also referred to as **non-vitamin K oral anticoagulants (NOACs)**, have been less extensively studied but appear to be equally efficacious than warfarin in stroke prevention. These drugs were developed to provide efficacious anticoagulation with rapid onset, a favorable side effect profile and predictable pharmacokinetic properties, obviating the need for therapeutic drug monitoring [106–108]. Two classes of NOACs have been developed: the direct thrombin inhibitors (Dabigatran [100]) and the direct factor Xa inhibitors (Rivaroxaban [101], Apixaban [99], and Edoxaban [102]; **Table 2**). All four agents have been found to be individually noninferior to warfarin for the prevention of stroke and systemic embolism in large, international randomized trials [99–102]. However, to date, there is no evidence to suggest that any of the NOACs are superior to the others for the prevention of stroke in AF.

**Apixaban**—Apixaban was compared with adjusted-dose warfarin in the ARISTOTLE trial, demonstrating to be even superior to warfarin in preventing stroke or systemic embolism (1.3% versus 1.6%) [109]. Apixaban also caused less major bleeding compared with warfarin (2.1% versus 3.1%) and resulted in lower overall mortality (3.5% versus 3.9%) [109]. Moreover, preliminary secondary analysis of data from the AUGUSTUS trial that enrolled patients suggested a superiority of apixaban to vitamin K antagonists with regard to intracranial bleeding and stroke/TIA/thromboembolism in AF patients with a recent acute coronary syndrome and a prior stroke/TIA/thromboembolism [110].

**Dabigatran**—Dabigatran was compared with adjusted-dose warfarin in a trial involving over 18,000 AF patients [100]. Dabigatran compared favorably to warfarin, including in the subset of participants with prior stroke.


**Edoxaban**—A trial comparing edoxaban 15 mg daily with placebo in patients with AF ≥80 years old with low body weight found a similar relative reduction in risk of stroke or systemic embolism than warfarin (2.3% versus 6.7%/year; hazard

#### **Table 2.**

*Main pharmacokinetic characteristics of warfarin and the new oral anticoagulants.*

#### *Atrial Fibrillation and Stroke DOI: http://dx.doi.org/10.5772/intechopen.104619*

ratio (HR) 0.34, 95% CI 0.19–0.61) [111]. Edoxaban was compared with warfarin in the ENGAGE TIMI 48 trial of over 21,000 patients [102]. Edoxaban was found to be noninferior with regard to the primary efficacy end point and caused less bleeding.

**Rivaroxaban**—Rivaroxaban was found to be non-inferior to warfarin in the ROCKET AF trial in preventing stroke or noncentral nervous systemic embolism [101].

## **7. Risk stratification**

Despite the advantages, OAC therapy is associated with an increased risk of bleeding. Then, benefit and risk ration must be taken into account to identify patients with AF who are likely to benefit from OAC. For each patient, the estimated absolute risk reduction for thromboembolic events is weighed against the estimated increase in absolute risk of intracranial hemorrhage and other major bleeding complications, along with patient preferences.

If AF develops, females are more symptomatic and at higher risk of thromboembolism than males. This is particularly true for age older than 65 years. In fact, female AF patients have an increased risk of stroke, aggravated by the lower oral anticoagulant prescription rate correlated with the concomitant higher bleeding risk profile. Catheter ablation is underutilized in female patients and, conversely, they are more commonly affected by the side effects of antiarrhythmic drugs [112].

To estimate thromboembolic risk in patients with AF, a variety of risk scores and biomarkers have been studied [113]. Unfortunately, imaging findings have not been shown to improve risk stratification in patients with AF [114].

The CHA2DS2-VASc score (**Table 3**) has been compared with other potential alternatives, resulting as the most accurate in identifying patients at lowest risk for thromboembolism.

The decision whether to prescribe OAC in AF should be based upon risk assessment, according to the following risk stratification:

	- 1.Patients between 65 to 74 years old, with CHA2DS2-VASc score of 1 in males and 2 in females, OAC is recommended [119].
	- 2.For patients with other risk factors, the decision to anticoagulated is based upon the specific nonsex risk factor and the burden of AF. For patients with very low burden of AF (e.g., AF that is well documented as limited to an isolated episode that may have been due to a reversible cause), it may be reasonable to institute close surveillance for recurrent AF.

According to the CHA2DS2-VASc score, anticoagulation is generally recommended for individuals with all but the lowest level of risk. The annual risk of ischemic stroke in untreated patients is estimated to be 0.2%, 0.6%, and 2.2% for those with CHA2DS2-VASc scores of 0, 1, and 2, respectively [115].

Unfortunately, the CHA2DS2-VASc score has several limitations: the risk associated with older age is not continuous, but lumped into categories, so that, for


#### **Table 3.**

*CHA2DS2-VASc risk stratification score.*

example, ages 65 years and 74 years each confer one point, despite the much higher actual risk associated with the older age. A history of prior stroke, transient ischemic attack, or thromboembolic event is assigned two points, but the risk associated with this risk factor is more than five times the risk associated with risk factors assigned one point. Risk factors assigned equal point values are associated with substantially different risks, and, again, ages between 65 and 74 years are associated with substantially greater stroke risk than other risk factors assigned one point.

A recent systematic review found that nonpermanent forms of AF may have a 25% lower risk of stroke compared with permanent forms of AF [120]. Short episodes of AF may occur in 30–60% of monitored patients [121]; however, their relevance is particularly questioned, especially regarding the duration of AF required to increase the risk of stroke independently from the general cardiovascular risk profile [122]. A post hoc analysis of the ASSERT trial (Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the AF Reduction Atrial Pacing trial) suggest that only episodes lasting longer than 24 h are relevant and carry a threefold risk of future thromboembolism over the next 2.5 years [123]. However, the AF burden (duration and frequency of episodes) is likely to vary over time, while a large proportion of patients with short episodes of AF will go on to

#### *Atrial Fibrillation and Stroke DOI: http://dx.doi.org/10.5772/intechopen.104619*

experience longer episodes, it is also true that the reverse occurs in a percentage of patients experiencing long episodes of AF [124]. Moreover, the extent to which thromboembolic risk may continue during periods of sinus rhythm is uncertain. As discussed earlier, the risk of thromboembolism is not reduced by clinical maintenance of sinus rhythm.

Unfortunately, so far none of the risk stratification schemes and guidelines have incorporated the type of AF or have adopted a different stance toward recommending anticoagulation in patients with paroxysmal AF.

Some clinical features or conditions may impact the risk of thromboembolism but are not included in risk models; these include the presence of conditions such as chronic kidney disease and elevated troponin level. Prediabetes has also been implicated as a possible risk factor for stroke in patients with AF [125].

AF is often diagnosed in the context of systemic conditions like pneumonia and thyroid disease or after cardiothoracic surgery [126]. In these patients, anticoagulation is not typically advised for the transitorily of the condition. However, recent data suggest that these patients are at high risk of recurrent AF and stroke [126–128]. Whether patients with secondary AF will benefit from early anticoagulation or should undergo repeated screening for AF is currently unknown [129].

## **8. Risk of bleeding**

For all potential candidates for OAC, bleeding risk and related possible contraindications to OAC should be carefully considered, especially for modifiable bleeding risk factors and to identify patients that rather than from OAC could benefit from left atrial appendage occlusion [112, 114, 130].

The major safety concern is risk of major bleeding, which includes events that require hospitalization, transfusion, or surgery, or that involve particularly sensitive anatomic locations, as intracranial bleeding. Among patients with AF, the three most important predictors of major bleeding (including ICH) are over-anticoagulation with warfarin (defined as an international normalized ratio greater than 3.0), prior stroke, and older patient age [116, 131].

ICH is the most serious bleeding complication, since the likelihood of mortality or subsequent major disability is substantially higher than with bleeding at other sites, and similar to that for ischemic stroke [132].

The HAS-BLED risk score (**Table 4**), based upon bleeding risk with warfarin, is the best predictor of bleeding risk [114] and can be used to identify patients at high risk of hemorrhage [98].

The annual risk of intracranial bleeding with warfarin is around 0.3%. Compared to warfarin, each of the NOACs dramatically reduces the incidence of intracranial hemorrhage [133], with subtle differences between NOACs regarding other types of major hemorrhage. Low-dose dabigatran (RR 0.80, 95% CI 0.69–0.93; *P* = 0.003), apixaban (RR 0.69, 95% CI 0.60–0.80; *P* < 0.001), and edoxaban at high (RR 0.80, 95% CI 0.70–0.91; *P* < 0.001) and low dose (RR 0.47, 95% CI 0.41–0.55; *P* < 0.001) have demonstrated a significant reduced rate of major hemorrhage compared to warfarin, while high-dose dabigatran and rivaroxaban seem equivalent to warfarin in terms of the incidence of major hemorrhage. In summary, in patients at high risk of gastrointestinal hemorrhage, it is reasonable to avoid high-dose dabigatran and high-dose edoxaban and rivaroxaban [133]; lowdose edoxaban may be preferred. In patients with high HAS-BLED scores who have suffered major hemorrhage, low-dose dabigatran, apixaban, and edoxaban are all appropriate choices of anticoagulant, but the risk of hemorrhage should be balanced carefully against the risk of stroke and patients' personal preferences.



**Table 4.** *HAS-BLED bleeding risk score.*

### **9. Alternatives to anticoagulation**

#### **9.1 Left atrial appendage occlusion**

It represents the primary alternative to long-term anticoagulation for patients with AF.

#### **9.2 Pharmacologic agents**

As we already said, no other antithrombotic regimen is as effective as chronic oral anticoagulation in AF patients. However, despite being less effective, in specific clinical setting, other antithrombotic regimens have to be considered in order to lower thromboembolic risk. Given the availability of the new class of anticoagulant agents, as alternatives to vitamin K antagonists, this situation should be extremely uncommon.

#### *9.2.1 Aspirin plus clopidogrel*

In patients with AF, dual antiplatelet therapy (with aspirin plus clopidogrel) reduces the risk of thromboembolism compared with aspirin monotherapy but offers less protection against thromboembolism than OAC. So, dual antiplatelet therapy is preferred to aspirin alone in the occasional high-risk patient with AF who cannot be treated with any OAC for a reason other than risk of bleeding. Of note, dual antiplatelet therapy and OAC have similar bleeding risks [134, 135].

#### *9.2.2 Aspirin monotherapy*

Aspirin (or other antiplatelet agent) is not an effective therapy for preventing thromboembolic events in patients with AF. The role of aspirin alone in lowering

#### *Atrial Fibrillation and Stroke DOI: http://dx.doi.org/10.5772/intechopen.104619*

the risk of stroke and systemic embolism in patients with AF is not confirmed in all meta-analyses of clinical trials [7, 113, 136]. In contrast, clinical trials have clearly demonstrated that OAC (with VKA or DOAC) lowers the risk of thromboembolism compared with aspirin [7, 84, 89, 92, 137].

## *9.2.3 Aspirin plus low-dose warfarin*

Low-dose warfarin (1.25 mg/day or target INR between 1.2 and 1.5) in combination with aspirin (300 to 325 mg/day) should not be used to reduce stroke risk in patients with nonvalvular AF [95, 138, 139].

## **10. Stroke while on anticoagulation**

Subtherapeutic anticoagulation and low compliance are the most common causes of treatment failure for patients taking warfarin and DOAC, respectively. Due to NOACs short half-lives, adherence to medication is of great importance and missed doses can lead to suboptimal anticoagulant effect and increased risk of stroke. Considerations about patient's compliance are essential when prescribing a twice-daily (dabigatran and apixaban) or once-daily regimen (rivaroxaban and edoxaban). However, in all AF patients experiencing a new ischemic cerebrovascular event while on OAC, a non-cardioembolic stroke mechanism (e.g., lacunar, large-artery stenosis, and malignancy) should be suspected. In case of a subtherapeutic anticoagulation (INR < 2) while on warfarin, continuing warfarin with renewed efforts to keep the INR in the therapeutic range (INR 2–3) or consideration of a change to a DOAC is recommended. When ischemic stroke occurs with a therapeutic INR (2–3), it is reasonable to perform a transesophageal echocardiogram (TEE) to assess for left atrial appendage (LAA) thrombus, though in these cases the ischemic stroke is often "lacunar," related to cerebral small artery disease, rather than cardioembolic. Increasing the target INR to 2.5–3.5 and switching from warfarin to a DOAC are both possible therapeutic strategies. Addition of antiplatelet therapy is generally not recommended, as it is known to increase major hemorrhage, particularly intracranial hemorrhage, and the benefit is not well defined. While data are limited, ischemic stroke during therapy with a DOAC for AF has been associated with several factors, including treatment at doses lower than recommended. Continuing anticoagulation therapy is generally indicated. If a thrombus is present despite appropriate dosing and compliance, it is reasonable to change to another DOAC, but optimal treatment is uncertain and no consensus exists. A retrospective study suggested that for patients with left ventricular thrombus, warfarin may be superior to DOAC for reducing the risk of stroke or systemic embolism. Unfortunately, analogous data for AF patients with left atrial appendage thrombi are lacking. As we already said, limited available data suggest that there is no benefit from adding aspirin to therapeutic OAC in patients with AF.

#### **10.1 Timing after acute ischemic stroke**

For medically stable patients with a small- or moderate-sized infarct with no intracranial bleeding, warfarin can be initiated soon (after 24 h) after admission with minimal risk of transformation to hemorrhagic stroke. As DOAC have a more rapid anticoagulant effect than warfarin, usually in these patients they are initiated after 48 h since ischemic stroke. Withholding anticoagulation for 2 weeks is generally recommended for those with large ischemic strokes [140], symptomatic hemorrhagic transformation, or poorly controlled hypertension. Patients who are

not treated with warfarin earlier may benefit from aspirin until therapeutic anticoagulation is achieved [141].

#### **10.2 Secondary prevention in patients with AF**

A recent meta-analysis of the RE-LY, ROCKET-AF, and ARISTOTLE trials demonstrated that dabigatran, rivaroxaban, and apixaban were all noninferior to warfarin in the secondary prevention of stroke in patients with AF [142].

Apixaban seems to confer the lowest risk of stroke or systemic embolism in patients who had already suffered a previous ischemic cerebrovascular event (RR 0.77, 95% CI 0.57–1.03); however, this finding was not statistically significant [99]. In the four major clinical trials of NOACs compared with warfarin, patients were stratified by stroke risk using the CHADS2 score. Both high-dose dabigatran (150 mg b.d.) (RR 0.73, 95% CI 0.58–0.91; *P* = 0.005) and apixaban (HR 0.79, 95% CI 0.66–0.95; *P* = 0.01 for superiority) demonstrated superiority to warfarin in the prevention of stroke and systemic embolism [99]. However, so far, evidences are not strong enough to suggest the NOACs are superior to warfarin in the secondary prevention of stroke in patients with AF.

### **11. AF and older age**

The consequences of AF are particularly pronounced in older individuals. In patients with documented frequent falls, the risks/benefits ratio of OAC should be carefully evaluated, and working to reduce the risk of falls is recommended. The risk of falls leading to subdural hematomas is increased in older adult patients taking oral anticoagulants independent of the agent chosen. A Taiwanese database study compared 15,756 older (≥90 years of age) adults with AF (11,064 receiving no antithrombotic therapy, 4075 receiving antiplatelet therapy, and 617 on warfarin) with 14,658 older adult patients without AF and without antithrombotic therapy [143]. In this study, patients with AF had a greater risk of ischemic stroke (5.75 versus 3.00%/year; hazard ratio [HR] 1.93, 95% CI 1.74–2.14) and a similar risk of intracranial hemorrhage (ICH; 0.97 versus 0.54%/year; HR 0.85, 95% CI 0.66–1.09) compared with those without AF. Among patients with AF, warfarin use was associated with a lower stroke risk (3.83% versus 5.75%/year; HR 0.69, 95% CI 0.49–0.96) compared with no antithrombotic therapy. There was a nominal but nonsignificant increase in risk of ICH (HR 1.26, 95% CI 0.70–2.25). In a second, later cohort of patients ≥90 years of age with AF, 768 patients treated with warfarin were compared with 978 patients treated with a direct oral anticoagulant (DOAC) [143]. DOACs were associated with a lower risk of ICH compared with warfarin (0.42% versus 1.63%/year; HR 0.32, 95% CI 0.10–0.97) and similar rate of ischemic stroke (4.07% versus 4.59%/year; HR 1.16; 95% CI 0.61–2.22).

### **12. Final remarks**

To date, we know that atrial fibrillation is the result of a complex interplay between genetic predisposition, ectopic electrical activity, and abnormal tissue pathology; AF is able to propagate itself feeding back to remodel and worsen tissue substrate. However, despite our understanding, the prevailing model of AF and thromboembolism is likely incomplete, and new strategies for identifying and treating patients at risk of thromboembolism are needed. More work is especially required to determine whether additional markers, such as cardiac magnetic resonance imaging of tissue fibrosis and computed tomographic assessment of left

*Atrial Fibrillation and Stroke DOI: http://dx.doi.org/10.5772/intechopen.104619*

atrial appendage morphology, may better identify the risk of atrial thromboembolism. The advent of NOACs have revolutionized the management of AF patients offering predictable, easy-to-use drugs that show similar efficacy than warfarin for stroke prevention, but lower rates of intracranial hemorrhage. However, despite the availability of these new drugs, selecting and adhering to anticoagulant therapy remains challenging for physicians and patients with AF. Further studies are needed to explore NOACs use, empowering physicians to manage stroke risk especially in high-risk patients, providing a subject-centered, tailored approach to the management of thromboembolic risk in AF patients.

## **Abbreviations**


## **Author details**

Francesca Spagnolo\*, Vincenza Pinto and Augusto Maria Rini Department of Neurology, Antonio Perrino's Hospital, Brindisi, Italy

\*Address all correspondence to: francesca.spagnolo81@gmail.com

© 2022 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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## **Chapter 4**
