Atrial Fibrillation: Stroke Prevention

Etiology and Pathogenesis

Approximately 800,000 strokes occur annually in the United States, and it is estimated that atrial fibrillation is the primary cause in approximately 15% of these events. The prevention of stroke remains a critical focus in the initial treatment of atrial fibrillation and should be carefully addressed at the time of presentation after symptoms are controlled, and the patient is able to engage in a complex decision-making process regarding the risks and benefits of oral anticoagulation (OAC). For some patients, the risk of stroke is outweighed by bleeding risk, and OAC therapy is deferred in lieu of strategies believed to be associated with a lower bleeding risk (aspirin alone or simple observation). However, there is considerable evidence that many patients and providers defer anticoagulation therapy despite low bleeding risk and elevated stroke risk, which results in undertreatment of this vulnerable population. It is estimated that of the older adult patients with atrial fibrillation in the United States with a CHADS score >3, <50% have ever filled a prescription for an anticoagulant.

Fortunately, there have been significant advances in stroke prevention therapies for atrial fibrillation in the last 5 years. Warfarin was the only OAC available until the approval of the first novel oral anticoagulant (NOAC) in 2009. Long-term warfarin therapy is associated with well-known limitations, including close regulation of vitamin K intake and regular blood testing to assure therapeutic levels. For patients who are not good candidates for warfarin therapy, there are now four NOAC agents widely available, all with favorable safety and efficacy profiles compared with warfarin in randomized clinical trials. In addition to widely available NOAC therapy, procedural options have progressed significantly, and there are now several catheter-based and open surgical techniques available to occlude the left atrial appendage (LAA), which is believed to be responsible for 90% of embolic strokes in patients with atrial fibrillation. In this chapter, we summarize the current strategies to determine stroke risk and bleeding risk in patients diagnosed with atrial fibrillation, and review the clinical usefulness of warfarin and newly available options for OAC and LAA occlusion.

Stroke Risk Stratification

The CHADS ₂ score was initially described in 2001 and was validated to estimate stroke risk among a cohort of approximately 1800 patients aged older than 65 years with an average follow-up of approximately >1 year. The CHADS ₂ score awards points for congestive heart failure, hypertension, age, diabetes, and history of embolic stroke. Stroke risk has generally been described as low (CHADS ₂ score 0–1), intermediate (CHADS ₂ score 1–2), and high (CHADS ₂ score ≥3). Patients at intermediate or high risk for stroke are likely to benefit from OAC, and it is generally accepted that risk of stroke outweighs the risk of bleeding from OAC. This is more controversial among patients with borderline stroke risk (score 1–2) and among patients at high bleeding risk. The CHADS ₂ score provides an easy and accessible method to document stroke risk and became the mainstay of stroke risk stratification for a decade until the model was updated to account for additional risk factors.

A refined version of the CHADS ₂ score was published in 2010 and sought to increase the predictive value by incorporating increased risk of stroke associated with advanced age, female sex, and known vascular disease and interventions (myocardial infarction, percutaneous coronary intervention and/or coronary artery bypass graft [CABG], and pulmonary vein disease). The CHA ₂ DS ₂ -VASc score is now a favored risk stratification tool and has been validated in several observational cohorts. It is viewed as a more complete risk stratification tool and has largely displaced the CHADS ₂ score in clinical practice. Its main advantage is that it better separates, and therefore, risk stratifies low- and moderate-risk patients

It is important to emphasize that not all stroke events in patients with atrial fibrillation are due to left atrial and/or atrial appendage thrombus. Many patients with atrial fibrillation also have an increased risk of atherosclerotic and hypertensive stroke, which are the leading causes of stroke worldwide. Therefore, the CHA ₂ DS ₂ -VASc score can be considered an “inventory of comorbidities,” and has also been shown to predict other acute cardiovascular events, including outcomes in patients with congestive heart failure. Because patients with elevated stroke risk also have an increased risk of bleeding events, significant efforts have been centered on bleeding risk prediction as well. Bleeding risk increases with age, and both the CHADS ₂ and CHA ₂ DS ₂ -VASc scores have been shown to predict elevated bleeding risk. When the bleeding risk outweighs the risk of stroke, many patients choose to forego OAC regimens in favor of treatment associated with lower bleeding risk. In the current era, these choices include medical therapy with aspirin alone, or consideration of LAA occlusion procedures. The HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding, Labile international normalized ratio, Elderly, Drugs or alcohol use) score has now been validated as the most predictive tool for estimating bleeding risk when counseling patients, and this is reflected in current guidelines.

HAS-BLED: Bleeding Risk Stratification

Every patient who receives OAC should be appropriately counseled regarding the risk of bleeding associated with all OAC therapies. Bleeding risk increases significantly with age, and the interpretation of the risk/benefit ratio becomes extremely challenging among older adults and frail patients, and among patients with a clinical history of significant bleeding events. The HAS-BLED bleeding risk score incorporates most important comorbidities (hypertension, abnormal renal and/or liver function, stroke, bleeding history or predisposition, labile international normalized ratio, older adults, drugs and/or alcohol concomitantly) and is now recommended in the American College of Cardiology/American Heart Association/Heart Rhythm Society and European and Canadian Atrial Fibrillation guidelines to estimate major bleeding risk in atrial fibrillation patients on anticoagulation. HAS-BLED has been shown to be a better predictor of serious bleeding both in clinical trial cohorts and in observational studies. It is noteworthy that it has been validated only among patients taking warfarin, not those on NOAC drugs, and it is not clear that bleeding risk will interact with pathologies similarly among patients taking the different classes of drugs. The HAS-BLED score also remains the only prediction model that has been shown to correlate with risk of intracranial hemorrhage. The HAS-BLED score has been validated in both patients with and without atrial fibrillation, but is typically applied and cited as rationale to avoid anticoagulation therapy in atrial fibrillation patients believed to be at high risk for bleeding. Table 39.1 summarizes the annual event risk for both stroke and bleeding based on these risk stratification models.

Oral Anticoagulation With Warfarin for Stroke Prevention

Warfarin therapy continues to be the most commonly prescribed regimen for OAC (although no longer for new prescriptions), and there is a large body of evidence from multiple randomized studies suggesting that the risk for stroke after initiation is reduced by >75%. Warfarin has been the standard of care for stroke prevention among atrial fibrillation patients for >30 years. However, maintenance of warfarin therapy has significant limitations. Although it is an effective antagonist of vitamin K−dependent clotting factors, determinants of hepatic metabolism can result in wide variability of effective doses among individuals. In addition, dietary intake of vitamin K can affect warfarin effectiveness, and patients must maintain significant discipline to avoid fluctuations in the international normalized ratio.

Genetic panels can be helpful to identify patients likely to require higher maintenance doses of warfarin. The VKORCI gene encodes the vitamin K epoxide reductase enzyme. A single nucleotide polymorphism G-A mutation in the promoter region of this gene results in less enzyme production, and therefore, decreased warfarin metabolism. In addition, several variant CYP2C9 alleles can also lower warfarin clearance due to reduced enzymatic activity. The wild-type CYP2C9*1 allele is associated with normal warfarin metabolism, whereas the CYP2C9*2 and CYP2C9*3 alleles result in decreased warfarin clearance and therefore require lower maintenance doses. A testing algorithm has been proposed and added to the warfarin label that suggests starting doses of warfarin based on this genetic testing information.

Novel Oral Anticoagulants for Stroke Prevention

The first NOAC therapy available in the United States was dabigatran, which was approved by the Food and Drug Administration (FDA) for stroke prevention in atrial fibrillation in 2009 based on the results of the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial. Dabigratran was associated with a lower risk of intracranial hemorrhage and embolic events compared with warfarin. Although an effective anticoagulant, this medication, in particular, has been associated with higher rates of dyspepsia and gastrointestinal bleeding, especially among older adults, in both the randomized trial and observational studies. Although dabigatran is the only NOAC associated with a lower risk of embolic stroke than warfarin, its side effect profile has led to declining use recently with increased availability of oral factor Xa inhibitors.

Oral factor Xa inhibitors are rapidly becoming the standard of care for OAC for newly diagnosed atrial fibrillation. These agents are now widely available, and there have been multiple randomized trials that have suggested that apixaban, rivaroxaban, and edoxaban are noninferior to warfarin for the prevention of thromboembolic stroke, and are associated with a significant decrease in the risk of major bleeding, most importantly, intracranial hemorrhage. Because they have a rapid onset of action (<3 hours), they do not require bridging therapy with parenteral agents during initiation. In addition, all of these agents are well tolerated and have minimal side effects. However, NOAC therapies have not been compared to each other in randomized trials, making it difficult to choose one in favor of another. The randomized trials do provide some insight into their effectiveness and limitations, and these trials are summarized in Table 39.2 . It is noteworthy that, although all NOACs were tested in patients at low, intermediate, and high risk of stroke, the edoxaban and rivaroxaban trials recruited, on average, patients with a higher vascular risk than the dabigatran and apixaban trials. It is not clear whether this difference should be used to guide therapy selection.

NOAC therapies have been approved for patients with nonvalvular atrial fibrillation. This has been a controversial stipulation because many patients with atrial fibrillation also have comorbid heart valve disease. Generally, nonvalvular atrial fibrillation has been defined as the absence of previous heart valve surgery or hemodynamically significant mitral valve stenosis. Patients with a history of heart valve surgery or mitral stenosis were excluded from all of the large randomized trials that compared NOAC therapy with warfarin. In practice, most physicians prescribe these agents for patients with treated and stable heart valve disease, with the exception of those with mechanical heart valve replacement. All patients with mechanical heart valves require anticoagulation therapy with warfarin, and there has been concern that NOAC therapies will be less effective in this population. Dabigatran, the only agent studied in a population with mechanical valves, was associated with increased risk of valve thrombosis compared with warfarin therapy.