Managing Stroke Risk in Patients With Atrial Fibrillation

Approximately 1 out of every 3 adults will develop atrial fibrillation (AF), typically later in life (aged 67 years in men and aged 75 years in women).¹ Patients with AF are at a 5-fold increased risk of stroke.¹ Patients with AF are also at increased risk for other thromboembolic events (systemic embolism, myocardial infarction), heart failure, cognitive decline, and death. Although chronic treatment with oral anticoagulants (OACs) reduces the risk for thromboembolic events (including ischemic stroke) and death from any cause, research has shown that 47% of patients with AF do not receive a prescription for OAC therapy.² Therefore, clinicians should redouble efforts to consider the role of OACs in preventing stroke and other thromboembolic events using a step-wise approach.

Step 1: Determine Type of AF 

Generally, chronic OAC therapy is considered for patients with AF lasting 48 hours or longer (or AF of unknown duration) for stroke prevention. Atrial fibrillation lasting 48 hours or longer can be categorized into 3 patterns:

• Paroxysmal AF: recurrent AF lasting less than 7 days that spontaneously returns to sinus rhythm without intervention;
• Persistent AF: recurrent AF lasting 7 or more days that requires electrical or pharmacologic intervention to return to sinus rhythm; and
• Permanent AF: recurrent AF lasting longer than 12 months without restoration of normal sinus rhythm.³

A common myth is that the amount of time a patient is in AF determines their stroke risk.  For example, some clinicians believe that paroxysmal AF is not as likely as persistent or permanent AF to produce a stroke. To the contrary; all 3 patterns appear to increase the risk for ischemic stroke to a similar degree.⁴ Thus, the decision to prescribe an OAC for stroke prevention is not based on type of AF pattern.⁴

Another distinction that clinicians need to consider when deciding the type of OAC to prescribe for stroke prevention (newer chronic OACs vs warfarin) is whether the patient’s AF is valvular or nonvalvular.  Valvular AF refers to having moderate to severe mitral stenosis (potentially requiring surgical intervention) or an implanted mechanical heart valve.⁴ Nonvalvular AF refers to the absence of these 2 clinical situations. Thus, nonvalvular AF does not require that the patient is without valve disease. Instead, in this context, patients with nonvalvular AF may have various valvular abnormalities (mild mitral stenosis, mitral regurgitation, aortic stenosis or regurgitation, and/or tricuspid regurgitation), may have undergone valve repairs or valvuloplasty, or may have had placement of a bioprosthetic valve.⁴

Step 2: Risk Stratify for Stroke Prevention

Risk stratification is used to determine the most appropriate treatment for stroke prevention — primarily whether to initiate chronic treatment with an OAC. Traditionally clinicians think of risk stratification as a way to identify patients who are at highest risk for an event. However, a better way to think about risk stratification in patients with AF is as a way to determine which patients are truly at lowest risk for stroke, thus potentially not needing chronic treatment with an OAC.

Assessment tools (also called scoring schema) are used to calculate stroke risk for patients with AF. In the past, the CHADS₂ scoring schema was the standard of care for determining stroke risk in patients with AF. The score is calculated by assigning 1 point each for the presence of Congestive heart failure, Hypertension, Age 75 years and older, and Diabetes mellitus and 2 points for a history of Stroke, transient ischemic attack (TIA), and/or thromboembolism.⁵  Scores range from 0 to 6, with higher scores indicating an increased risk for stroke.

More recently, CHADS₂ has been replaced with CHA₂DS₂-VAS_c, which has been shown to be better at predicting stroke risk.⁵ Although CHADS₂ was easier to use, it was not as good at determining those patients who were truly at low risk.  CHA₂DS_2-VAS_c adds 3 more risk factors (denoted as VAS_c): Vascular disease (myocardial infarction, peripheral artery disease, or aortic plaque); Age 65 to 74 years; and female Sex category.⁵ The CHA₂DS₂-VAS_c score is calculated by assigning 1 point each for the presence of Congestive heart failure, Hypertension, Age between 65 and 74, Diabetes mellitus, Vascular disease, and female Sex category and 2 points for Age 75 years and older and a history of Stroke, TIA, and/or thromboembolism. As with the CHADS₂, a higher CHA₂DS₂-VAS_c score indicates an increased risk for stroke (9 being the highest risk).⁵

Interpreting CHA₂DS₂-VAS_c  Scores

A CHA₂DS₂-VAS_c  score of 0 in patients with nonvalvular AF is considered low risk for stroke because no risk factors for stroke other than AF are present. It is therefore reasonable to omit chronic treatment with an OAC for these patients.⁴ This does not mean that the patient is not at risk for stroke; rather it considers the benefit vs risk for chronic OAC in this population.

A CHA₂DS₂-VAS_c  score of 1 indicates a moderate risk of stroke. An exception to this rule is for women who have a score of 1 due to being of female sex. In this case, which is similar to that in men with a score of 0, the patient is considered low risk, and it is reasonable to omit chronic treatment with an OAC.⁴ In patients who are at moderate risk for stroke (men with a score of 1 and women with a score of 2), defining risk depends on the guideline being followed. According to the 2019 American Heart Association/American College of Cardiology/Heart Rhythm Society focused update on AF, clinicians may consider OAC therapy to prevent stroke (as opposed to aspirin vs no treatment at all).⁴ This recommendation differs from the 2018 CHEST guidelines, which recommend OAC therapy rather than no therapy, aspirin, or a combination therapy with aspirin and clopidogrel.⁶

For patients who are at high risk for stroke (women with a score of 3 or higher and men with a score of 2 or higher), chronic OAC treatment is recommended (rather than no therapy, aspirin alone, or aspirin plus clopidogrel). Most patients with AF are 65 years of age and older and most will have at least 1 other risk factor; generally, treatment with an OAC is the rule rather than the exception. It is important to remember that clinicians do not have to use CHA₂DS₂-VAS_c to risk-stratify AF patients with valvular heart disease because chronic warfarin therapy is recommended regardless for stroke prevention, unless contraindicated.⁴

Step 3: Consider Bleeding Risk

Because the chronic use of OACs involves a risk of bleeding, clinicians also should consider those patients who are at high risk for bleeding. An evidence-based assessment tool makes this process more objective because clinicians tend to overestimate the bleeding risk associated with OAC treatment, which is a key barrier to the use of these agents.

The HAS-BLED score (Table 1) is recommended because it includes potentially modifiable bleeding risk factors such as uncontrolled hypertension, labile international normalized ratios (INRs) for patients on warfarin, excessive alcohol intake, and concomitant use of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) among patients prescribed OACs.^5,7 Abnormal kidney function is defined as the presence of chronic dialysis, kidney transplantation, or elevated serum creatinine (≥200 mmol/L), and abnormal liver function is defined as chronic liver disease or significant liver dysfunction.^5,7  History of bleeding also includes a predisposition for bleeding (anemia). Total scores range from 0 to 9, with a higher score indicating a higher bleeding risk.

A score of 3 or more indicates the patient is at high risk for bleeding. However, this does not mean that the patient has a contraindication for OAC. Instead, by using this tool, clinicians can identify those patients with higher risk for bleeding to potentially correct the modifiable risk factors and to monitor the patient more closely for bleeding.^5,7

Step 4:  Consider Anticoagulation Options

Traditionally chronic oral anticoagulation with warfarin has been the gold standard, more efficacious as compared to aspirin, to prevent ischemic stroke in patients with AF.⁷ Advantages of warfarin include that it is relatively inexpensive and has a reversal agent, if needed. However, clinicians and patients may be reluctant to use warfarin due to bleeding risk and because patients often only spend about half the time in therapeutic range, putting them at higher risk for stroke if the range is subtherapeutic or at higher risk for bleeding if INRs are too high. Other disadvantages of warfarin beyond the variable dosing and need for regular laboratory monitoring include multiple drug-drug and drug-food interactions and a long half-life (20-60 hours), which often requires bridging with heparin when the medication is started or stopped in advance of surgery or procedures.

Newer direct oral anticoagulants (DOACs) are now available for patients with nonvalvular AF that are at least as effective as (noninferior) or superior to warfarin in preventing stroke or thromboembolism.⁴ All of the newer agents have favorable bleeding profiles, including reduced intracranial bleeding, compared with warfarin.⁴ Current US Food and Drug Administration-approved options include an antithrombin agent (dabigatran) and 3 anti-factor Xa agents (rivaroxaban, apixaban, and edoxaban), with more in development (Table 2).^8-11 Initially, some clinicians were reluctant to use DOACs because there was no reversal agent. However, specific antidotes or reversal agents are now available for dabigatran, rivaroxaban, and apixaban in the event of life-threatening bleeding or if the need for urgent surgery occurs.^4,7

The DOACs are dosed once or twice daily and do not require INR testing. Because these agents have a rapid onset and termination of action, bridging with heparin is not needed.  However, the rapid “turn on” and “turn off” can be a blessing and a curse.  For patients who occasionally miss a dose, this missed dose may result in a period of time when they are not covered for stroke prevention. Another consideration is cost. DOACs are branded agents and therefore may be more expensive than warfarin upfront. Apixaban was granted generic approval in late 2019, but it may not be available for several years.¹² However, cost-effectiveness studies have shown that although the upfront cost of DOACs is more, after 2 years of therapy DOAC costs are not significantly different compared with warfarin.^13,14 Many patients in the United States who have commercial insurance are eligible for patient assistance programs to reduce the co-payment (most about $10/mo).¹²  Unfortunately, patients covered by Medicare and Medicaid are not eligible for these programs.¹²

Step 5:  Consider Patient Circumstances and Preferences

Because there are numerous OACs for patients with nonvalvular AF, clinicians need to consider the individual patient. One of the first things to consider prior to starting a DOAC and annually thereafter is the patient’s kidney and liver function. For example, if a DOAC is desired in a patient with chronic kidney disease, clinicians will likely avoid an agent such as dabigatran that has a higher percentage of renal excretion. Likewise lower doses of the newer agents are indicated in patients with chronic kidney disease. Notably, 3 of the 4 agents are contraindicated in patients with low creatinine clearance (CrCl <15 mL/min). For patients with end-stage renal disease or those on dialysis, only apixaban and warfarin may be considered as an OAC option.⁴ In the rare patient with CrCl >95 mL/min, edoxaban is contraindicated because these patients will clear the drug too quickly and not be protected from stroke. None of the DOACs are recommended for patients with severe liver dysfunction.⁴

Another consideration is once-daily vs twice-daily dosing. Some patients, especially those on multiple medications, prefer once-daily dosing, while other patients may prefer a capsule (dabigatran) rather than a tablet. Another consideration is whether the patient has a tendency to miss their medications. For these patients, warfarin may be a better option because of its longer half-life in the event a dose is missed. Similarly, if a patient’s time in therapeutic range has been difficult to maintain (<65%), then considering more stable coverage with a DOAC is recommended to prevent stroke and avoid bleeding.⁶ All of these considerations should be discussed with patients and caregivers using shared decision-making to incorporate patients’ preferences and values into treatment selection.

Conclusion

The take-home messages when managing stroke risk in patients with AF include:

• AF places a patient at high risk for stroke and other thromboembolic events; OACs reduce that risk
• Risk assessment is needed for stroke and bleeding risks at diagnosis of AF and annually thereafter
• It is more important to prevent stroke with any anticoagulant as appropriate then to languish over which specific OAC agent to use
• Individualize OAC options based on clinical factors, comorbidities, patient circumstances, and values
• If treatment with an OAC is contraindicated, consult with electrophysiology to discuss nonpharmacologic treatment options for stroke prevention.

Leslie L. Davis, PhD, RN, ANP-BC, FAANP, FACC, FAHA, FPCNA, is an associate professor at the University of North Carolina, Chapel Hill School of Nursing and an adult nurse practitioner and clinical assistant professor with the Department of Internal Medicine, Division of Cardiology at the University of North Carolina, Chapel Hill School of Medicine. Chiao-Hsin Teng, MSN, RN, is a doctorate nursing student at the University of North Carolina, Chapel Hill.

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