Case Study: Paroxysmal AF and Stroke Risk

A 57-year-old man presents with palpitations and a rapid, irregular heartbeat accompanied by breathlessness and fatigue. These symptoms began the prior evening, are ongoing and have occurred off and on over the past 2 months. He has not experienced recent chest pain, orthopnea, paroxysmal nocturnal dyspnea, edema or syncope, but he does have dyspnea with exertion.

The patient has a history of hypertension, diabetes, obstructive sleep apnea, dyslipidemia, obesity and chronic kidney disease. He does not have a history of valvular heart disease, heart failure, prior stroke, transient ischemic attack (TIA) or a bleeding disorder. He is on the following medications: atorva-statin 40 mg/day, lisinopril 10 mg/day, metformin 1,000 mg twice daily and aspirin 81 mg daily. He reports using no over-the-counter medications. He drinks alcohol on a social basis (< 1 to 2 drinks per day) and has no history of smoking or illicit drug use. He has a family history of premature coronary artery disease in his father and AF in his brother and mother.

On physical exam, the patient is not in any distress. Weight is 284 pounds, body-mass index 43.2, blood pressure 142/86 mm Hg, heart rate 138 bpm and irregular, respiratory rate 20 breaths/minute. No jugular venous distension is evident, the lungs are clear, no bruits are appreciated, cardiac exam demonstrates irregularly irregular and rapid heart sounds without murmurs. He has no peripheral edema; pulses are intact.

An electrocardiogram shows AF associated with an average ventricular rate of 125 bpm. Laboratory tests show blood urea nitrogen 20 mg/dL, creatinine 1.5 mg/dL, estimated glomerular filtration rate of 57 mL/min, glucose 118 mg/dL, HbA1c 7.0%, total cholesterol 150 mg/dL, LDL-C 85 mg/dL, HDL-C 35 mg/dL, and triglycerides 150 mg/dL. T3, T4 and TSH are normal. A recent echocardiogram showed normal left ventricular (LV) systolic function with an ejection fraction of 55% to 60%, no regional wall motion abnormalities, mild concentric LV hypertrophy and no valvular dysfunction. The left atrium was mildly dilated (4.2 cm), and abnormal left ventricular diastolic filling was observed, consistent with impaired diastolic relaxation.

Clinical Questions

• How should the patient’s newly diagnosed AF be managed?
• How would you characterize this patient’s risk of thromboembolism?
• Should this patient receive antithrombotic therapy?
• What is this patient’s bleeding risk if anticoagulant therapy is initiated?
• Would the patient’s risk for thromboembolic events be modified if a rhythm control strategy is implemented? Can antithrombotic therapies be avoided or discontinued if AF burden is reduced or eliminated?

AF Management

This patient has nonvalvular AF in the background of hypertension and diabetes. Although this is his first documented episode of AF, he has been having symptoms consistent with self-terminating episodes of AF for the past few months. Thus, his AF would be labeled as paroxysmal (generally lasting less than 7 days) and recurrent (at least 2 AF episodes).¹

AF is the most common sustained arrhythmia in clinical practice, preferentially affecting men and older adults. Lifetime risk of developing AF is about 1 in 4 in people older than 40, and prevalence increases markedly with age. AF is less common in those younger than 60 (<1% prevalence), but has a prevalence of almost 10% in those older than 80. In most cases, AF occurs in association with other cardiovascular comorbidities, including hypertension, diabetes, heart failure, ischemic heart disease, hypothyroidism and valvular heart disease, but in about 10% to 15% of patients with AF, no cardiopulmonary disease is present.

The likelihood of developing AF is increased among those whose parents had AF, suggesting that some patients with early onset may have a genetic predisposition. AF is associated with substantial morbidity including increased long-term risks of stroke and heart failure and an increase in all-cause mortality. The condition results in important symptoms that impair quality of life. AF-related hospitalizations have increased twofold to fourfold over the last 3 decades, especially in patients older than 65.

Click here for a larger view of this image.

Managing AF involves considering three primary treatment objectives: preventing thromboembolism, controlling ventricular rate and correcting the rhythm disturbance.¹ Under a rate-control strategy alone, the ventricular rate is prevented from being excessively rapid (< 100 to 110 bpm at rest) with no treatment efforts made to restore or maintain sinus rhythm. Randomized trials comparing outcomes of rhythm- versus rate-control strategies have not demonstrated major differences in important clinical outcomes, including stroke and mortality, between the two strategies. While it may be better to be in sinus rhythm, the potential benefits of sinus rhythm may be offset by the toxicity of rhythm-control drugs. Thus, treatment decisions should be individualized with the focus primarily guided by patient symptoms.

An important caveat in interpretation of the prospective rate- versus rhythm-control clinical trials is that subjects were older, minimally symptomatic and considered appropriate for either treatment strategy. That being said, ventricular rate control is effective for many patients with AF.

For this patient, a rate control strategy with a beta-blocker may be a reasonable initial approach. A patient with a first-documented episode of AF who is hemodynamically stable and in whom rate control is selected does not require acute hospitalization. Depending on the patient’s course, the initial strategy may prove unsuccessful and the alternate can then be adopted. Regardless of whether rate control or rhythm control is pursued, attention must also be directed to appropriate therapy for prevention of thromboembolism.

Stroke Risk

Since stroke is the leading cause of morbidity and mortality associated with AF, consideration of strategies that balance stroke prevention and bleeding risk is important. Stroke risk is not dependent on the burden of AF or whether sinus rhythm is maintained, but rather on the associated risk factors for thromboembolism. Stroke risk is approximately the same whether AF is paroxysmal, persistent or permanent, asymptomatic or symptomatic.

The commonly used algorithm for risk stratification for stroke in patients with AF is the CHADS2, a risk index based on a point system in which 2 points are assigned for a history of stroke or TIA and 1 point each for other risk factors.² The CHADS2 score divides the risk of thromboembolism into low, moderate and high: Patients at low risk have a score of 0 (adjusted stroke rate of 1.9% per year), moderate risk have a score of 1 (adjusted stroke rate of 2.8% per year) or 2 (adjusted stroke rate of 4% per year), and high risk have a score > 3 (adjusted stroke rate of > 5.9% per year) (Figure). Additional, less well-validated risk factors that may potentially modulate stroke risk include female sex, age 65 to 74 years, coronary artery disease and thyrotoxicosis.¹ These risk factors might be considered especially in patients with an intermediate risk score.

This patient has hypertension and diabetes but is younger than 75 and does not have a history of heart failure, prior stroke or TIA. He would have a CHADS2 score of 2 and at least a moderate risk of thromboembolism (stroke rate of 4% over 1 year if not treated with anticoagulant therapy).

Antithrombotic Therapy

Patients with AF should be treated on the basis of risk of thromboembolism. Guidelines indicate that patients such as this one, with a CHADS2 score of 2 or more, should receive anticoagulant rather than antiplatelet therapy for stroke prevention.¹ Anticoagulant therapy could be either adjusted-dose warfarin with the INR maintained at 2.0 to 3.0 or the newer direct thrombin inhibitor, dabigatran (150 mg twice daily). In general, patients at moderate to high risk of stroke should receive lifelong anticoagulation unless a clear reversible precipitating factor for AF is identified and corrected. The need for anticoagulation should be reevaluated periodically in all patients with AF.

In the RE-LY trial, 150 mg twice daily dabigatran was superior to warfarin for prevention of stroke or systemic embolism.³ Dabigatran has a class I recommendation as an alternative to warfarin for prevention of stroke and systemic thromboembolism in patients with paroxysmal to permanent nonvalvular AF and risk factors for stroke or systemic embolization.¹ Choice between warfarin and dabigatran should be made on the basis of patient preference, compliance with INR monitoring, time in therapeutic range on warfarin, the ability to comply with dabigatran dosing, and cost. Patients who have a prosthetic heart valve or hemodynamically significant valve disease, severe renal failure (creatinine clearance < 15 mL/min), or advanced liver disease (impaired baseline clotting function) should not receive dabigatran as an alternative to warfarin.

The rhythm-control strategy, using drugs, catheter ablation or both, has the advantage of potentially eliminating or reducing the burden of AF. However, clinical evidence is lacking to suggest that rhythm-control strategies reduce the risk of stroke or systemic embolism. Therefore, anticoagulation withdrawal is not recommended in patients with risk factors for stroke (CHADS2 score of 2 or more) even in patients in whom AF appears to be eliminated, because many patients may have ongoing episodes of asymptomatic AF. Thus, catheter ablation of AF is not indicated to avoid long-term, oral anticoagulation.

Bleeding Risk

Bleeding risk should be assessed before starting anticoagulation. In clinical trials, the risk of major bleeding with anticoagulant therapy is < 1.5% to 2.0% per year. Intensity of anticoagulation is a powerful predictor of major bleeding with an appreciable risk of major bleeding associated with INRs > 3.5. Dabigatran (150 mg twice per day) has a similar risk of major hemorrhage as warfarin but higher GI bleeding.³ Older people are at increased risk for anticoagulant-related bleeding but are less likely to be treated with oral anticoagulation, in part because of concerns regarding risks of bleeding (especially intracranial hemorrhage) and falls. A new bleeding risk score, HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, age older than 65, drugs or alcohol concomitantly) has been
developed.⁴ A score of 0 to 2 indicates low risk of bleeding; whereas a score of > 3 indicates high risk of bleeding with anticoagulant therapy.

This patient would be deemed at low risk of bleeding (HAS-BLED score of 1) and at least moderate risk of stroke (CHADS2 score of 2) using these risk-stratification algorithms. Therefore, his benefit-risk profile would be in favor of long-term anticoagulation to reduce the risk of thromboembolism.

New Anticoagulation Therapies

With the approval of the new direct thrombin inhibitor anticoagulant, dabigatran, pharmacologic therapy for stroke prevention in AF is changing. A number of other novel, investigational oral anticoagulants show promising data. New therapies offer the prospect of more effective stroke prevention with similar or lower rates of major bleeding. Importantly, as with dabigatran, these therapies will not require regular monitoring. Their prompt onset of action will provide adequate anticoagulation over a shorter period of time than warfarin, and these newer agents have fewer food and drug interactions than warfarin. Specific inhibitors of factor Xa, which converts prothrombin to thrombin, are being investigated. These agents include apixaban, edoxaban and rivaroxaban.

ARISTOTLE, a double-blind, prospective trial of apixaban versus warfarin in patients with AF and at least one other risk factor for stroke showed that apixaban may have several advantages over warfarin.⁵ The trial’s primary efficacy end point, ischemic or hemorrhagic stroke or systemic embolism, occurred in 212 patients given apixaban compared with 265 assigned to warfarin (p = 0.01). Additionally, the rate of death from any cause was significantly lower in the apixaban arm of the study (603 vs. 669 warfarin-treated patients; p = 0.047). Rates of major bleeding were significantly lower with apixaban relative to warfarin (major bleeding was documented in 327 vs. 462 patients, respectively; p < 0.001. For additional information, see page 15).

In the ROCKET AF trial, in patients with nonvalvular AF and a history of stroke, transient ischemic attack, systemic embolism or at least two other risk factors for stroke, rivaroxaban was noninferior to warfarin for prevention of stroke or systemic embolism.⁶ In the per-protocol, as-treated primary analysis, the primary end point occurred in 188 patients in the rivaroxaban group versus in 241 in the warfarin group (hazard ratio in the rivaroxaban group, 0.79; 95% confidence interval, 0.66 to 0.96; p < 0.001 for noninferiority). No significant difference was observed between rivaroxaban and warfarin in the risk of major bleeding. (For additional information, see page 15.)

A recent FDA panel voted to recommend approval of rivaroxaban for stroke prevention in AF. Novel anticoagulants could offer clinicians and patients new alternatives for stroke prevention in AF.

References

1. Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, et al. 2011 ACCF/AHA/HRS Focused Updates Incorporated Into the ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2011;123(10):e269–e367.
2. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA 2001;285(22):2864-2870.
3. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-1151.
4. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel userfriendly score (HAS-BLED) to assess one-year risk of major bleeding in atrial fibrillation patients: The Euro Heart Survey. Chest 2010;138(5):1093-1100.
5. Granger CB, Alexander JH, McMurray JJV, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-992.
6. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. N Engl J Med 2011;365(10):883-891.