Implications of New Oral Anticoagulants for Stroke Prophylaxis in Elderly Patients With Atrial Fibrillation

Affiliations:

¹Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY

²Department of Medicine, Icahn School of Medicine, Mount Sinai Hospital, New York, NY

Abstract: The prevalence of atrial fibrillation (AF) increases with age and is projected to escalate in coming decades as people have longer life expectancies. The burden of this disease has a substantial impact on healthcare costs and quality of life, particularly among AF patients who experience strokes. Until recently, the mainstays of stroke prophylaxis in patients with AF have been anticoagulation with warfarin or antiplatelet therapy with aspirin, depending on patient preferences, clinical risk stratification, and contraindications. However, the limitations of these conventional options, especially among elderly patients, have given rise to the first new oral anticoagulants in over half a century. Successful clinical trials have led to regulatory approval of several alternatives for clinical use. This article reviews the evidence supporting antithrombotic prophylaxis, describes current practice guidelines, and discusses the use of novel therapeutic options for elderly patients with nonvalvular AF.

Key words: Anticoagulants, antiplatelet agents, antithrombotic prophylaxis, atrial fibrillation, nonvalvular atrial fibrillation, stroke.
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Atrial fibrillation (AF) is the most common clinically significant cardiac arrhythmia, affecting an estimated 2.6 million persons in the United States and millions more worldwide.¹ The prevalence of AF increases with age and is expected to continue rising as people live longer with advanced cardiovascular disease.² The most worrisome complication of AF is ischemic stroke, which is associated with greater morbidity and mortality than strokes with noncardioembolic etiologies.³ As a consequence, AF imposes a substantial burden among the elderly. In addition, because persons who have had a stroke are often permanently disabled, the impact on independence can be overwhelming for these patients and their caregivers, eventually necessitating institutionalization.

Until recently, the mainstays of stroke prophylaxis in patients with AF were warfarin and aspirin, which are selected based on clinical risk stratification, contraindications, and patient preferences. The limitations of these agents, especially with regard to elderly patients, and the scope of the population at risk prompted a search for safer, easier-to-administer alternatives, resulting in clinical trials and regulatory approval of the first new oral anticoagulants in over half a century. This article reviews the evidence supporting antithrombotic prophylaxis, current practice guidelines, and the clinical use of novel therapeutic options for elderly patients with nonvalvular AF.

Selection of Antithrombotic Therapy Based on Risk Stratification

Data from more than 20 randomized trials involving more than 20,000 patients established the benefit of antithrombotic therapy.³ Beginning in the early 1990s, anticoagulation with a vitamin K antagonist (VKA), typically warfarin in the United States, became the accepted therapy for stroke prevention in patients with AF. Because anticoagulation carries a risk of bleeding, attention should be focused on appropriate patient selection. Practice guidelines recommend stratifying patients based on risk factors derived from multivariate analyses of clinical trial data and population-based cohorts treated with aspirin or no antithrombotic therapy.³ Of the various available schemes, the following CHADS₂ score is the most widely used, with a score of 1 indicating intermediate risk and 2 or more indicating high risk:

C: Congestive heart failure (1 point)

H: Hypertension (1 point)

A: Age ≥75 years (1 point)

D: Diabetes mellitus (1 point)

S₂: Prior stroke/transient ischemic attack/thromboembolism (2 points)

Recognizing age as a continuous variable, the following CHA₂DS₂VASc schema refined stroke risk stratification for patients with AF,⁴ allocating two points each for age 75 years or older and previous stroke, transient ischemic attack, or thromboembolism, and one point for each of the other features:

C: Cardiac failure (1 point)

H: Hypertension (1 point)

A₂: Age ≥75 years (2 points)

D: Diabetes mellitus (1 point)

S₂:  Prior stroke/transient ischemic attack/thromboembolism (2 points)

V: Vascular disease (prior myocardial infarction, peripheral arterial disease, or morphologically complex atheromatous plaque in the aorta) (1 point)

A: Age 65-74 years (1 point)

Sc: Sex category (female) (1 point)

By assessing additional risk factors, the CHA₂DS₂VASc score more accurately identifies truly low-risk patients (ie, those without risk factors) who can be treated without antithrombotic therapy and, compared with the CHADS₂ schema, it assigns fewer patients to the intermediate-risk category, for which optimum antithrombotic therapy is undefined.

Warfarin Versus Aspirin for Stroke Prevention

The stroke prophylaxis best supported by evidence is oral anticoagulation with warfarin. Aspirin is considerably less effective than warfarin for stroke prevention in patients with AF,³  but aspirin may prevent less disabling noncardioembolic strokes better than more severe cardioembolic events.⁵

The 1989 Copenhagen AFASAK (Atrial Fibrillation, Aspirin and Anticoagulation) study was the first randomized, placebo-controlled trial to evaluate adjusted-dose warfarin and aspirin in patients with nonvalvular (nonrheumatic) AF.⁵ The authors reported a significantly greater reduction in thromboembolic complications in patients assigned to warfarin compared with those assigned to aspirin 75 mg once daily (P<.05).

Subsequent trials have confirmed the benefit of anticoagulation, and a meta-analysis established an aggregate risk reduction of 67% versus placebo or no therapy.⁶ The absolute increase in extracranial hemorrhage associated with antithrombotic therapy in these trials was substantially less than the reduction in ischemic stroke.⁶ The meta-analysis also showed that in patients with AF, adjusted dose-warfarin reduced stroke risk by approximately 60%, while antiplatelet agents reduced stroke risk by 20%.⁶

But a persistent concern has been generalizing trial results and applying them in clinical practice. In a large cohort of Medicare beneficiaries (mean age, 79 years), for instance, warfarin was less efficacious for ischemic stroke prevention than that reported in the AFASAK study (35% relative risk [RR] reduction compared with no antithrombotic therapy and 25% RR reduction compared with aspirin).⁷ This reflects the difficulty older patients face sustaining VKA therapy.

The fundamental limitation of warfarin is its narrow therapeutic window compounded by its unpredictable pharmacology related to genetic variations and food and drug interactions.⁸ The risk of bleeding is particularly problematic among the elderly, as hemorrhagic risk increases with age.³ For patients aged 80 years and older, the odds ratio for intracerebral hemorrhage and subdural hemorrhage in individuals taking warfarin versus control patients was 2.8 (95% confidence interval [CI], 1.3-5.8; P=.006) and 5.7 (95% CI, 2.0-16.4; P=.001), respectively.⁹

The BAFTA (Birmingham Atrial Fibrillation Treatment of the Aged) study found that warfarin (adjusted to target international normalized ratio [INR], 2-3) was more effective than low-dose aspirin (75 mg/day) in preventing both ischemic and intracranial strokes, intracranial hemorrhage, and arterial embolism in patients aged 75 years and older (yearly risk, 1.8% vs 3.8%; RR, 0.48; 95% CI, 0.28-0.80; P=.003; absolute yearly RR, 2%; 95% CI, 0.7-3.2).¹⁰ However, the study had limited power to detect a difference in major hemorrhage between the two agents.

Combining Anticoagulation and Antiplatelet Therapy

Combining anticoagulants with antiplatelet therapy does not decrease the risk of stroke compared with either agent alone in patients with AF, but rather accentuates the risk of intracerebral hemorrhage, particularly in the elderly.³ It is important to note that maximum protection against ischemic stroke in the elderly is achieved at an INR range of 2.0 to 3.0, while an INR of less than 2.0 increases the odds of a severe stroke. The risk of intracerebral hemorrhage doubles even at mean INR levels of 2.0 to 2.5.¹¹

In the SPAF-III (Stroke Prevention in Atrial Fibrillation III) trial, for example, combining low-dose warfarin (INR, 1.2-1.5) with aspirin 325 mg per day did not reduce stroke or bleeding in individuals with AF.¹² In fact, the rate of ischemic stroke and systemic embolism in those who were administered the combination therapy was significantly higher than in those who were administered adjusted-dose warfarin (INR, 2-3), but the rates of major bleeding were similar in both treatment groups.¹²

 In the SPORTIF-III and SPORTIF-IV (Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation) trials, combining low-dose aspirin (<100 mg/day) with warfarin (INR, 2-3) or fixed-dose ximelagatran in patients with AF did not reduce stroke, myocardial infarction, or mortality, and aspirin plus warfarin increased major bleeding compared with anticoagulation alone.¹³ Clinicians should be aware that the anticoagulant ximelagatran is no longer available for clinical use. The drug was pulled from further development in 2006 after reports of severe liver injury risk.¹⁴

Dual-Antiplatelet Therapy: Aspirin Plus Clopidogrel

The ACTIVE-W (Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events) study, in which patients with CHADS₂ scores of 1 or higher were randomly assigned to receive anticoagulation therapy (target INR, 2.0-3.0) or dual-antiplatelet therapy with aspirin 75-100 mg/day plus clopidogrel 75 mg/day, was terminated because of the superiority of anticoagulation.¹⁵ There was a trend toward a reduction in vascular events (RR, 1.50; 95% CI, 1.19-1.80) and significantly less major bleeding (P=.03) with VKA therapy among patients who were anticoagulated before study entry compared with those who were naïve to anticoagulation.

In the double-blind ACTIVE-A trial, 7554 patients (mean CHADS₂ score, 2.1) deemed unsuitable for VKA therapy were randomly assigned to clopidogrel (75 mg once daily) plus aspirin (75-100 mg daily) versus aspirin plus placebo.¹⁶ The reports of major vascular events were lower in the dual-antiplatelet therapy group compared with the aspirin-plus-placebo group (RR with clopidogrel, 0.89; 95% CI, 0.81-0.98; P=.01), driven primarily by a reduction in stroke rates with clopidogrel (2.4% per year for clopidogrel plus aspirin vs 3.3% per year for aspirin plus placebo; RR, 0.72; 95% CI, 0.62-0.83; P<.001). The rate of major bleeding was 2% per year with dual-antiplatelet therapy compared with 1.3% per year with aspirin plus placebo (RR, 1.57; 95% CI, 1.29-1.92; P<.001). There was no significant difference in mortality between the two groups. Overall, therapy with clopidogrel plus aspirin reduced stroke by 28% while increasing major extracranial hemorrhage by 51% and intracranial hemorrhage by 87%.¹⁶ In comparison, a meta-analysis of other trials reported that warfarin reduced stroke by 38% but increased both extracranial and intracranial hemorrhage by 70% and 128%, respectively.⁶

New Oral Anticoagulants

The oral, direct thrombin inhibitor dabigatran etexilate and the direct factor Xa inhibitors rivaroxaban and apixaban are available alternatives to VKA for stroke prevention in patients with AF. Edoxaban is an investigational oral, direct factor Xa inhibitor. What follows is a review of the safety and efficacy of these drugs.

Dabigatran Etexilate

Dabigatran etexilate was the first non-VKA anticoagulant to gain US Food and Drug Administration (FDA) approval for this indication. It has predictable pharmacokinetic and pharmacodynamic profiles, little variability among individuals with normal renal function, and few clinically relevant interactions with food or other drugs, permitting fixed dosing without the routine measurement of coagulation. Dose adjustment is necessary based on renal function.¹⁷

The open-label, multinational RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial studied more than 18,000 patients with AF, of whom 82% were aged 65 years and older and 40% were aged 75 years and older.¹⁸ The study included a balanced proportion of VKA-naïve and VKA-experienced patients. The primary outcome was all stroke (ischemic and hemorrhagic) and systemic embolism; safety outcomes included bleeding, hepatic dysfunction, and other adverse events. Dabigatran 150 mg twice daily was superior to adjusted-dose warfarin in stroke prevention (RR, 0.66; 95% CI, 0.53-0.82; P<.001 for superiority), whereas the 110-mg twice daily dose was noninferior in terms of the primary outcome (RR, 0.91; 95% CI, 0.74-1.11; P<.001 for noninferiority) with safety superiority to warfarin in terms of major bleeding (3.36% yearly rate for warfarin group vs 2.71% yearly rate for dabigatran 110-mg group; P=.003).¹⁹ There was a slight excess (0.2%) of myocardial infarction with dabigatran that did not reach statistical significance when clinically silent infarctions were counted.²⁰ Dyspepsia occurred in 11.8% and 11.3% of patients in the 110- and 150-mg dabigatran groups, respectively, compared with 5.8% of patients in the warfarin group (P<.001 for both comparisons), the etiology of which has not been determined. There was more gastrointestinal bleeding with the higher dose of dabigatran, but intracerebral hemorrhage was significantly less frequent with both doses of dabigatran (approximately 0.1% per year) than warfarin (approximately 0.4% per year).¹⁸

Similar to the overall findings of the RE-LY trial, the rate of stroke or systemic embolism (primary events) among patients aged 75 years and older (n=7238) was lower with dabigatran 150 mg twice daily (1.4% per year) than with dabigatran 110 mg twice daily (1.9% per year), but the rate of major bleeding was higher with the higher dose (5.1% vs 4.4% per year). Based on the premise that adverse health consequences of strokes and embolic events are greater than those of nonfatal bleeding, the FDA regarded the higher dose as more favorable for elderly patients.²¹ While the benefit of dabigatran over warfarin in reducing major bleeding was attenuated by increasing age, reduction in intracranial hemorrhage with dabigatran was maintained.²² Caution is needed when using these agents in older individuals, however, because renal impairment, lower body weight, and drug interactions are more frequent in the elderly, sometimes resulting in fatal bleeding.²³

Rivaroxaban

Rivaroxaban is an oral, direct factor Xa inhibitor with a rapid onset and offset of action.²⁴ It has predictable, dose-dependent pharmacokinetic and pharmacodynamic profiles not influenced by age, sex, or body weight. Rivaroxaban was studied in the 2011 ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) study.²⁵ The primary efficacy end point was all-cause stroke and systemic embolism, and the principal safety outcome was major and clinically relevant nonmajor bleeding. The ROCKET AF population had a higher mean CHADS₂ score than other VKA-controlled studies (median score ≥3 vs approximately 2.1 in RE-LY¹⁸), ARISTOTLE (Apixaban for the Prevention of Stroke in Subjects with Atrial Fibrillation) trial,²⁶ and AVERROES (Apixaban Versus Acetylsalicylic Acid to Prevent Strokes in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment) trial.²⁷

The ROCKET AF trial had a double-blind design and included 14,264 patients with nonvalvular AF who were randomly assigned to either rivaroxaban 20 mg once daily or dose-adjusted warfarin. The per-protocol analysis demonstrated a significant difference in event rates between rivaroxaban and warfarin; the primary end point occurred in 188 patients in the rivaroxaban group (1.7% per year) and in 241 in the warfarin group (2.2% per year; hazard ratio [HR] in rivaroxaban group, 0.79; 95% CI, 0.66-0.96; P<.001 for noninferiority).²⁵ By intention-to-treat analysis, the primary outcome rate with rivaroxaban (269 events) was 2.1% per 100 patient-years compared with warfarin (306 events; 2.4% per 100 patient-years; HR, 0.88; 95% CI, 0.74-1.03; P<.001 for noninferiority; P=.12 for superiority). Major and clinically relevant nonmajor bleeding was reported in 1475 patients (14.9% per year) with rivaroxaban and in 1449 patients (14.5% per year) with warfarin (HR, 1.03; 95% CI, 0.96-1.11; P=.44). There were significant reductions in intracerebral hemorrhage (0.5% vs 0.7%; P=.02) and fatal bleeding (0.2% vs 0.5%; P=.003) with rivaroxaban. No significant differences were observed between groups in terms of major bleeding rates, although intracranial and fatal bleeding were less frequent with rivaroxaban.²⁵

Apixaban

Apixaban is another oral, direct selective factor Xa inhibitor.²⁸ ARISTOTLE was a double-blind, event-driven trial of apixaban 5 mg twice daily versus warfarin (target INR, 2-3) in 18,206 patients with AF treated for 1 to 4 years.²⁶ The dosage of apixaban was reduced to 2.5 mg twice daily in patients with two or more of the following characteristics associated with increased drug exposure: age 80 years and older; weight 60 kg or less; or serum creatinine level of 1.5 mg/dL (133 µmol/L) or higher. The primary end point was stroke (ischemic or hemorrhagic) or systemic embolism. Key secondary end points were major bleeding and the combined end point of stroke, systemic embolism, and all-cause mortality. Apixaban met the primary efficacy objective of noninferiority to warfarin for the outcome of stroke and systemic embolism (1.27% vs 1.60% per year; HR, 0.79; 95% CI, 0.66-0.95; P<.001 for noninferiority; P=.01 for superiority), reduced major bleeding compared with warfarin (2.13% vs 3.09% per year; HR, 0.69; 95% CI, 0.60-0.80; P<.001), and reduced all-cause mortality (3.52% vs 3.94% per year; HR, 0.89; 95% CI, 0.80-0.99; P=.047). The rate of hemorrhagic stroke was 0.24% per year with apixaban compared with 0.47% per year with warfarin (HR, 0.51; 95% CI, 0.35-0.75; P<.001), but there was no significant difference in rates of ischemic stroke or stroke of uncertain type (0.97% per year with apixaban vs 1.05% per year with warfarin; HR, 0.92; 95% CI, 0.74-1.13; P=.42). Apixaban reduced stroke or systolic embolism and major bleeding by 21% and 31%, respectively, and death by 11%.²⁶

The double-blind AVERROES trial randomly assigned patients deemed unsuitable for or unwilling to take VKA to apixaban 5 mg twice daily or to aspirin 81 to 324 mg daily.²⁷ The study was terminated when interim analysis showed rates of the primary outcome (stroke or systemic embolism) at 3.7% per year for the aspirin group versus 1.6% per year for the apixaban group (P<.001).²⁷ There were no significant differences in the rates of major bleeding or intracerebral hemorrhage between groups, although the trial’s power was limited by premature termination. The 54% reduction in primary end points without excess bleeding suggests that apixaban may be preferable to aspirin in patients who are unable to tolerate VKA therapy, but identifying such patients in clinical practice is challenging.

Taken together, the RE-LY, ROCKET AF, and ARISTOTLE trials found that dabigatran, rivaroxaban, and apixaban produce greater reductions in the rate of intracerebral hemorrhage compared with warfarin. The extent of the reduction in all-cause mortality was similar across the trials (approximately 10%), although statistical significance varied.²⁹ The higher dose of dabigatran (150 mg twice daily) achieved a significant reduction in ischemic stroke compared with warfarin; rivaroxaban achieved a reduction in fatal bleeding; and apixaban achieved a reduction in overall bleeding.

Edoxaban

Edoxaban is an oral, direct factor Xa inhibitor that is currently being investigated for long-term safety and efficacy in patients with AF.³⁰ In November 2013, investigators reported the results of the ENGAGE-AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation Thrombolysis in Myocardial Infarction 48) trial, which compared the safety and efficacy of dose-adjusted warfarin (INR, 2-3) with a low dose (30 mg) and high dose (60 mg) of edoxaban once daily in 21,000 AF patients with moderate to high risk for stroke.³¹ The primary end point was time to first stroke or systemic embolic event.

The trial found both doses of edoxaban noninferior to well-managed warfarin. The annualized rate of the primary end point during treatment was 1.50% with warfarin (median time in the therapeutic range, 68.4%), as compared with 1.18% with high-dose edoxaban (HR, 0.79; 97.5% CI, 0.63-0.99; P<.001 for noninferiority) and 1.61% with low-dose edoxaban (HR, 1.07; 97.5% CI, 0.87-1.31; P=.005 for noninferiority). Both edoxaban regimens were associated with significantly lower rates of bleeding and death from cardiovascular causes.³¹

In the randomized Hokusai-VTE trial, the drug also demonstrated safety and efficacy in treating more than 8000 patients with symptomatic venous thromboembolism.³² The trial showed that edoxaban administered once daily at 30-mg or 60-mg doses after initial treatment with heparin is noninferior to warfarin and is associated with significantly less bleeding. Daiichi Sankyo funded both ENGAGE-AF-TIMI 48 and Hokusai-VTE. Based on the results of these trials, Daiichi Sankyo recently submitted a new drug application for edoxaban to the FDA.³³ Currently, edoxaban is approved for use only in Japan.

Conclusion

AF is prevalent among the elderly, and its incidence is rising as people who have more advanced cardiovascular disease are living longer. AF-related strokes are associated with considerable morbidity and mortality and contribute to rising healthcare costs. Oral anticoagulants of the VKA class have proven effective for stroke prevention in patients with AF and are recommended for those patients at moderate to high risk of ischemic stroke. The drawbacks of VKAs include a narrow therapeutic window and the effects of food and drug interactions that necessitate coagulation monitoring. The new oral anticoagulants are attractive alternatives for stroke prophylaxis as they overcome many of these limitations while also demonstrating equal or superior efficacy compared with VKAs. Long-term analyses are needed to verify that these benefits can be sustained in older patients with AF.

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Disclosures: Dr. Halperin reports having received consulting fees from Astellas Pharma US, Inc; AtriCure; AstraZeneca; Bayer HealthCare AG; Biotronik, Inc; Boehringer Ingelheim; Boston Scientific; Bristol-Myers Squibb Company; Daiichi Sankyo, Inc; Johnson & Johnson; Medtronic; Pfizer, Inc; and Sanofi-Aventis. Dr. Malhotra reports no relevant financial relationships.

Address correspondence to: Jonathan L. Halperin, MD, Cardiovascular Institute, Mount Sinai Medical Center, One Gustave L. Levy Place, New York, NY 10029; jonathan.halperin@mountsinai.org