Atrial fibrillation (AF) is a disorder found in approximately 2.2 million Americans, and the number of people with AF in the United States is expected to double over the next 30 to 40 years (Figure). Published data have estimated that about 15% of all strokes occur in people with AF, and the risk factors for stroke in patients with nonvalvular AF are substantial. The likelihood of developing AF increases with age, and data suggest that 3% to 5% of people 65 and older have the condition. “AF impacts the elderly substantially because they typically have more comorbidities,” says Gerald V. Naccarelli, MD. “This has raised concern over how to manage these patients.”
According to the National Heart, Blood, and Lung Institute, AF is more common in people with coronary heart disease, heart failure, rheumatic heart disease, structural heart defects (eg, mitral valve disorders), pericarditis, congenital heart defects, and sick sinus syndrome. AF also is more common in people with heart attacks or who have just had surgery. Other conditions that increase AF risk include hyperthyroidism, obesity, hypertension, diabetes, and lung disease (Table 1). “The increasing incidence of AF has raised awareness of the importance of stratifying stroke risk,” Dr. Naccarelli says. “The key for clinicians is to determine who should receive anticoagulation and who should not [Table 2]. Unfortunately, studies show that about half of people with AF who are candidates to receive vitamin K antagonists (VKAs), such as warfarin, are not receiving the drug. Of that half, only two-thirds of these patients are actually taking VKAs as prescribed.”
VKAs, most notably warfarin, have long been used for the prevention of stroke in AF patients with a moderate-to-high risk of stroke. However, they have a narrow therapeutic window. Insufficient anticoagulation can result in strokes, and over-anticoagulation can increase the risk of bleeding. “VKAs are largely unpredictable because they can be affected by genetic factors, drug-drug interactions, and consumption of foods containing vitamin K,” explains Dr. Naccarelli. “As a result, regular monitoring and dose adjustments of VKAs are needed to ensure that anticoagulation effects occur. The limitations of VKAs highlight the need for new anticoagulants to prevent stroke in patients with AF.”
Several oral, direct-thrombin inhibitors have undergone clinical development or are being tested for stroke prevention in patients with AF. In October 2010, the FDA approved dabigatran (Pradaxa, Boehringer Ingelheim) for the pre-vention of stroke and blood clots in patients with AF. The safety and efficacy of dabigatran were studied in a clinical trial comparing it with warfarin. In the trial, patients taking dabigatran had fewer strokes than those who took warfarin. The trial that led to its approval also showed that dabigatran significantly reduced the risk of hemorrhagic stroke. “Warfarin requires that patients undergo periodic monitoring with blood tests,” adds Dr. Naccarelli, “but such monitoring is not necessary for dabigatran.”
An attractive alternative to direct-thrombin inhibition is selective inhibition of Factor Xa. Early investigations suggest that it causes fewer side effects. Numerous direct and indirect Factor Xa inhibitors are currently at various stages of clinical development. “A few of the Factor Xa inhibitors—including rivaroxaban (Bayer), apixaban (Bristol-Myers Squibb), and edoxaban (Daiichi Sankyo)—have been shown in early-phase trials to reduce the risk of stroke, but more data are needed,” Dr. Naccarelli says. “As these data emerge, the hope is that these drugs will add to the armamentarium of therapies that may be useful for stroke prevention in pa-tients with AF.”
An Exciting Time
Dr. Naccarelli says it is an exciting time for clinicians who are managing patients with AF. “More data and medications are continuing to materialize. This is helping clinicians better understand how to treat these individuals. The hope is that this explosion of new treatments will reduce the need for monitoring interna-tional normalized ratios and blood to be drawn, while also leading to fewer interactions with vitamin K. The new wave of therapies offers the potential for being more user-friendly, with rapid onsets of action and fewer food interactions. We’re still awaiting more evidence, but the renewed enthusiasm in the management of AF may ultimately lead to more significant break-throughs in the years to come.”
Turpie AG. New oral anticoagulants in atrial fibrillation. Eur Heart J. 2008;29:155-165. Available at:http://eurheartj.oxfordjournals.org/content/29/2/155.full.pdf+html.
NHLBI website. Atrial Fibrillation: Who Is At Risk for Atrial Fibrillation? Available at:http://www.nhlbi.nih.gov/health/dci/Diseases/af/af_risk.html. Accessed January 10, 2011.
NHLBI website. What is AFib? Available at: http://www.nhlbi.nih.gov/health/dci/Diseases/af/af_what.html. Accessed: August 2, 2010.
Nagarakanti R, Ezekowitz MD, Oldgren J, et al. Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion. Circulation. 2011;123:131-136.