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Cardiac Arrhythmia Cardiac Arrhythmia Chapter 1 Stroke Prevention in Atrial Fibrillation Todd Mendelson1 and David Lin1* 1 Hospital of the University of Pennsylvania, USA Corresponding Author: David Lin, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA, Email: [email protected] * First Published April 24, 2016 Copyright: © 2016 Todd Mendelson and David Lin. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source. 2 www.avidscience.com Atrial fibrillation (AF) is one of the most common arrhythmias in the United States and a significant cause of morbidity. Using historical data from the Framingham Study, prevalence has been estimated to be up to 12% [1]. More recently, the ARIC study has evaluated the incidence of atrial fibrillation based on race and found it is more incident in whites than blacks. From their data, the cumulative risk of AF at age 80 is 21% for white men, 17% in white women, and 11% in African-American men and women [2]. Based on estimates from Olmsted County data, the number of people in the United States with atrial fibrillation will reach 10 million by the year 2050 [3]. As risk factors (such as hypertension, diabetes, obesity and sleep apnea) for atrial fibrillation become more common and as the population continues to age, atrial fibrillation will continue to be a common arrhythmia. Thrombo-embolic stroke is a dreaded complication of this common arrhythmia. Early attempts to quantify the risk of stroke led to the commonly used CHADS2 risk stratification system [4]. This scoring system was an advancement in the risk evaluation of stroke due to its ease of use; however, it was criticized for adjudicating many people to the intermediate risk group. Therefore, another group added/updated the CHADS2 score to include vascular disease to improve the ability of clinicians to evaluate use of oral anticoagulation [5]. The CHA2DS2-Vasc scoring system is the most widely used method for clinicians to determine the risk of stroke in patients with atrial fibrillation and, in fact, is the guideline recommended method [6]. Yet it is important to keep in mind that these www.avidscience.com 3 Cardiac Arrhythmia Cardiac Arrhythmia risk calculators are specifically for non-valvular atrial fibrillation and do not include other potential mediators of thrombo-embolism such as thyroid disease. Furthermore, whether these risk calculators still apply after successful AF ablation remains a question to be answered. Recent studies have shown enhanced hypercoagulability in hyperthyroidism and atrial fibrillation (above atrial fibrillation alone or hyperthyroidism alone) [7]. Warfarin is the oldest of the anticoagulants used to prevent stroke in atrial fibrillation and remains the gold standard for stroke prevention in AF. As is well known, it was first developed as a pesticide in the 1940s and was approved for use in humans by the FDA in the 1950s. Since then, it has been studied multiple times as a strategy to prevent stroke in atrial fibrillation. In fact, a Cochrane review of patients with atrial fibrillation and no prior history of stroke, found that warfarin compared to placebo prevented 25 strokes for every 1000 patients treated with warfarin [8]. There have not been many recent advances in warfarin; however, it remains one of the dominant strategies to prevent stroke in atrial fibrillation. There were attempts to analyze genetic variation in response to warfarin [9]; however, when used in a prospective clinical trial, there was no clinical benefit [10]. Perhaps the biggest advance in warfarin has been the ability for patients to use home monitoring with excellent time in therapeutic range [11]. For the forseeable future, warfarin will likely continue to be the anticoagulant of choice for patients with 4 www.avidscience.com valvular heart disease and end-stage renal disease (ESRD) not yet on dialysis. The past several years have seen the rise of a new generation of oral anticoagulants which were initially referred to as novel oral anticoagulants; however, as time has gone by, the utilization of these agents have increased as the novelty has worn off. The two main classes of anticoagulants are direct thrombin inhibitors and Factor Xa inhibitors (whereas warfarin is a vitamin K antagonist). The overall class has some advantages over warfarin. First, there is no monitoring of anticoagulant level needed. Second, the onset of action and time to achieve a therapeutic level is on the order of hours rather than days. Third, there are fewer dietary and drug interactions as compared to warfarin. They are limited though as none has been studied in patients with ESRD not yet on dialysis. There has been only one study evaluating a novel oral anticoagulant in patients with mechanical valves; and it showed harm with the novel anticoagulant compared with warfarin [12]. Therefore, it is unlikely that others will be tested in the near future. The guidelines continue to endorse the newer anticoagulants for patients with non-valvular atrial fibrillation. Dabigatran (Pradaxa) is a direct thrombin inhibitor that was first approved in Europe for DVT prophylaxis is orthopedic surgery patients. In the fourth quarter of 2010, the U.S. Food and Drug administration approved www.avidscience.com 5 Cardiac Arrhythmia Cardiac Arrhythmia dabigatran for the prevention of stroke in patients with non-valvular atrial fibrillation. After oral administration, dabigatran reaches peak concentration in a few hours (depending on whether or not it is taken with a fatty meal). The elimination half-life is 12-17 hours. The elimination is renal and so dose reduction is recommended for patients with impaired renal function. The standard dose is 150 mg twice a day if CrCl>30 mL/min. If CrCl is 15-30 mL/min, then a dose of 75 mg twice a day is recommended [13]. There is no data regarding CrCl<15mL/min. The clinical trial leading to approval of dabigatran was the Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) trial [14]. The trial randomized approximately 18,000 patients to either dabigatran or warfarin. The trial was designed as a non-inferiority trial with the upper bound of non-inferiority being 1.46. The follow up time was 2 years and the primary outcome was stroke or systemic embolism. The dabigatran arm consisted of two different doses (110 mg or 150 mg). The trial showed that the 150 mg arm compared to the warfarin arm had lower rates of stroke and systemic embolism; however, similar rates of hemorrhage. Interestingly, the 110 mg dose showed similar rates of stroke/embolism, but lower rates of hemorrhage compared to warfarin. Nonetheless, the approved dose for atrial fibrillation in the U.S. is 150 mg twice a day (or 75 mg twice a day for renal impairment). The most common side effect seen in the trial was dyspepsia (11% 6 www.avidscience.com incidence). From approval in October 2010 through August 2012, there were 3.7 million prescriptions dispensed according to an FDA statement [15]. Rivaroxaban (Xarelto) is a direct factor Xa inhibitor that was also first approved for an orthopedic indication. The U.S. FDA approved rivaroxaban in November 2011 for stroke prevention in patients with non-valvular atrial fibrillation. The absorption of rivaroxaban varies depending on whether or not the medication was ingested with (out) food. Therefore, the manufacturer recommends taking rivaroxaban with food [16]. The half-life of the drug is 5 to 9 hours, though, the inhibition of factor Xa lasts for approximately 24 hours; therefore, the medication is dosed once a day. The standard dose is 20 mg daily and there is a lower dose (15 mg) for those with CrCl between 15 and 50 mL/min. The clinical trial supporting use of rivaroxaban in non-valvular atrial fibrillation was the ROCKETAF trial [17]. The study randomized approximately 14,000 patients to either warfarin or rivaroxaban (20 mg) and measured the primary outcome of stroke or systemic embolism. The median follow up time was just under 2 years (707 days) and the trial was designed as a non-inferiority trial. The trial showed that rivaroxaban was not inferior to warfarin for the prevention of stroke or systemic embolism. The risk of major bleeding between groups was similar; however, there was a lower rate of fatal bleeding and intracranial bleeding in the rivaroxaban group. The most www.avidscience.com 7 Cardiac Arrhythmia Cardiac Arrhythmia common adverse event was epistaxis which was more common in the treatment group. Currently, rivaroxaban is the only once daily medication amongst the oral factor Xa or direct thrombin inhibitors. Apixiban (Eliquis) was the second direct factor Xa inhibitor to arrive to the U.S. market. It was approved by the FDA in 2012 for stroke prevention in atrial fibrillation. In contrast to the two prior drugs, apixiban was first approved for atrial fibrillation and subsequently for DVT/PE prevention and treatment. The half-life is approximately 12 hours and the absorption is independent of food coadministration [18]. There are two doses available: the standard dose is 5 mg twice a day. For patients with two of the three following conditions, the recommended dose is 2.5 mg twice a day: age ≥ 80 years, weight ≤ 60 kg, serum creatinine ≥ 1.5 mg/dL. The major clinical trial leading to approval of apixaban was the ARISTOTLE trial [19]. The trial randomized approximately 18,000 to apixiban or warfarin and was designed as a non-inferiority trial. The primary endpoint was ischemic or hemorrhagic stroke or systemic embolism. The median follow up was 1.8 years. The study showed that apixiban was not inferior to warfarin with respect to the primary endpoint. One of the secondary endpoints was mortality and it showed the warfarin group had a statistically significantly higher mortality rate. However, the rates were low and it just barely met statistical significance. As a general summary, the new 8 www.avidscience.com anticoagulants seem to have similar efficacy with regard to stroke prevention and have a slightly more favorable bleeding profile compared to warfarin [20]. Even newer oral anticoagulants are currently in the pipeline. Edoxaban is another direct factor Xa inhibitor which is dosed once a day. In the ENGAGE-AF TIMI 48 trial, subjects were randomized to low-dose edoxaban (30 mg), high-dose edoxaban (60mg), or warfarin [21]. In keeping with the prior trials, the rates of stroke or systemic embolism were similar (non-inferior) between edoxaban and warfarin. There was also the same signal toward less risk of bleeding in the factor Xa inhibitor. It was approved by the FDA in January 2015. Another direct factor Xa inhibitor betrixaban is a little earlier in the pipeline as the most recent data is a phase 2 clinical trial [22]. Bextrixaban is predominantly metabolized by the liver (in contrast to the others which are predominantly metabolized by the kidneys). The small phase 2 trial showed similar rates of bleeding compared to warfarin and that the medication was well tolerated. It is also being studied for DVT prophylaxis and is on fast-track for FDA approval for that indication. Perhaps the most novel medication on the scene regarding novel anticoagulants is the first approved reversal agent. One of the major criticisms of the novel oral anticoagulants was the lack of reversibility. Idarucizumabwas studied in the RE-VERSE AD trial [23]. Idarucizumab www.avidscience.com 9 Cardiac Arrhythmia Cardiac Arrhythmia (Praxbind) is a monoclonal antibody fragment which has two orders of magnitude more affinity for dabigatran than thrombin does. There is a single, standard 5 gram IV dose. The FDA approved the drug in the fall of 2015. While idarucizumab is specific to dabigatran (a direct thrombin inhibitor), there is another drug in the pipeline which looks to be an anti-factor Xa inhibitor. Andexanet Alfa is a recombinant factor Xa decoy protein which can bind the factor Xa inhibitors. In the ANNEXA-A and the ANNEXA-R, andexanet alfa was evaluated for its ability to reverse both apixaban and rivaroxaban [24]. There is an ongoing phase 3 trial of this drug and it is yet to be approved by the FDA. The ANNEXA 4 trial is set to finish in 2022 (according to ClinicalTrials.gov). Nonetheless, there is an approved dabigatran reversal agent available and there is a factor Xa inhibitor reversal agent in phase 3 trials. In addition to the evolution of anticoagulants, there has also been an evolution in non-pharmacologic stroke prevention. As is commonly agreed upon today, the left atrial appendage is felt to be the site of origin of most thrombi that go on to systemic embolism in atrial fibrillation. The earliest cited reference to this theory is from the late 1960s [25]. One of the first discussions of techniques to prevent stroke in rheumatic mitral stenosis dates back to the early 1950s [26]. In the modern era, Blackshear and Odell reviewed outcomes of left atrial appendage obliteration in non-rheumatics and found some promising evi10 www.avidscience.com dence [27]. It is in this background, that many surgeons who are performing MAZE procedures to prevent atrial fibrillation will now over-sew or exclude the left atrial appendage (with the goal to reduce stroke). There are many echocardiographic studies that question the efficacy of left atrial appendage exclusion [28] and find that certain techniques are more efficacious than others [29]. Nonetheless, for patients undergoing cardiac surgery and have a history of atrial fibrillation, one option to decrease the risk of stroke is to exclude the left atrial appendage at the time of surgery. As the role of left atrial appendage exclusion has become entrenched as a method for stroke prevention, there has been a race to develop percutaneous methods to achieve this goal, thereby potentially eliminating the need for open-heart surgery for left atrial appendage ligation. There have been descriptions of using cardiac plugs, suture devices, and umbrella devices. The premise is based on sealing the left atrial appendage from communicating with the left atrium proper. One of the first was studied in Europe; however, the device is no longer on the market [30]. There have been Amplatzer devices as well which have been explored in two generations [31,32]. There is a technique to ligate the appendage via a percutaneous epicardial approach with a snare/suture device [33,34]. This technique has been widely performed off label (as the device is not approved by the FDA for left atrial appendage closure) and a recent report questioned the safety of the www.avidscience.com 11 Cardiac Arrhythmia Cardiac Arrhythmia technique [35]. Currently, in the United States, there is only one FDA approved device for the indication of percutaneous left atrial appendage exclusion to prevent stroke in the setting of atrial fibrillation. There have been two trials evaluating the safety and efficacy of the Watchman Device [36,37]. In the PROTECT-AF study, patients were randomized to warfarin or left atrial appendage occlusion. The results showed that the device was non-inferior to warfarin with respect to the combined endpoint of stroke, systemic embolism, or cardiovascular death [37]. There were some safety concerns and so the FDA required a second study to evaluate the safety of the device. In the PREVAIL trial, the non-inferiority of the device compared to warfarin and the study showed improvement with regard to safety of the device [36]. Currently, the device is implanted in patients who have a contra-indication to long-term anticoagulation and have a high risk of systemic embolism. Of note, patients are recommended to stay on warfarin for at least several weeks post-implantation. Regarding stroke prevention, one common scenario surrounds patients asking about continuation of anticoagulation after ablation of atrial fibrillation. There have been no randomized clinical trials evaluating the need for ongoing anticoagulation after atrial fibrillation has been successfully eliminated. There has been a single large, multiple center review of outcomes [38]. It showed that the risk of ongoing anticoagulation may be greater than the risk of 12 www.avidscience.com stroke. The future direction of stroke prevention research in atrial fibrillation will likely include these two final issues. Are there non-pharmacologic, durable methods to prevent stroke? Does left atrial appendage ligation and ablation effectively mitigate stroke risk? Further clinical trials will shed light on this very important clinical question. References 1. Wolf PA, Benjamin EJ, Belanger AJ, Kannel WB, Levy D. Secular trends in the prevalence of atrial fibrillation: The Framingham Study. Am Heart J. 1996; 131: 790-795. 2. Alonso A, Agarwal SK, Soliman EZ, Ambrose M, Chamberlain AM. Incidence of atrial fibrillation in whites and African-Americans: the Atherosclerosis Risk in Communities (ARIC) study. Am Heart J. 2009; 158: 111-117. 3. Miyasaka Y, Barnes ME, Gersh BJ, Cha SS, Bailey KR. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation. 2006; 114: 119-125. 4. 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