Advances in Therapy for Atrial Fibrillation

Foreword Lane & Lip Foreword

Advances in therapy for atrial fibrillation

Two epidemiological studies have demonstrated led to the development of novel anticoagulants; Deirdre A Lane† that the lifetime prevalence of atrial fibrillation the forerunner, dabigatran, is discussed by sev- & Gregory YH Lip (AF) among people aged 40 years or more is eral of the authors in this themed issue. There are †Author for correspondence: roughly one in four [1,2]. AF increases in preva- also several other ‘new’ oral anticoagulants cur- University of Birmingham lence with age, ranging from 0.5% in people aged rently under examination in clinical trials, such Centre for Cardiovascular 50–59 years to almost 9% in those aged 80 years as rivaroxaban, apixaban, AZD0837, DU-176 Sciences, City Hospital, or more, and is associated with a high risk of and so on, and we eagerly await the results of Dudley Road, Birmingham, morbidity and mortality from heart failure, these trials. These are exciting times in the man- B18 7QH, UK stroke and thromboembolic complications [3]. In agement of AF, with the emergence of promis- Tel.: +44 121 507 5080 addition, when strokes do occur in association ing new antiarrhythmic drugs, vernakalant and Fax: +44 121 507 5907 with AF, patients have a substantial mortality, dronedarone, and novel oral anticoagulants, [email protected] morbidity, disability and longer hospital stays [3]. such as dabigatran, among others. In patients with AF there are two important This themed issue provides an excellent decisions to make: overview of the evidence regarding the current

n Whether to employ a rate- or rhythm-control rhythm-control strategies and antithrombotic strategy; management options for patients with AF, as well as the exciting new antiarrhythmic and n What antithrombotic regimen to utilize. anticoagulant drugs that are emerging, which For younger, symptomatic patients, and those will hopefully transform the management of AF, with paroxysmal or persistent AF (<1 year dura- in particular antithrombotic therapy. tion), a rhythm-control strategy to restore and Four review articles cover a diverse range of maintain sinus rhythm may be the preferred topics from gender differences in AF to new per- option, but cardioversion and antiarrhythmic spectives in the mechanisms of AF. Kühne and drugs are not without their problems, as dis- Conen’s excellent review of gender differences in cussed by Fitzmaurice [4], Singh and Singh [5], AF provides an insight into the epidemiology of and others in this themed issue of Therapy. The AF in women, describing the risk factors associ- other, perhaps more important consideration ated with AF among women and focusing on the given the associated thromboembolic complica- implications of female gender in the presentation tion of AF, is whether or not to anticoagulate and management of AF [6]. Evidence suggests patients. Currently, guidelines recommend anti- that women have poorer AF-related outcomes, coagulation for patients at high risk of stroke which may be associated with gender differences and aspirin for those at low risk. However, the in the treatment of AF, although the authors antithrombotic treatment recommendations conclude that the pathophysiological mecha- for those patients at moderate risk, often the nisms to explain gender differences in AF are majority of patients based on current stroke risk missing and further studies are needed. stratification schema, are ambiguous, suggesting The benefits and complications of ablation either aspirin or warfarin. Despite the evidence therapy for AF are comprehensively reviewed from clinical trials that thromboprohylaxis with by Shin and Deneke, who suggest that whilst warfarin significantly reduces the incidence of the treatment is very effective, efficacy needs to stroke and mortality [101], such therapy still be improved [7]. Singh and Singh then review remains grossly underutilized. This underuti- emerging drugs for the management of AF, lization is due, in part, to the inherent difficul- including rhythm-control and oral anticoagula- ties associated with warfarin, such as the incon- tion. Their article focuses mainly on two new venience of regular monitoring, interactions antiarrhythmic drugs, vernakalant and drone- with drug/alcohol/diet, difficulties managing darone [5]. Vernakalant and the results of the therapeutic international normalized ratios three Atrial Arrhythmia Conversion Trials (INRs) and dose adjustments, all of which have (ACT) [8–10], also discussed in the Research

Highlights by Elder et al. [11], seem a viable a few, resulting in the journey to discover an option for the pharmacological conversion of alternative to warfarin, the most promising of AF, but currently await final FDA approval. which to date is dabigatran. Some of the advan- The evidence from the ATHENA trial [12] sug- tages of the latter drug over warfarin (fixed dose, gests that dronedarone is associated with a sig- no monitoring and rapid anticoagulant effect) nificant reduction in cardiovascular hospitaliza- but also some of the problems that may limit tions or death (mainly driven by a reduction in its applicability (dyspepsia, price/affordability AF-related hospitalizations), although results for patients, safety/efficacy in AF patients with from the ANDROMEDA trial [13] mean that acute coronary syndromes requiring percutane- dronedarone is absolutely contraindicated in ous coronary intervention ± stent, and patient patients with recent symptomatic or decompen- willingness to switch from a stable, established sated heart failure. This excellent review also oral anticoagulation), should it be granted FDA briefly discusses two new oral anticoagulants: approval, are discussed. tecarfarin, a structural analog of warfarin, and Another Editorial discusses the controversial the direct oral thrombin inhibitor, dabigatran, topic of the most appropriate antithrombotic

the latter of which is discussed in more detail in treatment for AF patients with a CHADS2 the Research Highlights by Elder et al. [11] and in score of 1, who are defined as being at ‘mod- the two Editorials by Sullivan and Olshansky [14], erate risk’ of stroke with an annual stroke risk and Fauchier et al [15]. of 2–4% [3], where current guidelines recom- The molecular basis of alternations in sacro- mend either aspirin or warfarin [3,19,20,101]. This 2+ plasmic reticulum Ca handling in AF and Editorial by Fauchier et al. [15] examines the risks their potential therapeutic implications is the and benefits of anticoagulation in such patients, focus of a review by Wehrens et al [16]. It has drawing upon post hoc analyses from recent anti- been suggested that changes in the sacroplasmic thrombotic trials in AF patients where the evi- reticulum Ca2+ homeostasis might contribute dence for the benefit of warfarin among such to a reduced contractile function and promote patients is conflicting. They argue for refinement arrhythmogenesis in the atria. Pharmacological of stroke risk stratification to prevent the major- inhibition of aberrant SR Ca2+ release might be a ity of patients being defined as moderate risk, promising new strategy for the treatment of AF. where current treatment guidance is dependent Fitzmaurice controversially asks whether on physician discretion, patient preference and there is a role for cardioversion in the modern development of bleeding risk predictors. management of AF in a Perspective article [4]. Finally, in the Research Highlights section, He argues for the abolition of electrical cardio Elder et al. focus on some recent drug develop- version in the routine management of AF, ments for use in AF patients [11]. First, they exam- given that several randomized controlled tri- ine the results of the Randomized Evaluation of als of rate- versus rhythm-control (AFFIRM, Long-term Anticoagulation Therapy (RE‑LY) STAF, HOT CAFE) [17] have all demonstrated study [21], where dabigatran 150 mg twice daily that electrical cardioversion does not confer a or 110 mg, a direct oral thrombin inhibitor, were mortality benefit over rate-control and that the compared with warfarin. The RE‑LY study dem- antiarrhythmic drugs needed to maintain sinus onstrated that dabigatran 150 mg twice daily rhythm may actually be associated with increased had superior efficacy to warfarin, with a similar mortality. He asserts that the place for electri- bleeding risk, whilst dabigatran 110 mg twice cal cardioversion is in the acute setting or for daily demonstrated a similar efficacy to warfarin those who remain symptomatic despite optimal but with a significant reduction in major bleed- medical therapy, where long-term anticoagulant ing, particularly intracranial hemorrhage, com- therapy should also be continued. pared with warfarin [21]. Second, they discuss The management of thromboembolism in AF vernakalant, an atrial-selective early activating patients is the focus of an Editorial by Sullivan potassium and frequency-dependent sodium and Olshansky, highlighting the importance channel blocker. The ACTs (I–III) [9–11] have of stroke risk stratification with newer schema, demonstrated the efficacy and safety of vernaka-

such as CHA2DS2-VASc [18], to identify patients lant in AF patients, and we currently await the who may benefit from oral anticoagulation. This results of the AVRO trial, where vernakalant Editorial highlights the inherent difficulties is being tested in a head-to-head comparison associated with warfarin therapy: maintenance with amiodarone. The third paper reviewed by of a therapeutic INR, increased risk of bleed- Elder et al. concerns the use of polyunsaturated ing, underutilization of warfarin, to name but fatty acids in the prevention of postoperative

104 Therapy (2010) 7(2) future science group Foreword Lane & Lip Advances in therapy for atrial fibrillation Foreword

AF. Although existing results are disappoint- Financial & competing interests disclosure ing, we await the results of larger randomized The authors have no relevant affiliations or financial controlled trials to define the role of polyunsatu- involvement with any organization or entity with a finan- rated fatty acids in postcoronary artery bypass cial interest in or financial conflict with the subject matter graft patients. or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or Acknowledgements options, expert testimony, grants or patents received or We would like to thank all of the contributors for their pending, or royalties. involvement in this themed edition of Therapy on No writing assistance was utilized in the production of atrial fibrillation. this manuscript.

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