Pharmacologic Advancements in Atrial Fibrillation

Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice, currently affecting more than 2.5 million people in the United States alone. The prevalence of this arrhythmia has reached epidemic proportions, and such numbers are expected to grow exponentially over the coming years. The national implications of such a significant public health issue are undeniably great, imposing enormous healthcare resource utilization and overwhelming cost. Optimization of effective preventive and therapeutic strategies is therefore of pivotal importance in reducing the burden of atrial fibrillation. Atrial fibrillation is associated with a considerable increase in morbidity and mortality, and negatively impacts the quality of life of those patients whom it afflicts. The clinical impacts of AF that are of greatest concern are its associated risks of thromboembolic events as well as its role in the development and/or exacerbation of symptomatic heart failure, related to tachycardia-induced systolic dysfunction. Therapies aimed at treating AF are primarily focused on prevention of embolic stroke, control of ventricular response, and restoration and maintenance of normal sinus rhythm. Pharmacologic Management of AF - Rate Versus Rhythm Control There are two elements to consider in the pharmacological management of atrial fibrillation: 1) management during the acute presentation, and 2) choosing the appropriate effective long-term management, be it rate control or rhythm control. At the time of initial presentation, acute ventricular rate control is a priority of primary concern in order to control patient symptoms and maintain hemodynamic stability. Calcium channel blockers and beta-blockers are typically the first line agents used to achieve adequate heart rate control, which is generally considered to be a ventricular rate less than 100 bpm.1 If AF persists and symptoms are unrelieved, despite attempts at rate control, electrical or pharmacological cardioversion should also be employed. Emergent electrical cardioversion is indicated for patients who present with hemodynamic collapse. Long-term management also centers on either a rhythm or rate control strategy. The goals of a rhythm control strategy are restoration and maintenance of sinus rhythm, which allows for normal atrial activation and contraction, atrioventricular (AV) synchrony, normal hemodynamic AV valve function, and a regular, rate-controlled rhythm. Controlling the ventricular rate alone is generally considered an acceptable long-term treatment strategy for those patients with permanent AF in whom restoring sinus rhythm is unachievable. Recently presented results of the RACE II trial at the 2010 ACC conference challenged the dogma of strict heart rate control, suggesting that a lenient heart rate control (110 bpm) was equally as good.2 The results of the landmark Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial established that there is no significant difference in mortality between a rhythm control strategy versus one of rate control.3 Ultimately, due to the low rate of sinus rhythm maintenance in the antiarrhythmic arm, the study was unable to clearly address the benefits of a rhythm control approach to that of rate control. However, recent advances in the treatment of atrial fibrillation with catheter ablation procedures do suggest that there remains an overwhelming interest in the ultimate restoration and maintenance of sinus rhythm. The primary goal of treating AF, with either strategy, is to improve the patient’s quality of life by diminishing the frequency, intensity and overall burden of AF-related symptoms.4 Current Antiarrhythmic Drugs Currently, class I and class III antiarrhythmics are the pharmacologic agents primarily used in clinical practice for rhythm control.1 Among the presently available antiarrhythmic drugs (AADs), amiodarone, a class III agent, is the most potent and effective in maintaining sinus rhythm. Unfortunately, it is also the most toxic and is laden with potentially significant adverse effects, including those of pulmonary, thyroid, and hepatic toxicity. Dofetilide and sotalol, also both class III agents, are generally considered relatively safe and effective, although both drugs require hospital admission during initiation of therapy given the risk of proarrhythmia and potential development of Torsades. Both dofetilide and sotalol are eliminated via the kidneys and must therefore be used with caution in patients with renal impairment. These two drugs are not as effective for AF conversion as they are for maintenance of normal sinus rhythm. The IC agents flecainide and propafenone can be quite effective in both conversion to and maintenance of sinus rhythm. However, they must be avoided in patients with structural heart disease, as evidence from the CAST trial showed an associated increase in mortality in this patient population.5,6 Such drugs are also associated with a risk of proarrhythmia. (Table 1.) Unfortunately, the long-term effectiveness of these antiarrhythmic drugs in maintaining sinus rhythm is quite poor. Several studies have shown that the likelihood of AF recurrence within 6 to 12 months of initiation of drug therapy approaches 50%.7 Therefore, evidence of inconsistent effectiveness coupled with a relatively high incidence of adverse effects renders current pharmacological treatment options quite limiting. Emerging Antiarrhythmic Agents There are several emerging antiarrhythmic agents for both the acute and chronic management of atrial fibrillation. Vernakalant, an intravenous agent for the acute conversion of AF, is an atrial selective potassium channel blocker that is in advanced stages of development. Recent phase III trials comparing vernakalant to placebo for acute cardioversion in patients with new onset AF demonstrated its effectiveness. Sinus rhythm was restored in 52% of patients receiving vernakalant versus 4% of patients receiving placebo. The drug was well tolerated and there were no reports of Torsades or sustained ventricular arrhythmias in the first 24 hours post-infusion. Vernakalant is currently under review by the FDA. The oral analogue of vernakalant for long-term maintenance of sinus rhythm is also currently being examined. The newest AAD currently utilized in clinical practice is dronedarone, which was recently approved as an AAD for the long-term management of AF. This drug has electrophysiologic effects similar to those of amiodarone; however, it is devoid of iodine constituents and its related adverse effects. There is evidence of multiple ion channel blockade, which leads to a propensity for markedly prolonging the atrial effective refractory period as well as demonstrated effectiveness in maintaining sinus rhythm without significantly prolonging the QT interval, which suggests a measure of atrial selectivity.8 Several recent trials have highlighted the clinical significance of this emerging antiarrhythmic agent. The results of the four landmark trials, namely EURIDIS/ADONIS, ANDROMEDA, ATHENA and DIONYSOS are summarized in Table 2. While dronedarone has not been shown to be more effective than the most demonstratively potent antiarrhythmic, it has proven to be effective in reducing symptoms of atrial fibrillation while conferring no risk of proarrhythmia or chronic toxic effects, which are inherent to other currently available antiarrhythmic agents. Several studies have shown dronedarone to be more effective than placebo at maintaining sinus rhythm. Both prevention of recurrent AF as well as adequate rate control during arrhythmia recurrence likely account for the reduction in time to first symptomatic event (EURIDIS/ADONIS) and that of hospitalization due to CV events (ATHENA). It is important to note that dronedarone must not be used in patients with moderate to severe heart failure (ANDROMEDA). Non-Antiarrhythmic Agents While rate and rhythm controlling agents are targeted towards treatment of existing AF, several other agents are becoming increasingly important in the potential prevention of AF development. These non-antiarrhythmic drugs exhibit antiarrhythmic effects through a spectrum of actions such as reducing inflammation and oxidative injury, or altering atrial myocyte metabolism and extracellular matrix remodeling. There is complex interplay between risk factors and potential triggers that serve to initiate AF and abnormalities in atrial substrate that allow perpetuation of the arrhythmia once it develops. Hypertension represents one of the major underlying diseases in many patients with AF, owing largely to resultant atrial dilation and stretch caused by left ventricular hypertrophy. In a study conducted by Hennersdorf et al, regression of left ventricular hypertrophy achieved with antihypertensive therapy led to a reduction in left atrial diameter and a consequent decrease in the overall incidence of atrial fibrillation, from 12.5% to 1.8%.9 More recently, treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) in patients at risk for developing AF, namely those patients with hypertension and LV hypertrophy as well as those with heart failure, has revealed a marked overall suppression in arrhythmia development. Such results are thought to be due to the impact of ACE inhibitors on modifying atrial substrate by improving LV hemodynamics, reducing atrial dilation, and suppressing atrial fibrosis.10 In addition to their impact on structural remodeling, there is also evidence that ACE inhibitors and ARBs play a role in preventing AF recurrence by affecting electrical remodeling through shortening of the atrial effective refractory period.11 Inflammation and oxidative stress have been effectively attenuated through the use of both statins and omega-3 fatty acids. The use of statins has been shown to significantly reduce the incidence and recurrence of atrial fibrillation in patients undergoing cardiac surgery, which is likely, at least in part, attributable to their capacity to reduce inflammation.12 Several small trials have also demonstrated the role of omega-3 fatty acids in membrane stabilization and protection from oxidative stress, exerting both antiarrhythmic and anti-inflammatory effects. A prospective study designed by Pratt et al is currently underway to evaluate the efficacy of prescription omega-3 in the prevention of symptomatic atrial fibrillation.13 While more prospective data is needed to address the impact of such agents in the treatment of atrial fibrillation, the notion of upstream therapy is clearly important in the prevention and delay of atrial fibrillation onset. Several newer agents are currently undergoing active investigation in clinical trials. Ranolazine (a pFox inhibitor) originally marketed for refractory angina, has been shown to have an impact on the inward sodium channel and consequently an antiarrhythmic effect, preventing AF. Other investigational agents that act upstream by impacting the atrial remodeling process may modify the substrate and prevent AF. Both pirfenidone, an antifibrotic agent that inhibits collagen synthesis and downregulates cytokine-induced fibroblast proliferation, and rotigaptide (ZP123), which enhances gap junction conductance, impact AF through the atrial remodeling process. An equally important concept is the potential role that all of the aforementioned so-called non-antiarrhythmic agents play in halting structural changes following catheter ablation. In current practice, antiarrhythmic agents are typically employed for the first three months post-ablation to encourage normal sinus rhythm. Perhaps a hybrid strategy, implementing upstream therapy in addition to AAD therapy, should be considered to modify the substrate and enhance long-term post-ablation outcomes, as reversibility of structural changes lags behind that of electrical changes.14 Pharmacologic Agents for Stroke Prevention Atrial fibrillation is startlingly associated with a five-fold increase in stroke incidence.15 Current guidelines suggest the implementation of a risk stratification system, such as the CHADS2 risk index, to identify patients at high risk for stroke, in whom treatment with anticoagulation is recommended. This stroke risk classification uses a point system to assign a high versus low risk of stroke, with 1 point each for congestive heart failure, hypertension, age >75 years, and diabetes, and 2 points for a history of stroke or TIA (CHADS2). The current recommendation is that those patients with a CHADS2 score greater than or equal to 2 warrant treatment with an oral anticoagulant. The risk of thromboembolism in AF patients who are not treated with antithrombotic agents is approximately 5% per year. The prevalence of AF rises rapidly with the progression of age, as does the risk of stroke. In the Framingham study, strokes attributable to atrial fibrillation rose from 1.5% for patients between 50-59 years to 23.5% for those patients between 80-89 years.15 The occurrence of stroke is reduced approximately 60% in patients appropriately treated with antithrombotic therapy.16 Therefore, anticoagulation is a critical element in the treatment of many patients with atrial fibrillation whose risk score merits the burden and risk of warfarin therapy. Vitamin K antagonists such as warfarin confer an enormous protective benefit, but are associated with several clinical practice challenges. There is often a delayed time to effective therapy, and once established, the narrow therapeutic window frequently leads to intermittently inadequate anticoagulation. Finally, warfarin is quite cumbersome to use, having numerous food and drug interactions that impact efficacy and requiring frequent monitoring to establish therapeutic levels, which leads to a high rate of discontinuation. Thus, there is clearly a need for newer, equally effective anticoagulation agents that are more convenient to use and promote patient adherence. The challenges inherent to anticoagulation therapy with warfarin have led to the development of several new anticoagulants that target different aspects of the coagulation cascade, namely rivaroxaban and apixaban, which target factor Xa, and ximelagatran and dabigatran, which are direct thrombin inhibitors. Ximelagatran was the first direct thrombin inhibitor developed as a potential alternative to warfarin. Two large phase III non-inferiority studies, the Stroke Prevention Using an Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) III and V trials, demonstrated a fixed dose of ximelagatran to be as effective as adjusted dose warfarin in preventing thromboembolism in patients with atrial fibrillation.17 Unfortunately, due to evidence of hepatotoxicity, with serum alanine aminotransferase levels rising to greater than three times the upper limit of normal, as well as a few deaths in the ximelagatran arm owing to liver failure, the drug was withdrawn from further development in 2006. Dabigatran is a newer anticoagulant that like ximelagatran is a direct, competitive inhibitor of thrombin with evidence of rapid achievement of therapeutic effect, fixed dosing that does not necessitate monitoring of drug levels, and enhanced safety. The RE-LY trial, a non-inferiority trial, directly compared dabigatran to warfarin, with a primary outcome of stroke or systemic embolism and a primary safety outcome of major hemorrhage. A total of 18,113 patients were randomly assigned, in a blinded fashion, to two fixed doses of dabigatran versus adjusted-dose warfarin, in a non-blinded fashion. Eligibility included patients with AF and at least one other clinical criteria for stroke risk, such as prior CVA/TIA, LVEF Conclusions The current mainstays in the pharmacological management of AF are centered on rhythm and rate control strategies, as well as effective anticoagulation. Presently available antiarrhythmic agents are only modestly effective and inherently associated with a number of risk factors and toxic effects. Vitamin K antagonists, the only existing oral anticoagulation agents available for stroke prevention in patients with AF, are saddled with inconveniences and are far from ideal agents. Fortunately, pharmacologic research is actively focused on the development of novel agents with heightened efficacy and improved safety profiles. Several existing agents are also becoming increasingly important in the potential prevention of AF development. Advances in the treatment of AF are of pivotal importance in confronting this progressive public health problem.