Risk of atrial fibrillation with high-dose corticosteroids

Atrial fibrillation (AF) is the most common sustained arrhythmia observed in clinical practice. Some drugs have been associated with the onset of AF, but knowledge about the role of drugs in the development of AF is scarce. High-dose corticosteroid therapy has been associated with the development of AF, but this is mainly based on case reports. Therefore, the authors review the available data in the international literature about the cause–effect relationship between corticosteroid therapy and the onset of AF.     

Atrial-selective sodium channel block for the treatment of atrial fibrillation

The pharmacological approach to therapy of atrial fibrillation (AF) is often associated with adverse effects resulting in the development of ventricular arrhythmias. As a consequence, much of the focus in recent years has been on development of atrial-selective agents. Atrial-selective sodium channel blockers have recently been shown to exist and be useful in the management of AF. This review summarizes the available data relative to current therapies, focusing on our understanding of the actions of atrial selective sodium channel blockers in suppressing and preventing the induction of AF and electrophysiological properties that confer atrial-selectivity to these antifibrillatory drugs.     

Drug-induced atrial fibrillation

Atrial fibrillation (AF) is a common cardiac arrhythmia that is associated with severe consequences, including symptoms, haemodynamic instability, increased cardiovascular mortality and stroke. While other arrhythmias such as torsades de pointes and sinus bradycardia are more typically thought of as drug induced, AF may also be precipitated by drug therapy, although ascribing causality to drug-associated AF is more difficult than with other drug-induced arrhythmias. Drug-induced AF is more likely to occur in patients with risk factors and co-morbidities that commonly co-exist with AF, such as advanced age, alcohol consumption, family history of AF, hypertension, thyroid dysfunction, sleep apnoea and heart disease. New-onset AF has been associated with cardiovascular drugs such as adenosine, dobutamine and milrinone. In addition, medications such as corticosteroids, ondansetron and antineoplastic agents such as paclitaxel, mitoxantrone and doxorubicin have been reported to induce AF. Whether bisphosphonate drugs are associated with new-onset AF remains controversial and requires further study. The potential contribution of specific drug therapy should be considered when patients present with new-onset AF.     

Atrial fibrillation. The therapeutic options

Atrial fibrillation (AF) is a common cardiac arrhythmia which is particularly prevalent among the elderly. In patients with AF of recent onset, restoration of sinus rhythm may be feasible and this can be achieved by DC cardioversion, or by the use of one of a number of drugs including amiodarone, flecainide or propafenone. Neither digoxin nor the calcium antagonists facilitate the restoration of sinus rhythm. Recurrence of AF is common after successful cardioversion and, although long term antiarrhythmic drug therapy may help to maintain sinus rhythm, all such drugs are potentially toxic and can have important proarrhythmic actions. In patients with chronic AF, restoration of sinus rhythm is rarely possible and treatment is directed towards control of the ventricular response rate, which may be achieved with digoxin and/or a rate-limiting calcium antagonist such as verapamil or diltiazem; beta-blockers may also be used although they appear to impair effort tolerance. In addition, long term anticoagulation may be indicated to reduce the risks of systemic embolisation, even in patients with 'nonrheumatic' AF; antiplatelet drugs are of no apparent value in this context. A minority of patients present with AF associated with ventricular pre-excitation; in these individuals both digoxin and the calcium antagonists are contraindicated and the ventricular response rate should be controlled with flecainide, amiodarone or propafenone.     

Pharmacologic targets for atrial fibrillation

Despite advances in treatment, atrial fibrillation (AF) remains the most common arrhythmia in humans. Antiarrhythmic drug therapy continues to be a cornerstone of AF treatment, even in light of emerging non-pharmacologic therapies. Conventional antiarrhythmic drugs target cardiac ion channels and are often associated with modest AF suppression and the risk of ventricular proarrhythmia. Ongoing drug development has focused on targeting atrial-specific ion channels as well as novel non-ionic targets. Targeting non-ionic mechanisms may also provide new drugs directed towards the underlying mechanisms responsible for AF and possibly greater antiarrhythmic potency. Agents that act against these new targets may offer improved safety and efficacy in AF treatment.     

Pharmacologic targets for atrial fibrillation

Despite advances in treatment, atrial fibrillation (AF) remains the most common arrhythmia in humans. Antiarrhythmic drug therapy continues to be a cornerstone of AF treatment, even in light of emerging non-pharmacologic therapies. Conventional antiarrhythmic drugs target cardiac ion channels and are often associated with modest AF suppression and the risk of ventricular proarrhythmia. Ongoing drug development has focused on targeting atrial-specific ion channels as well as novel non-ionic targets. Targeting non-ionic mechanisms may also provide new drugs directed towards the underlying mechanisms responsible for AF and possibly greater antiarrhythmic potency. Agents that act against these new targets may offer improved safety and efficacy in AF treatment.     

Novel anti-arrhythmic drugs for atrial fibrillation management

Atrial fibrillation (AF) is a highly prevalent arrhythmia and responsible for significant morbidity, mortality and health care cost. Considerable work has been performed to improve medical options but treatment success still remains suboptimal. The use of conventional anti-arrhythmic agents has been limited by potentially fatal ventricular proarrhythmia. Thus, novel drug targets have been characterised and are currently being tested in experimental and clinical studies. The atrially (but not ventricularly) expressed ion channel subunit Kv1.5 (conducting the ultra-rapid delayed rectifier, I(Kur)) is a prominent candidate. A variety of drugs that inhibit this current is being evaluated. Human experience with these agents is limited. Atrial expression of connexin 40 and downregulation of this protein in AF turn its modulation into a potential therapeutic approach. The acetylcholine-activated current (I(KACh)) is another novel candidate target for drug therapy. The constitutively active form of this current is increased in human AF and pharmacological inhibition might be of therapeutic value. Certain drugs have I(KACh) blocking properties, but as for I(Kur)-blockers none to date has shown pure selectivity for this current. This article summarizes relevant aspects of the cellular electrophysiology of AF and reviews the actions of pharmacological agents presently available or in development as novel anti-arrhythmic therapy.     

Prevention of atrial fibrillation complications with antiarrhythmic drugs: still an unmet need in clinical practice

Atrial fibrillation (AF) is the most common arrhythmia and is associated with substantial cardiovascular morbidity and mortality, with stroke being the most important complication. Present drugs used for the therapy of AF (antiarrhythmic drugs and anticoagulants) have major intrinsic limitations, including moderate efficacy and increased risks of life-threatening proarrhythmic effects and bleeding complications. There is great diversity in the pathophysiological substrate, clinical presentation and prognosis of AF. Therefore, assessing the risk of AF-associated stroke and choosing the most appropriate antithrombotic therapy, selecting in which patient to pursue a rhythm- versus a rate-control approach, and when to consider nonpharmacological therapies, such as catheter ablation, remain difficult decisions in most patients. Antiarrhythmic drugs like dronedarone have the potential to prevent AF-related complications like stroke and provides clinicians with a new option when choosing antiarrhythmic therapy. However, major concerns with dronedarone are its low efficacy for AF and lack of evidence for effectiveness in patients failing other antiarrhythmic agents. New oral anticoagulants like dabigatran have important safety advantages versus traditional vitamin-K antagonists in preventing stroke, but they do not arrest or prevent AF. Thus, there is still a clear unmet need for new and more effective antiarrhythmic drugs that prevent AF-related complications. Hopefully such new drugs will lead to improved patient management in the future.     

Current management of symptomatic atrial fibrillation

Atrial fibrillation (AF) is the commonest arrhythmia. It presents in distinct patterns of paroxysmal, persistent and chronic AF, and patient management aims differ according to the pattern. In paroxysmal AF, drug treatment with beta-blockers, class Ic and class III agents reduce the frequency and duration of episodes. In persistent AF (recent onset, non-paroxysmal), early cardioversion with either pharmacological agents or by direct current (DC) cardioversion should be actively considered, in those patients who are suitable. Patients most likely to cardiovert and remain in sinus rhythm include those with duration of AF of <1 year, an acute reversible cause, left atrial diameter <50 mm and good left ventricular function on echocardiography. Recent data show that maintenance of sinus rhythm after successful cardioversion is enhanced by the use of class III drugs including amiodarone and dofetilide. In chronic or permanent AF, management is aimed at controlling the ventricular rate response with combinations of digoxin, beta-blockers and calcium antagonists with atrio-ventricular nodal activity (diltiazem and verapamil). There is some debate about the prognostic significance of AF. Certainly AF is associated with an excess mortality but this is largely accounted for by its association with serious intrinsic heart disease and the thrombo-embolic complications of the arrhythmia. Atrial fibrillation is a common default arrhythmia for the sick heart.     

ELECTROPHYSIOLOGICAL PROPERTIES OF THE FIBRILLATING ATRIUM: IMPLICATIONS FOR THERAPY

1. Atrial fibrillation (AF) is the most commonly occurring cardiac dysrhythmia and remains a challenge to medical therapy. Although the disorder has been recognized for over 100 years, surprisingly very little is understood about its pathophysiology. Over the past decade, a variety of experimental and animal models of AF have been developed and these have provided insights into the mechanism of AF. 2. The pathophysiology of AF is complex. Atrial fibrillation can be caused either by a single source of very rapid impulses or, in the majority of cases, by multiple random re-entering wavelets. The notion that AF may be initiated by a single rapid firing focus and the perpetuation of AF may be partly dependent on macro re-entry around the natural atrial orifices provides a new potential curative therapy for AF by radiofrequency ablation. 3. Shortening of atrial wavelength, either by slow atrial conduction velocities, short atrial refractory periods or both, seems to predispose to development of intra-atrial re-entry and, thus, AF. The functional mechanism by which anti-arrhythmic drugs terminate AF appears to be by prolonging the wavelength and decreasing the number of re-entry wavelets. These understandings are important for the future development of effective anti-arrhythmic agents against AF. 4. The presence of a short and variable excitable gap during AF may be potentially important for termination of AF by pacing. 5. New insights are being gained into the potential role and mechanism of electrical remodelling of the atrium due to AF. Repeated induction of AF by rapid atrial pacing leads to a shortening of atrial refractoriness with loss of rate adaptation, which favours the induction and maintenance of AF. These electrophysiological changes were assumed to occur during repeated AF and to facilitate the generation of multiple re-entrant wavelets. These data suggest that prompt restoration of sinus rhythm and new novel therapy that prevents or diminishes electrical remodelling may promote maintenance of sinus rhythm after successful cardioversion.     

A comprehensive insight of novel antioxidant therapies for atrial fibrillation management

Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and is associated with decreased quality of life, and increased mortality and morbidity from stroke and thromboembolism. The underlying mechanisms involved in the development of AF have yet to be fully elucidated. However, once initiated, AF tends to self-perpetuate, due to structural and electrical remodeling in the atria. Currently, therapies for AF, such as, antiarrhythmic drugs and catheter ablation, have significant limitations. Antiarrhythmic drugs target one or a few cardiomyocyte ion channels and have considerable pro-arrhythmic and non-cardiac adverse effects. On the other hand, catheter ablation is an expensive treatment associated with measurable complications and its long-term success in management of AF is controversial. Current consensus guidelines recommend β-blockers, amiodarone, digitalis glycosides and non-dihydropyridine calcium channel antagonists or a combination of them for AF treatment, but bradycardia and heart block may occur as an unwanted effect. On the other hand, antioxidant agents have recently attracted much interest in AF treatment because they have been associated with a reduction in lone AF and post-operative AF, and in some cases, with a decrease in long-term hospitalization time. Moreover, antioxidants can be considered a cheap treatment with reduced side effects. In this review, we will comprehensively review the effects and the mechanisms of action of several antioxidant agents, such as vitamin E, ascorbic acid, carotenoids, statins, omega-3 polyunsaturated fatty acids and N-acetylcysteine.     

Dofetilide: a new drug to control cardiac arrhythmia

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Mortality, and especially morbidity caused by AF, are major and growing health problems in the western world. AF is strongly associated with arterial hypertension, congestive heart failure, valvular heart disease, ischaemic heart disease, and with prevalence increasing with age. A variety of drugs have been used to terminate or prevent AF but, as many antiarrhythmic agents have the potential life-threatening pro-arrhythmia, safety problems remain. Dofetilide (Tikosyn, Pfizer), a new Vaughan Williams class III antiarrhythmic agent, has been developed and approved for the treatment of AF. In contrast to most antiarrhythmic agents, the development programme included two safety studies in high-risk patients. Dofetilide is effective and safe when an elaborate procedure for dosing is implemented. Along with amiodarone and betablockers, dofetilide is the only antiarrhythmic drug, which is recommended by guidelines for the treatment of AF in a wide range of patients.     

Pharmacological Management of Atrial Fibrillation following Cardiac Surgery

Atrial fibrillation (AF) is the most common complication following coronary artery bypass graft surgery (CABG). Post-CABG AF occurs most commonly on the second postoperative day and declines in incidence thereafter. A number of risk factors have been found to be associated with a higher frequency of post-CABG AF. These risk factors include advanced age, a prior history of AF, hypertension, and heart failure. Postoperative complications--including low cardiac output, use of an intra-aortic balloon pump, pneumonia, and prolonged mechanical ventilation--are also associated with higher rates of post-CABG AF. Post-CABG AF increases the risk of stroke, and the length and cost of hospitalization. Prophylactic administration of conventional beta-adrenoceptor antagonists (beta-blockers) or sotalol produces a consistent and significant reduction in the incidence of post-CABG AF; however, results with prophylactic amiodarone or magnesium are less consistent. Termination of post-CABG AF, once it occurs, can be accomplished with a number of antiarrhythmic agents. Ibutilide has been the most widely studied agent for this indication. Sotalol is not indicated for cardioversion of AF and has not been studied in the post-CABG setting. Electrical cardioversion and biatrial pacing have also been used to terminate post-CABG AF. Ventricular rate is best controlled with beta-blockers and calcium channel antagonists. Esmolol has a rapid onset of action and is easily titrated to effect. Digoxin can control the ventricular rate, but has a slow onset of action. There are limited data available to guide decisions regarding the optimal management of post-CABG AF.     

Dofetilide: a new drug to control cardiac arrhythmia

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Mortality, and especially morbidity caused by AF, are major and growing health problems in the western world. AF is strongly associated with arterial hypertension, congestive heart failure, valvular heart disease, ischaemic heart disease, and with prevalence increasing with age. A variety of drugs have been used to terminate or prevent AF but, as many antiarrhythmic agents have the potential life-threatening pro-arrhythmia, safety problems remain. Dofetilide (Tikosyn^®, Pfizer), a new Vaughan Williams class III antiarrhythmic agent, has been developed and approved for the treatment of AF. In contrast to most antiarrhythmic agents, the development programme included two safety studies in high-risk patients. Dofetilide is effective and safe when an elaborate procedure for dosing is implemented. Along with amiodarone and β-blockers, dofetilide is the only antiarrhythmic drug, which is recommended by guidelines for the treatment of AF in a wide range of patients.     

Atrial fibrillation: the nonpharmacologic strategy

Pharmacologic treatment has been used for decades for conversion and prevention of recurrent atrial fibrillation (AF). But the use of antiarrhythmic drugs is associated with substantial side effects and mortality in some patients. Accordingly, it is not surprising that nonpharmacologic techniques have been developed for the management of AF, including the use of atrial defibrillators, atrial pacing methods, and several surgical and radiofrequency catheter ablation procedures. The atrial defibrillator has been found to detect and treat atrial and ventricular arrhythmias appropriately, with successful termination of spontaneous AF through low energy shocks. Although these devices are promising, the factor which limits their widespread use is not safety or efficacy, but patient comfort. Several studies suggest that atrial-based cardiac pacing may have a beneficial effect in decreasing and preventing AF episodes in patients with sick sinus syndrome. Palliative ablative procedures also available for the treatment of atrial fibrillation include AV junctional modification and AV nodal ablation with permanent pacing, the latter technique being associated with improvements in ejection fraction. Two potentially curative procedures are the surgical MAZE and endocardial catheter ablation. These techniques are based on placing strategically located lesions in the atrium to disrupt the conduction pathway(s). Recent studies have focused on ablative therapies aimed at the area of the pulmonic veins. The main therapy for maintaining sinus rhythm after conversion is predominantly pharmacologic. Similarly, in the absence of heart block, if conversion to sinus rhythm is not successful, pharmacologic modalities may be required to control ventricular rate. In any case, planning a treatment regimen for the management of AF should include evaluation of the risks inherent in the use of various drugs as well as more invasive strategies.     

Levocabastine. A review of its pharmacological properties and therapeutic potential as a topical antihistamine in allergic rhinitis and conjunctivitis.

Levocabastine is a long acting, highly potent and selective histamine H1-receptor antagonist, which has been developed for nasal and ocular administration. In controlled trials performed to date levocabastine was effective and well tolerated in the treatment of allergic rhinitis and allergic conjunctivitis. Comparative studies have demonstrated that levocabastine is superior to placebo and at least as effective as sodium cromoglycate (cromolyn sodium) in alleviating symptoms associated with seasonal allergic conditions. Although levocabastine appears to be less effective than the topical corticosteroid beclomethasone with regard to relieving runny and blocked nose, further comparative trials between these 2 agents would be desirable. Similar to other antihistamines, levocabastine provides minimal relief of nasal blockage, but this symptom is believed to be mediated by receptors other than histamine H1. The prompt onset of antiallergic activity after application differentiates levocabastine from the reference topical antiallergic, sodium cromoglycate, which has an onset of efficacy characterised by a lag period, thereby necessitating maintenance treatment. The incidence of adverse effects associated with levocabastine therapy is low and is similar to that observed with placebo and sodium cromoglycate. Levocabastine provides prophylactic protection as well as acute relief from nasal and ocular symptoms in patients with seasonal allergic disorders. With the ever increasing trend towards topical therapy for the treatment of allergic rhinitis and allergic conjunctivitis, levocabastine is a useful addition to the range of drugs currently available. Possible avenues for additional research should include determining whether the antiallergic efficacy of topical levocabastine is superior to that of oral agents such as astemizole and terfenadine, and whether topical therapy is indeed preferred, considering the relative ease of administration of effective oral antiallergic agents.     

Ipratropium bromide: a review of its pharmacological properties and therapeutic efficacy in asthma and chronic bronchitis

Ipratropium bromide is an anticholinergc bronchodilator administered by inhalation. Although producing bronchodilation in most patients with obstructive airways disease, it is somewhat less effective than beta 2-adrenoceptor agonist drugs such as salbutamol or fenoterol in patients with asthma, but is at least as effective as these agents in bronchitis. As with the beta 2-adrenoceptor agonists, the onset of maximum effect with ipratropium (about 1.5 to 2 hours) is slower than with isoprenaline (although significant bronchodilation usually occurs within seconds or minutes of ipratropium inhalation), and the duration of effect (about 4 to 6 hours) is longer. Studies of concomitant use of ipratropium and other agents such as beta 2-adrenoceptor agonists, theophylline, or sodium cromoglycate, have usually shown a greater response in many patients than with single drug therapy, as might be expected from the different mechanisms of action of these groups of drugs. Usual inhaled doses of ipratropium were well tolerated in all studies. Ipratropium thus appears to be a suitable alternative to beta 2-adrenoceptor agonist drugs in patients not fully responding to these agents, and combined therapy with ipratropium and other bronchodilating drugs may prove to be an important area of use in patients failing to respond adequately to a single drug regimen. (nevertheless, in asthma patients in whom a 'non-responsive' state is developing, initiation of corticosteroid therapy should not be delayed). Ipratropium may also be useful in the occasional patient in whom side effects such as palpitations or tremor are troublesome with usual inhaled doses of beta 2-adrenoceptor agonists.     

Clinical studies, the interests and limits of using dabigatran in atrial fibrillation

Atrial fibrillation (AF) is the most frequent cardiac arrhythmia, especially in older people. This condition is associated with an increased risk of stroke, and long-term anticoagulation treatment is therefore needed. Vitamin K antagonists are effective in reducing the risk of stroke but optimal use of these drugs remains difficult. The development of new oral anticoagulant drugs is therefore highly relevant. Dabigatran is an oral direct thrombin inhibitor. Its prodrug, dabigatran etexilate, is marketed under the name of Pradaxa and was initially approved for the prevention of thromboembolic events in major orthopedic surgery. It has been recently approved for stroke prevention in patients with AF. The purpose of this paper is to review--in light of current knowledge--the interests and limits of using dabigatran etexilate in AF. Briefly, dabigatran etexilate is not inferior to warfarin in AF. However many questions remain unanswered, including questions related to the concomitant use of dabigatran etexilate and acetylsalicylic acid, the possible increased risk of myocardial infarction and the need for drug monitoring.     

Vernakalant hydrochloride for the treatment of atrial fibrillation

Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. Rhythm control strategy for AF is limited by drug toxicity and side effects, and recent trials have shown that this strategy is not superior to a rate control one. New antiarrhythmic drugs, free of undesired effects, would enhance rhythm control, with the possibility of sinus rhythm restoration and maintenance. A promising find in the search for new antiarrhythmic therapies is atrial-tissue specific ion channels. The findings that the ultrarapid delayed rectifier (I_Kur) and the inwardly rectifying, acetylcholine-regulated current (I_K-Ach) exist in atrial but not ventricular tissue increase the probability that atrioselective drugs without ventricular proarrhythmic toxicity can be developed for treatment of patients with AF. There are also other potential targets for atrial-selective therapy: transient outward current (I_to), rapidly and slowly activating delayed rectifier currents (I_Kr and I_Ks), atrial sodium current (I_Na) and atrially expressed connexins. New drugs under development with promising atrial-selectivity include: tertiapin, NIP-142, NIP-141, JTV-519, AVE0118, AVE1231, DPO-1, AZD7009 and many others. Among such new agents, vernakalant hydrochloride is currently in an advanced phase of development and has already been evaluated in clinical trials. In this overview, we describe the history and current state of developmental process of the drug, as well as its mechanism of action and influence on electrophysiological parameters. Vernakalant seems to be effective in terminating recent-onset AF, but is not efficacious in long-lasting AF and atrial flutter. The drug may be relatively free of proarrhythmic effects, and exerts a protective effect on ventricular tissue and ventricular repolarization. It is expected that the intravenous formulation will soon be approved for the pharmacological termination of recent-onset AF.