Review Article

Recent advances in pharmacotherapy of atrial fibrillation J. Singh, J.S. Braich

ABSTRACT

Atrial fibrillation (AF) is the most common sustained associated with increased Department of Pharmacology morbidity and mortality. Efficacy and safety of currently employed antiarrhythmic drugs Pt. BD Sharma PGIMS, (AADs) continue to be less optimal in AF. Development of newer AADs has recently been Rohtak-124 001, India. made possible through a greater understanding of electro-pathophysiology of AF. Highly specific drugs acting on atria are currently being explored, although there is little data RReceived:eceived: 14.12.2008 RRevised:evised: 17.04.2009 available on effectiveness of atrial specific agents in maintaining . Combining AAccepted:ccepted: 01.07.2009 AADs and non-AADs such as converting enzyme inhibitors (ACEIs) and angiotensin blockers (ARBs) may increase effectiveness of AADs in patients with DDOI:OI: 10.4103/0253-7613.56064 AF. Controlled clinical trials are required to precisely define the efficacy of single agents versus various combinations in maintaining sinus rhythm in patients with AF. This review CCorrespondenceorrespondence to:to: describes some of the most promising therapeutic approaches that may overcome some Dr. Jarnail Singh of the limitations of drugs used at present for the management of AF. E-mail: [email protected] KKEYEY WWORDS:ORDS: Atrial fibrillation, antiarrhythmic drugs, angiotensin-converting enzyme inhibitors, angiotensin II type1 receptor blockers, normal sinus rhythm

Introduction and electrical remodeling.[4,5] Experimental evidence suggests that RAAS activates mitogen activated protein kinase Atrial fibrillation (AF) is a common and distressing (MAPK) causing proliferation of fibroblast and hypertrophy of arrhythmia with a prevalence of about one per cent in adult US myocytes. [6] The resulting atrial scarring causes prolongation of [1] population. It is a major risk factor for stroke and mortality in refractory period and maintenance of arrhythmogenic substrate [2] North America. The prevalence of AF increases with age such in the atrium resulting in AF.[7] Oxidative stress has recently that eight per cent of people above 80 years of age have AF. The been reported to be implicated in the pathophysiology of AF.[8] life time risk for development of AF is one in four for men and Additionally, stretch receptor antagonism, sodium-calcium women aged 40 years and older. Projected data from population exchanger blockade, late inhibition and gap based studies in the US suggests that by 2050 a 2.5 to three junction modulation have also been shown to be anti-arrhythmic [1] fold upsurge in the number of adults with AF is expected. mechanisms.[9] However, even these projections may represent conservative estimates because of undiscovered silent AF. The high lifetime Pharmacotherapy of Atrial Fibrillation risk for AF and increased longevity underscore the important In acute AF the precipitating cause which could be. fever, public health burden posed by it. presently cost pneumonia, intoxication, thyrotoxicosis, pulmonary approximately one per cent of the health care budget in the US, emboli, CHF or pericarditis should be treated first.[10] In severe UK and France. Because of the clinical importance and lack of cases electrical cardioversion is the treatment of choice, highly satisfactory management approaches, AF is a subject otherwise slowing of the ventricular rate should be the initial of active clinical and research efforts. This review describes therapeutic goal by using β-blockers, blockers some of the most promising approaches to new therapies of AF. (CCBs) or digitalis.[10] Conversion to a sinus rhythm may be Pathophysiology of Atrial Fibrillation attempted using AADs like , , etc. Direct current (DC) cardioversion is the most effective method AF has a multiplicity of causes ranging from genetic for restoring a sinus rhythm. To prevent recurrence of AF, to degenerative but and failure are quinidine, flecainide, , , or epidemiologically most prevalent conditions associated with should be used.[10] Ablation therapy or MAZE it. Atrial structural remodeling creates a substrate for AF.[3] procedure for cure of AF are other options.[10] At present both Renin- angiotensin-aldosterone system (RAAS) and Angiotensin rate control and anticoagulation are recommended in elderly

II type1 receptor (AT1) have been implicated in atrial structural asymptomatic patients whereas in younger patients with

Indian J Pharmacol | Aug 2009 | Vol 41 | Issue 4 | 153-157 153 Singh and Braich: Advances in pharmacotherapy of atrial fi brillation symptomatic recurrent AF pulmonary vein isolation ablation blocker inhibiting the ultra rapid component of the delayed rectifier [9] is the treatment of choice. (IKur) which is present only in the atria and the transient outward

Conventional AADs are often used for conversion and current (Ito) that is found more prominently in the atria. In animals, long term suppression of AF in treatment, however, in limited AVE0118 prolonged atrial refractoriness, notably in electrically use because of the modest efficacy, tolerability and potential remodeled atria, prolonged atrial wave length in a dose dependant for serious ventricular proarrhythmia and organ toxicity. The fashion, reduced AF ability to induce and acutely converted efficacy of AADs in maintaining normal sinus rhythm (NSR) is persistent AF to sinus rhythm without altering the QT interval.[19] disappointing because most of the patients have recurrent AF AZD 7009: AZD7009 is a mixed blocker, despite treatment. Many trials with different AADs (CAST and blocking the delayed rectifier potassium current (IKr), SWORD) have shown increased mortality in the presence of sodium current (INa) and IKur, with eletrophysiological effects structural heart disease.[11-12] The utility of pharmacotherapy to predominantly on the atrial tissue.[20] Both an I.V. formulation for restore and maintain NSR has been questioned in recent trials acute conversion and oral formulation for long term treatment which do not show a mortality benefit.[13-14] Therefore, there is of AF are under phase II trials of development. It shows only a still a need for more effective and safer drugs to promote NSR. small effect on the ventricular effective refractory period (ERP) and QT interval.[21] In animal models AZD 7009 was effective Antiarrhythmic Drugs Under Investigation for cardioversion of AF and atrial flutter. A human study had Atrial selective agents shown that 70% of the patients with AF receiving a high dose An attractive prospect for pharmacotherapy of AF is the AZD 7009 were cardioverted at two hours with no cases of [22] introduction of agents with selective affinity to ion channels TdP. However, the presence of mild prolongation of the QT interval, probably mediated by ventricular I current, suggest specifically involved in atrial repolarization; the so called kr atrial repolarization delaying agents. Presently there are some likely risk of TdP. several AADs with this mode of action under preclinical and XEND 0101: It blocks a single atrial specific membrane [9] clinical development. The development of AADs with selective current. Success of such agents depends critically on the atrial channel blocking profile has been made possible by a greater eletrophysiological selectivity, freedom from cardiac adverse understanding of the pathophysiology of AF.[15] The finding that effects and general safety. the ultra rapid delayed rectifier (IKur) exists in the atria but not in Amiodarone congeners ventricular tissue has offered the prospect of developing atrial : It is a non-iodinated amiodarone benzofurane selective drugs devoid of ventricular proarrhythmic toxicity. with many antiarrhythmic properties corresponding to those of [23] These atrial selective agents include IKur blockers, atrial selective amiodarone. A change in molecular structure leads to decline sodium channel blockers, muscarinic (M2) receptor blockers and in adverse effects on and lung function while retaining [16] five-HT4 receptor blockers. the electro-physiological properties of amiodarone. In addition, Vernaklant (RSD 1235) is in the most advanced phase the non specific sympatholytic (α and β-receptor blocking) and of investigation and its (IV) formulation has recently been Ca2+ channel blocking actions of dronedarone confer a potential recommended for approval for pharmacological conversion of for ventricular rate control in AF recurrence. Dronedarone AF.[9] It is relatively atrial specific, the most completely studied inhibits multiple ion channels in the heart including sodium, atrial specific agent to date, AAD with mild voltage and frequency potassium and calcium currents (L-type), the rapid delayed [17] dependant sodium channel block as well as IKur and Ito block. rectifier and acetylcholine-activated potassium currents. In One phase II study with I.V. formulations has been published guinea pig ventricular myocytes dronaderone blocks sodium [18] 2+ (CRAFT) in which 56 patients with AF of 3-72 hours were current (INa), L-type Ca current and several potassium currents randomized to RSD 1235 dose group or placebo. Thirty minutes (IKr, IKs, IKi). The sodium channel blocking activity has also been after infusion AF was terminated in 61% of the patients in the demonstrated in human atrial myocytes.[23] In a rabbit model higher dose drug group compared with five per cent in the placebo comparing long term oral administration of oral dronedarone group. The drug did not prolong QTc or QRS intervals or produce with amiodarone, both the drugs increased action potential torsade de pointes (TdP). Adverse effects were rare and mild. duration (APD) and effective refractory period (ERP) of the Preliminary results have shown that 38% of patients receiving atrial tissue to a similar degree. the drug were cardioverted versus four per cent in the control Dronedarone has been widely studied with several group. ACT-3 was a second pivotal trial that enrolled 276 patients completed trials related to AF therapy. In a pooled analysis and found a 41% conversion rate for the drug group versus four of results from two international phase III trials (EURIDIS and per cent for the placebo group. For recent onset AF, 52% of the ADONIS) of dronedarone in maintenance of sinus rhythm in patients converted versus four per cent in the placebo group. The 1250 patients, with either paroxysmal (70%) or persistent drug was well tolerated and no TdP was observed. A separate AF, the first year data showed that compared with placebo trial on postoperative patients is also ongoing (ACT-2). When the time of AF recurrences was 2.3-2.7 times longer after compared with the placebo I.V., appears to be both treatment with dronedarone 400 mg twice daily. Safety data effective and safe for acute conversion in patients with AF.[18] were promising but patients with a heart failure were excluded However, its efficacy in patients with atrial flutter is uncertain. from the trials.[24] A phase II study, DAFNE, enrolled patients An oral formulation of Vernakalant is under development for long undergoing cardioversion for AF with primary end point as term maintenance of NSR following cardioversion. time to AF recurrence; and a significant increase in time before AVE0118: AVE0118 is an atrial selective AF recurrence was seen with dronedarone, in dose 800 mg/d,

154 Indian J Pharmacol | Aug 2009 | Vol 41 | Issue 4 | 153-157 Singh and Braich: Advances in pharmacotherapy of atrial fi brillation group (60 days versus five days in placebo group). Higher doses AF in a canine model of atrial ischemia.[34] Identification of were not effective. At a dose 800 mg/d the QT interval was not those patients who will benefit from improving gap-junction prolonged and there was no evidence of ocular, pulmonary conduction will require further study. [25] or thyroid toxicity. A multinational study ATHENA is being Serotonin (5-HT4) receptor antagonists: According to conducted in over more than 4000 high risk patients with recent data 5-HT4 receptor antagonists could be promising AF for further data on efficacy and safety of dronaderone; drugs in patients with AF as infusion of serotonin induces sinus with the primary end point all cause mortality combined with and other atrial tachyarrhythmias including AF. [26] cardiovascular hospitalization. Additional studies are being Atrial-specific 5-HT4 receptor subtypes have been observed and conducted to evaluate use of dronedarone in patients with can be targeted pharmacologically without potentially inducing implantable cardioverter defibrillators. ventricular side effects. Serotonin 5-HT4 receptor antagonists, currently in development, include RS-100302, SB-207266 and Celivarone (SSR 149744C) CVT-150.[35] It is another non-iodinated amiodarone derivative Angiotesin converting enzyme inhibitors and undergoing phase II human trials. It exhibits eletro-physiological angiotensin receptor blockers: ACEIs or ARBs may prevent and hemodynamic properties characteristic of dronedarone.[27] AF in some patients. Angiotensin system inhibition appears ATI-2042: In this congener, iodination has been retained to protect against AF in patients with hypertension, LV in phase II trials to assess the ability of the compound to hypertrophy, post MI with LV dysfunction and chronic CHF. The suppress AF in patients with pacemakers. There is much effect is clearest in patients with LV systolic dysfunction and evidence that amiodarone is a desirable model for development CHF.[36] Kishley demonstrated that administration of ACEIs or of antiarrhythmic compounds.[16] ARBs was associated with overall 18% risk reduction in new : There is increasing data indicating that onset of AF across the trials and 43% risk reduction in patients [37] amiodarone and its congeners i.e. dronedarone and ranolazine with heart failure. Kalus demonstrated that administration of have the potential to variably increase ventricular repolarization ACEIs or ARBs for at least three months prior to cardiothoracic [38] by ionic mechanisms such that they are unlikely to provoke early surgery was associated with reduction in postoperative AF. There are several potential mechanisms by which these drugs depolarization produced by IKr blockers and thus have a lower risk of inducing TdP.[16] may reduce AF. these include direct modulation of ion channels, hemodynamic improvement, electrical structural remodeling, Other antiarrhythmic drugs antifibrotic, anti-inflammatory, antiplatelet, antiproliferative : It is a selective Class-III AAD that blocks both and reducing Ca2+ influx and oxidative stress etc.[39] These rapid (I ) and slow (I ) components of the delayed rectifier Kr Ks drugs appear to have promising use following cardioversion, [28] potassium current. It prolongs cardiac APD and refractory but require further study. period. Its long half life (up to four days) allows one daily dosing Statins: Statins appear to have a role in prevention of AF. and limits major fluctuations in blood concentration. Several In a randomized trial (ARMYDA-3) enrolling 200 statin-naïve randomized, placebo controlled clinical trials have demonstrated patients to atorvastatin or placebo before cardiac surgery, the efficacy of azimilide in prolonging symptom free interval in atorvastatin treated group showed 61% reduction in risk of [29] patients with AF or atrial flutter. In meta- analysis, azimilide postoperative AF.[40] Bhavnani et. al demonstrated that among in dose 10mg and 125 mg demonstrated greater efficacy a cohort with implantable cardioverter defibrillators (ICDs) at when compared with placebo in prolonging the symptomatic high risk of cardiac arrhythmias, statin therapy was associated [30] arrhythmia free interval. However the effects of the drug with with reduction in AF and atrial flutter (AF/AFL); adjusted hazard respect to maintaining sinus rhythm remain unclear. ratio was less for the development of AF/AFL with shock therapy : An antianginal agent possessing multiple than without shock therapy.[41] ion channel effects including blockade of transient outward Fish oil (Omega-3PUFA): There is an inverse epidemiological [31] current Ito, in addition to IKr, IKs, IKur, IK-ATP and even I Na also association between fish consumption and incidence of AF, with causes reverse, rate dependant QT interval prolongation. In a 31% reduction in AF for elderly US adults who eat fish more a multicenter, double blind, randomized placebo controlled than five times a week compared those with less than once study in 175 patients with symptomatic recent onset AF a month.[42] This protective effect was not found by another or atrial flutter, 41-51% of patients receiving tedisamil group using the Rotterdam data base.[43] One trial randomized (0.4 or 0.6 mg/kg I.V.) converted to sinus rhythm in an average 160 patients to 2g/d poly-unsaturated fatty acids or placebo time of 35 minutes with two instances of (1.8%) of possible before coronary artery bypass graft. There was 54% reduction proarrhythmia.[32] in post-operative AF in drug group.[44] There is now a large Rotigaptide (ZP 123): It is a specific gap-junction -facilitating ongoing prospective trial of omega-3 PUFA in patients with drug. Gap junctions are specialized pores that coordinate paroxysmal or persistent AF. cell-to-cell transmission of electrical impulses essential for Fibrosis is a feature of mechanical remodeling in long synchronized contraction.[33] Gap-junction modulation may standing AF, particularly when associated with heart failure. present a novel therapeutic target in some forms of currently Pirfenidone, an antifibrotic drug, significantly reduced being studied in a phase II trial on rotigaptide. Rotigaptide arrhythmogenic atrial remodeling and AF vulnerability in a has been demonstrated to reduce AF vulnerability in a canine dog model of heart failure.[45] Ozaydin et al. demonstrated that model of chronic mitral regurgitation but not in a ventricular N-acetycysteine treatment decreased incidence of postoperative tachy-pacing model that results in atrial fibrosis. It also reduces AF in 115 patients that undervent coronary artery bypass or

Indian J Pharmacol | Aug 2009 | Vol 41 | Issue 4 | 153-157 155 Singh and Braich: Advances in pharmacotherapy of atrial fi brillation valve surgery.[8] Mutations in the connexin-40 protein have 5. Healey JS, Morillo CA, Connolly SJ. Role of rennin angiotensin aldosterone system recently been identified in sporadic cases of human AF and gap in atrial fi brillation and cardiac remodeling. Curr Opin Cardiol 2005;20:31-7. 6. D’Amora A, Black MJ, Thomas WG. The angiotensin II type 2 receptor causes junctions are an emerging target for AF.[46] constitutive growth of cardiomyocytes and does not antagonize angiotensin II Combined Therapy in Atrial Fibrillation Management type 1 receptor mediated hypertrophy. Hypertension 2005;46:1347-54. 7. Aime-Sempe C, Folliguet T, Rucker-Martin C. Myocardial cell death in fi brillation Recently it has been shown that sinus rhythm achieved and dilated human right atria. J Am Coll Cardiol 1999;34:1577-86. after conversion of AF may be prolonged by certain non- 8. Ozaydin M, Peker O, Erdogan D, Kapan S, Turker Y, Varol E. N-Acetyl cysteine for antiarrhythmic drugs such as ACEIs, corticosteroids, prevention of post operative atrial fi brillation: A prospective, randomized, placebo controlled pilot study. Eur Heart J 2008;29:625-31. aldosterone antagonists, statins and omega 3-PUFA. Rate of AF 9. Savelieva I, Camm J. Antiarrhythmic drug therapy for atrial fi brillation: Current recurrence was lower when amiodarone combined with ACEI anti- arrhythemic drugs, investigational agents and innovative approaches. than with amiodarone alone.[47] Madrid et al. compared two Europace 2008;10:647-65. groups of patients with one episode of AF for more than seven 10. Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL editors in th days; after conversion one group was treated with amiodarone Harrison’s principles of Internal Medicine. 16 ed. New York, Toronto: McGraw-Hill Medical Publishing Division; 2005. p. 1345-47. (400mg/d) and second group with amidarone plus irbesartan 11. Rogers WJ, Epstein AE, Arciniegas JG, Dailey SM, Key N, Little RE, et al. Effect (150-300 mg/d). Of the total 186 patients for follow up time of and fl ecainide on mortality in a randomized trial of arrhythmia 245 days, patients treated with irbesartan plus amiodarone suppresioon after myocardial infarction. N Engl J Med 1989;321:406-12. had a greater probability of remaining free of AF (79.52% vs. 12. Waldo AL, Camm AJ, de-Ruter H, Friedman PI, MacNeil DJ, Pauls JF, et al. Effect 55.91%, p = 0.007).[48] Pedersen et al. investigated the effect of of d-sotalol on mortality in patients with left ventricular dysfunction after recent trandolapril on the incidence of AF, concluding that significantly and remote myocardial infarction. Lancet 1996;348:7-12. 13. Wyse DG, Waldo AL, Di Marco JP, Domanski MJ, Rosenberg EB, Schron JC, more patients on placebo developed AF (n = 42; 5.3%) than et al. A comparison of rate control and rhythm control in patients with atrial those on trandolapril (n = 22; 2.8%). The data, though promising fi brillation. N Engl J Med 2002;347:1925-33. has not been derived from prospective blind and control clinical 14. Van Gelder IC, Hagens VE, Bosker HA, Kingma JH, Kamp O, Kingma T, et al. trials. It has been emphasized that both β-blockers and ACEIs A comparison of rate control and rhythm control in patients with recurrent persistent exert significant effect on long term maintenance of sinus atrial fi brillation. N Engl J Med 2002;347:1834-40. [49] 15. Nattel S. Therapeutic implications of atrial fi brillation mechanisms: Can mechanistic rhythm in patients with AF. β-blockers and ACEIs can be insights be used to improve AF management? Cardiovas Res 2002;54:347-60. combined with long term amiodarone therapy to prolong the 16. Singh BN, Aliot E. Newer antiarrhythmic agents for maintaining sinus rhythm in duration of sinus rhythm after in a majority of patients with AF. atrial fi brillation: Simplicity or complexity? Eur Heart J 2007;9:G17-25. 17. Fedida D, Orth PM, Chen JY. The mechanism of atrial antiarrhythmic action of Conclusion RSD1235. J Cardiovasc Electrophysiol 2005;16:1227-38. AF remains a difficult clinical condition for the cardiologist 18. Roy D, Rowe BH, Stiell IG, Eoutu B, Ip JH, Phaneuf D, 1. A randomized, controlled trial of RSD 1235, a novel in the treatment of recent onset as current AADs are unsatisfactory with limited efficacy and atrial fi brillation. J Am Coll Cardiol 2004;44:2355-61. serious side effects. Atrial selective agents such as Vernakalant, 19. Blaauw Y, Gogelein H, Tieleman RG, Van Hunnik A, Schotten U, Allessie M. Early AVEO 118 and AZD 7009 are promising. Dronedarone, with class IIIdrugs for the treatment of atrial fi brillation: Effi cacy and atrial selectivity less adverse effects is useful particularly for long term of AVE 0118 in remodeled atria of the goat. Circulation 2004;110:1717-24. treatment AF and may become first line agent for patients with 20. Goldstein RN, Christion C, Carlson L, Waldo AL. AZD 7009: A new antiarrhythmic drug with predominant effect on the atria effectively terminates and prevents AF. Currently, amiodarone is the first line agent for maintaining reinduction of atrial fibrillation and flutter in the sterile pericarditis model. NSR in patients with heart failure or significant LV hypertrophy. J Cardiovasc Electrophysiol 2004;15:1444-50. Drugs that modulate fibrosis and connexins are undergoing 21. Carlsson L, Chartier D, Nattel S. Characterization of the in vivo and in vitro testing in animal models and may provide new targets for electrophysiological effects of the novel antiarrhythmic agent AZD7009 in atrial treatment of AF. Statins and omega3-PUFA appear to be and ventricular tissue of the dog. J Cardiovas Pharmacol 2006;47:123-32. effective in preventing AF in some of the patients, but further 22. Grijns HJ, Van Gelder IC, Walfridsson H. Safe and effective conversion of persistent atrial fi brillation to sinus rhythm by iv. AZD7009. Heart Rhythm trials are required to establish the role. Antifibrotic effects of 2006;3:1321-31. angiotensin system antagonism and gene therapy approaches 23. Sun W, Sarma JS, Singh BN. Chronic and acute effects of dronedarone on the might add to AF therapeutic options in future. Results of still action potential of rabbit atrial muscle preparations: Comparison with amiodarone. pending trials, novel compound development and evolution of J Cardiovas Pharmacol 2002;39:677-84. ablation procedures will determine the treatment of AF in the 24. Singh BN, Connolly SJ, Crijns HJ, Roy D, Kowey PR, Capucci A, et al. Dronedarone for maintaining sinus rhythm in atrial fi brillation or fl utter. N Engl J near future. Med 2007;357:987-9. References 25. Tauboul P, Brugada J, Capucci A. Dronedarone for prevention of atrial fi brillation: A dose ranging study. Eur Heart J 2003;24:1418-87. 1. Go AS, Hylek EM. Philips KA. Prevalence of diagnosed atrial fi brillation in 26. Dale KM, White CM. Dronedarone: An amiodarone analog for treatment of atrial adults: Normal implications for rhythm management and stroke prevention: The fi brillation and fl utter. Ann Pharmacother 2007;41:599-605. anticoagulation and risk factors in atrial fi brillation(ATRIA) study. J Am Med Assoc 27. 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