Management Options in Atrial Fibrillation The Role of Vernakalant

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1 ATRIAL FIBRILLATION REVIEW Management Options in Atrial Fibrillation The Role of Vernakalant Stefan H. Hohnloser, MD 1 and Sami A. Omar, MBBS, MRCP 2 Received 17/8/2011, Reviewed 27/8/2011, Accepted 21/9/2011 Key words: atrial fibrillation, management options, anti-arrhythmic drugs, vernakalant DOI: /ejcm Atrial Fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice and is associated with significant mortality and morbidity mainly due to thromboembolic complications and heart failure. Furthermore, it is an important contributor to the increasing costs of healthcare. This article provides a short summary of our current knowledge related to some important aspects of AF. Particular emphasis is given to chemical restoration of sinus rhythm by means of intravenous administration of vernakalant (Brinavess, Merck Sharp & Dohme Ltd, UK), a novel antiarrhythmic agent that has been approved in the EU and is undergoing marketing approval in the USA. 1. J. W. Goethe University, Frankfurt, Germany, 2. St Thomas s Hospital, Kings College University, London, UK. CORRESPONDENCE ATRIAL FIBRILLATION AF is characterised by uncoordinated electrical activation of the atria, apparent as the absence of coordinated P waves on the ECG. This rapid supraventricular activity then leads to an irregularly irregular and usually rapid ventricular response rate. [1] The pathophysiology of AF is complex and likely to be multifactorial. Its existence is reliant on the structural and electrical remodelling of the left atrium, which provides the substrate that sustains the arrhythmia. Often, AF is initiated by a trigger originating from the root of the pulmonary veins. [2, 3] AF is usually classified according to its temporal and rhythm-based patterns. However, this method of classification can be difficult and may be fraught with errors. [4] Furthermore, the guidelines for the treatment of AF suggest that patients with risk factors and what is perceived to be paroxysmal AF should be considered to be at a similar risk of complications, particularly thromboembolic events, as those with so called persistent or permanent AF.[5] Epidemiology The lifetime risk of developing AF in a person above the age of 40 is about 25%. The risk is elevated in individuals with cardiovascular disease, such as valvular heart disease or hypertension, and diabetes mellitus. [6] It is estimated that % of the population are affected by AF. In 2001 it was thought to affect 2.3 million adults in the USA. [7] In 2005 it was estimated that the condition affected 3.03 million of America s population and the number is expected to reach 7.56 million by the year [1] In Scotland the prevalence of AF was around 0.65% and the hospitalisation rate for AF was found to have doubled between 1986 and [8, 9] One of the factors leading to the rise in AF is the increasing age of the population. The incidence of AF in individuals aged >65 years is approximately 5%. [2] This increases rapidly up to 10% in the population aged >80 years. Furthermore, the improved medical care to patients with cardiac problems and the improved survival rates is another important contributor to the increasing incidence of AF. [1] Morbidity and mortality The Framingham study found that AF was an independent predictor of mortality both in healthy individuals and in subjects with concomitant morbidity, such as cardiovascular disease, hypertension or diabetes mellitus. The relative risk (RR) for death in this population was 1.5 and 1.9 in men and women, respectively, after adjustment for important baseline variables. [10] More recently the Renfrew/ Paisley Study conducted in Scotland demonstrated similar findings with AF again being an independent predictor of mortality with a RR for death of 1.5 and 2.2 in men and women, respectively. [9] The findings were consistent with other reports from other European countries, such as the UK [11], Denmark [12], Iceland [13] and the Netherlands [14]. Stefan H. Hohnloser, MD, FACC, FESC, FHRS Division of Clinical Electrophysiology, J. W. Goethe University Hospital, Theodor-Stern-Kai 7, D Frankfurt, Germany Tel: Fax: Hohnloser@em.uni-frankfurt.de ISSN

2 MANAGEMENT OPTIONS IN ATRIAL FIBRILLATION THE ROLE OF VERNAKALANT AF is a well recognised independent risk factor for stroke increasing the risk up to 5-fold. AF accounts for approximately 15% of all ischaemic strokes and up to 23.5% of strokes in patients aged 80 to 89 years in the USA. [1, 15] In Europe 18% of patients presenting with strokes were found to have concomitant AF. In addition, stroke patients with AF were found to have a worse outcome with regards to morbidity and mortality, where at 3 months 32.8% of the patients had died in contrast to 19.9% in the sinus rhythm (SR) group. [16] Impact on quality of life AF can be a debilitating arrhythmia with symptoms such as palpitations, dizziness, shortness of breath, fatigue and exercise intolerance. [17] A study based on interviews with 100 patients who had sought hospital assistance for AF symptoms showed that the vast majority of respondents (86 to 88%) experienced palpitations both during exercise and at rest, and felt that their physical ability was reduced due to their symptoms. Moreover, 70% reported shortage of breath during exertion, and 59% reported anxiety in connection with their AF symptoms. [18] In addition, patients with atrial fibrillation irrespective of the classification were found to suffer from signs of depression, social isolation and impaired emotional reaction compared to their counterparts with SR. [19] Hospitalisation also had a negative impact. A recent study found that particularly hospitalisation secondary to AF had an adverse effect on the QOL. [20] Economics The economic burden of AF is substantial and is particularly related to hospital admissions. As highlighted earlier the number of admissions to hospital due to AF as the primary diagnosis in Scotland doubled in the years between 1986 and [8] These findings were similar to those observed in the USA between the years 1985 and [23] In the UK it is estimated that AF accounts for about 1% of the expenditure of the National Health Service. [24] In the European Union the overall cost of managing AF has been estimated at approximately 3,000 EUR per patient per year. [25] In the USA the cost of treating AF is estimated to be in the region of $6.65 billion. [26] MANAGEMENT OF AF When managing AF one should aim to exclude reversible causes, adopt an appropriate treatment strategy by either targeting the rate or the rhythm, and choose an appropriate anticoagulant by weighing the risk of a thromboembolic event against that of bleeding. Reversible causes of AF It is important that reversible causes of AF are identified. Attempting to treat the arrhythmia without addressing the underlying cause is likely to be futile; on the other hand the appropriate management of the underlying cause may be all that is required to abolish the AF. The causes of AF can divided into two groups, cardiac and non-cardiac. The cardiac causes include hypertension, myocardial infarction, myocarditis, pericarditis and valvular heart disease. The non-cardiac causes include recreational drug use, alcohol ingestion acute (the holiday heart syndrome) and chronic, pulmonary embolism, hyper- or hypothyroidism, infection and ongoing inflammatory disease, amongst others. [27] Rate control vs. rhythm control Multiple studies (PIAF, AFFIRM, RACE, STAF, AF CHF) have been conducted comparing the outcomes of adopting a rate control strategy, in patients with AF, against those found when adopting rhythm control. [28-30, 32] The primary endpoint in PIAF was improvement in symptoms, the success rates of the two approaches were 95% in rate control vs. 88.9% in rhythm control (P=0.317). [28] In AFFIRM the endpoint of all-cause mortality occurred in more patients assigned to rhythm control group than in the rate control group; the difference was not statistically significantly different (hazard ratio 1.15, 95% CI ; p=0.08). [29] RACE had the primary endpoint of a composite of cardiovascular death, hospitalisation for heart failure, thromboembolic complications, severe haemorrhage, pacemaker implantation and severe adverse events. This occurred in 17.2% of patients treated with rate control vs. 22.6% of the patients treated with rhythm control (P=0.11). [30] Hence, rate control proved to be non-inferior to rhythm control in RACE. The last of the rhythm versus rate control trial, AF-CHF, was conducted in patients with heart failure. [32] The primary endpoint of cardiovascular death was not significantly different in both strategies. However, there are situations where a rhythm control strategy would be more desirable than one adopting rate control physicians are likely to attempt rhythm control in individuals in whom AF causes severe symptoms. In addition to improvement in symptoms, effective rhythm control may have a positive impact on the electrical and anatomical remodelling of the left atrium. [33] Rate control The drugs which can be used for a rate control strategy include beta-blockers, calcium channel blockers and digoxin. There are no scientific data on what constitutes the most effective target heart rate for rate control in AF, many opt to maintain a heart rate of <80 bpm at rest and <110 bpm with exercise. Recently, however, RACE II has suggested that a more lenient rate control strategy aiming for heart rates of <110 bpm is also acceptable and more easily achievable. [34] Rhythm control The emphasis in rhythm control is on the restoration and maintenance of SR. In up to 50% of cases of new onset AF, spontaneous conversion to sinus rhythm occurs within 24 to 48 hours. [35] In the absence of spontaneous conversion, one may consider electrical and or chemical cardioversion to restore SR, followed by either chemical or ablation therapy to maintain it. Electrical cardioversion Direct current (DC) cardioversion is highly effective with success rates well above 90% if properly performed in suitable patients. [36] However, it is not without risks and complications, which include burns, ventricular fibrillation in cases of failed R-wave triggering of the DC shock, and others. Moreover, the need for general anaesthesia is often cumbersome and may delay cardioversion unnecessarily. 3

3 HEALTHCARE BULLETIN ATRIAL FIBRILLATION Chemical cardioversion A wide range of anti-arrhythmic drugs (AADs) is available to achieve this goal, each with its relatively unique mechanism of action. Most AADs have the potential of precipitating fatal arrhythmia due to their proarrhythmic effect. The guidelines applying to chemical cardioversion advocate that the choice AAD should be governed by the safety of the drug rather than by its efficacy. [5, 37] Table 1 gives a list of AADs which are most commonly used for maintenance or restoration of sinus rhythm, their side effects and efficacy. Catheter ablation therapy For patients with symptomatic AF who have failed a rhythm control strategy using medical therapy, there is the option of curative catheter ablation therapy. This is achieved by isolating the pulmonary veins from the atrium using either linear or circumferential ablation; this in turn quarantines the triggers from the substrate. The success rates of the procedure are quoted to be around 75 90% after repeat interventions. However, it has never been shown to affect mortality or alleviate the need for anticoagulation therapy. [40] Table 1: (Adapted by permission of the American Board of Family Medicine & Int J Cardiol, 2011) [38])[39] Drug Mechanism of action Contraindications Potential side effects Efficacy Flecainide Sodium channel blocker Structural and or coronary heart disease AV conduction abnormality Cardiogenic shock CHF VT Dizziness Visual disturbances May potentiate 1:1 conduction 34 42% Propafenone Sodium channel blocker CHF Cardiogenic shock Conduction abnormalities Bradycardia Hypotension Bronchospastic disorders Electrolyte imbalance Dizziness Nausea Vomiting Unusual taste Constipation 35 40% Amiodarone Blocks multiple cardiac ion channels Severe sinus node dysfunction 2nd or 3rd degree AV block Bradycardia causing syncope Hypersensitivity to Iodine Thyroid dysfunction Liver dysfunction Pulmonary fibrosis Photosensitivity Visual disturbances Nausea Vomiting 50 78% Dronedarone Blocks multiple cardiac ion channels CHF 2nd or 3rd degree AV block Bradycardia Severe hepatic impairment Concomitant use of drugs which prolong the QT 33 39% Dofetilide Long QT Severe renal impairment Multiple interactions with other drugs Headache Chest pain Dizziness Dyspnea 66 71% Ibutilide Blocks atrial and ventricular K+ channels CHF Long QT Coronary artery disease Prolonged QT 31 44% 4

4 MANAGEMENT OPTIONS IN ATRIAL FIBRILLATION THE ROLE OF VERNAKALANT Anticoagulation Anticoagulation therapy forms a cornerstone in the management of patients with AF in view of its essential role in stroke prevention. Appropriate anticoagulation with vitamin K antagonists can reduce the risk of stroke by 64% in patients with non valvular AF. [41] The CHADS2 score is widely used to assess stroke risk in individual patients. In this scoring system 1 point is allocated to each of the following risk factors: congestive cardiac failure, hypertension, age >75 years and diabetes mellitus; 2 points are allocated to a previous transient ischaemic accident or ischaemic stroke. [42] The European guidelines have advised the adoption of the CHAD2S2-VASc score which takes into consideration the presence of vascular disease and the patients sex (female gender) and the age group years allocating a further point to each, patients above the age of 74 years are now allocated 2 points. Individuals who score 2 points are considered to be of high risk and anticoagulation therapy is recommended. Patients who score 1 are considered to be of moderate risk and would also benefit from formal anticoagulation, however, antiplatelet therapy in the form of aspirin can be considered. ACT I recruited 336 patients, 220 had short duration AF and 116 had long duration AF. Of the patients given vernakalant 37.6% reverted to SR compared to 2.6% in the placebo group (P<0.001). The highest success rates were demonstrated in the patients with short duration AF (51.7% vs. 4.0%, P< 0.001) as opposed to those with long duration AF (7.9% vs. 0%, P=0.09). [Fig 1.] The median time for conversion to SR in the 75 patients in the short duration AF group in whom vernakalant was 11 minutes; 57 of them required only a single dose; only 1 patient relapsed back into AF within 24 hours. [Fig 2] [46] Figure 1: Success rates in conversion from AF to SR in short duration, long duration and overall AF populations in ACT I. [46] A score of 0 denotes low risk and antiplatelet therapy alone or no antithrombotic therapy at all would suffice. Anticoagulation therapy should always be weighed against the risk of bleeding. [5, 37]. Several new anticoagulants are currently being developed and the first of these, dabigatran, which is a direct thrombin inhibitor, has been approved for stroke prevention in AF in several jurisdictions. VERNAKALANT Vernakalant is a novel and new relatively atrial selective AAD. Through its blocking action on early-activating K+ and frequencydependent Na+ channels it selectively prolongs the atrial action potential, which in turns gives it its efficacy in converting AF. [43] It has half life of 2-3 hours and it s metabolism is dependent on the cytochrome P450 system. The 2D6 genetic subtype of the cytochrome P450 system rapidly inactivates vernakalant. This leads to the presence of two distinct population phenotypes the extensive metaboliser (EM) and the poor metaboliser (PM). [43, 44] The differences in pharmacokinetics of the drug between these two groups were more pronounced with the oral administration. However, this difference is unlikely to be clinical significance. [45] Adapted by permission Circulation, (12) Figure 2: Cumulative success rates based on time after start of study drug infusion for the short duration AF group [46] The four ACT s development programme of vernakalant The Atrial arrhythmia Conversion Trials (ACT I, ACT II and ACT III) were phase 3 prospective, randomised, double-blind, placebo-controlled, multicentre studies conducted to assess the use of vernakalant in the treatment of AF. ACT I and III recruited patients presenting with AF and atrial flutter (AFL) that lasted more than 3 hours and less than 45 days. Patients were subdivided into two groups those deemed to have AF onset of short duration lasting between 3 hours to 7 days and those with long duration AF lasting between 8 to 45 days. ACT II evaluated the use of vernakalant in a population developing AF post cardiac surgery. ACT IV was an open-label study designed to assess the safety profile of vernakalant. [46-49] Adapted by permission Circulation, (12) 5

5 HEALTHCARE BULLETIN ATRIAL FIBRILLATION ACT II recruited 160 patients who had developed AF (150) or AFL (10) 24 hours to 7 days following cardiac valvular and/or coronary surgery. The duration of the arrhythmia was between 3 hours and 3 days. The results demonstrated that vernakalant was successful in reverting 44.9% of the patients with AF/AFL to SR as opposed to 14.8% that reverted with placebo (P<0.001). This was, however, driven by the effects of vernakalant on the patients with AF as 47% reverted to SR vs. 14% with placebo (P<0.001); none of the patients with AFL reverted to SR when given vernakalant.[fig 3] [47] Figure 3: Vernakalant after cardiac surgery (ACT II): Success rates in patients with AF or AFL and in those AF patients alone. [47] The median time for conversion to SR in the 48 patients with AF/ AFL in whom vernakalant was successful was 12.4 minutes; 36 of them requiring only a single dose, and 19 patients relapsed back into AF within 24 hours.[fig 4] [47] ACT III recruited a total of 265 patients. Of the patients treated with vernakalant 39.8% reverted to SR compared to the 3.3% seen in the placebo group (P<0.0001). Again the highest success rates were demonstrated in the patients with short duration AF (51.2% vs. 3.6%, P<0.0001). [Fig 5] The median interval to conversion of short-duration AF to SR in the responders given vernakalant was 8 minutes [Fig 6]. [48] Figure 5: Success rates in conversion from AF to SR in short duration, long duration and overall AF populations; data from the ACT III trial. [48] Adapted by permission Circ Arrhythm Electrophysiol, (6) Figure 4: Cumulative success rates (conversion to sinus rhythm) of vernakalant or placebo in patients after cardiac surgery [47] Adapted by permission Circ Arrhythm Electrophysiol, (6) Figure 6: Cumulative success rates (conversion to sinus rhythm) of vernakalant or placebo in patients after cardiac surgery [47] Adapted by permission Circ Arrhythm Electrophysiol, (6) Adapted by permission Am J Cardiol, (9) 6

6 MANAGEMENT OPTIONS IN ATRIAL FIBRILLATION THE ROLE OF VERNAKALANT In ACT IV 236 patients were treated with vernakalant in an openlabel fashion, 167 with short duration AF and 69 with long duration AF. Vernakalant was successful in reverting 39.4% of the patients to SR. There was greater success in the short duration group 50.9% than in the long duration group 11.6%. The median conversion time to SR was 14 minutes. Only 1.9% of the patients in whom vernakalant was successful relapsed back into AF within 24 hours. [49] Figure 7: Cumulative success rates based on time after start of study drug infusion in AVRO [50] AVRO Following the results of the ACT studies, AVRO (A Randomized Active-Controlled Study Comparing the Efficacy and Safety of Vernakalant to Amiodarone in Recent-Onset Atrial Fibrillation) a phase 3, randomised, double-blind, double-dummy, active-controlled, multicentre trial was designed as a head-to-head study comparing vernakalant against amiodarone, the most commonly used antiarrhythmic agent in the treatment of AF. [50] The study enrolled 254 presenting with AF of 3 to 48 hours duration; of those 232 were randomised in 1:1 fashion to receive either vernakalant (at a dose of 3 mg/kg for 10 minutes followed by an additional 2 mg/kg 10-minute infusion if required, after which a saline infusion was continued to maintain blindness) or amiodarone (at a dose of 5 mg/kg over 60 minutes, followed by 50 mg over a further 60 minutes). The results of the study demonstrated that vernakalant was more successful than amiodarone in the conversion of AF to SR both within the first 90 minutes (51.7% vs. 5.2%, P< ) and at 4 hours post dose (54.5% vs. 22.6%, P< ). [Fig 7] Furthermore 37.1% of patients treated with vernakalant were suitable for discharge at 2 hours as opposed to 9.5% of patients treated with amiodarone (P< ). [50] SAFETY The safety data of vernakalant has been evaluated based on clinical studies involving 883 patients. A total of 5 deaths occurred during the course of the trials. In ACT I 3 patients died all of whom had received vernakalant; however none of the deaths were attributed to the drug as they were caused by aortic dissection, pulmonary oedema secondary to congestive cardiac failure and pneumonia. In ACT III one vernakalant patient who had severe aortic stenosis experienced hypotension and ventricular fibrillation and died. In ACT IV there was a single reported death, which was deemed not to be related to the drug. It was a result of an upper GI bleed in a patient diagnosed with breast cancer. There were no reported deaths in ACT II. Adapted by permission J Am Coll Cardiol, (3) A serious adverse event (SAE) was defined as any event that may be significantly incapacitating, require prolonged hospitalisation, require medical or surgical intervention, life-threatening or fatal. In ACT I such a SAE occurred in 13.1% of patients treated with vernakalant and in 18.3% of the placebo group. The most common event was recurrent AF leading to hospitalisation. However, there were four serious adverse events, which were thought to be related to vernakalant, two incidents of severe hypotension, an episode of cardiogenic shock and an episode of complete heart block after DC cardioversion. In ACT II SAEs occurred in 9.3% of the patients treated with vernakalant and 11.1% of those on placebo. There were 2 serious adverse events that were attributed to the drug one was a case of significant hypotension and the other was complete AV block. [46-49] 7

7 HEALTHCARE BULLETIN ATRIAL FIBRILLATION Table 2: The most common occurring AE with the use of Vernakalant ACT I ACT III ACT IV Adverse event Vernakalant Placebo Vernakalant Placebo Vernakalant Dysgeusia 29.9%, 0.9% 21% 5% 18.6% Sneezing 16.3% 0% 23% 0% 16.1% Paresthesia 10.9% 0% 8% 3% 7.6% Nausea 9.0% 0.9% 5% 0% NA Hypotension 6.3% 3.5% 5% 1% 5.5% Bradycardia 6% 0% 5.1% Cough NA NA NA NA 5.5% Eur J Cardiovasc Med Healthcare Bulletin 2011 In all the hypotension cases the effects were transient and responded to treatment with saline. CONCLUSION AF is a common condition with significant implications on the individual s mortality, morbidity and quality of life. There are many management options; each needs to be considered on a case-bycase basis. A rhythm control strategy may be more appropriate in some patients in order alleviate symptoms and improve quality of life. This approach, however, is limited as all the available options have their inherent limitations, potential risks and possible side effects. Vernakalant is a promising, novel, and new addition to the armamentarium of treatments available to us in dealing with this fast approaching epidemic. The drug acts rapidly in converting new onset AF back to sinus rhythm and can be administered to patients with structural heart disease, such as coronary artery disease, hypertensive heart disease or mild heart failure. REFERENCES Valderrama, A.L., S.B. Dunbar, and G.A. Mensah, Atrial fibrillation: public health implications. Am J Prev Med, (5 Suppl 1): p Allessie, M.A., et al., Pathophysiology and prevention of atrial fibrillation. Circulation, (5): p Kourliouros, A., et al., Current concepts in the pathogenesis of atrial fibrillation. Am Heart J, (2): p Lubitz, S.A., et al., Challenges in the classification of atrial fibrillation. Nat Rev Cardiol, (8): p Camm, A.J., et al., Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J, (19): p Lloyd-Jones, D.M., et al., Lifetime risk for development of atrial f ibrillation: the Framingham Heart Study. Circulation, (9): p Go, A.S., et al., Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA, (18): p Stewart, S., et al., Trends in case-fatality in patients admitted for the first time with atrial fibrillation in Scotland, Int J Cardiol, (3): p Stewart, S., et al., A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/ Paisley study. Am J Med, (5): p Benjamin, E.J., et al., Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation, (10): p Majeed, A., K. Moser, and K. Carroll, Trends in the prevalence and management of atrial fibrillation in general practice in England and Wales, : analysis of data from the general practice research database. Heart, (3): p Boysen, G., et al., Stroke incidence and risk factors for stroke in Copenhagen, Denmark. Stroke, (11): p Onundarson, P.T., et al., Chronic atrial fibrillation - epidemiologic features and 14 year follow-up: a case control study. Eur Heart J, (5): p Langenberg, M., et al., Atrial fibrillation in elderly patients: prevalence and comorbidity in general practice. BMJ, (7071): p

8 MANAGEMENT OPTIONS IN ATRIAL FIBRILLATION THE ROLE OF VERNAKALANT REFERENCES (Continued) 32 Roy, D., et al., Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med, (25): p Roger, V.L., et al., Heart disease and stroke statistics update: a report from the American Heart Association. Circulation, (4): p. e18-e Wijffels, M.C., et al., Atrial fibrillation begets atrial fibrillation. A study in awake chronically instrumented goats. Circulation, (7): p Lamassa, M., et al., Characteristics, outcome, and care of stroke associated with atrial fibrillation in Europe: data from a multicenter multinational hospital-based registry (The European Community Stroke Project). Stroke, (2): p Lane, D.A. and G.Y. Lip, Quality of life in older people with atrial fibrillation. J Interv Card Electrophysiol, (1): p Hansson, A., B. Madsen-Hardig, and S.B. Olsson, Arrhythmiaprovoking factors and symptoms at the onset of paroxysmal atrial fibrillation: a study based on interviews with 100 patients seeking hospital assistance. BMC Cardiovasc Disord, : p. 13. Dabrowski, R., et al., Quality of life and depression in patients with different patterns of atrial fibrillation. Kardiol Pol, (10): p Reynolds, M.R., E. Morais, and P. Zimetbaum, Impact of hospitalization on health-related quality of life in atrial fibrillation patients in Canada and the United States: results from an observational registry. Am Heart J, (4): p Van Gelder, I.C., et al., Lenient versus strict rate control in patients with atrial fibrillation. N Engl J Med, (15): p Bajpai, A., I. Savelieva, and A.J. Camm, Treatment of atrial fibrillation. Br Med Bull, (1): p Mittal, S., et al., An update on electrical cardioversion of atrial fibrillation. Card Electrophysiol Rev, (3): p Fuster, V., et al., 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation, (10): p. e Camm, J., Antiarrhythmic drugs for the maintenance of sinus rhythm: Risks and benefits. Int J Cardiol, Nair, M., L.K. George, and S.K. Koshy, Safety and efficacy of ibutilide in cardioversion of atrial flutter and fibrillation. J Am Board Fam Med, (1): p Thrall, G., et al., Quality of life in patients with atrial fibrillation: a systematic review. Am J Med, (5): p. 448 e1-19. Bohnen, M., et al., Quality of life with atrial fibrillation: do the spouses suffer as much as the patients? Pacing Clin Electrophysiol, (7): p Wattigney, W.A., G.A. Mensah, and J.B. Croft, Increasing trends in hospitalization for atrial fibrillation in the United States, 1985 through 1999: implications for primary prevention. Circulation, (6): p Verma, A., et al., Canadian Cardiovascular Society atrial fibrillation guidelines 2010: catheter ablation for atrial fibrillation/atrial flutter. Can J Cardiol, (1): p Medi, C., G.J. Hankey, and S.B. Freedman, Stroke risk and antithr ombotic strategies in atrial fibrillation. Stroke, (11): p Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med, (13): p Stewart, S., et al., Cost of an emerging epidemic: an economic analysis of atrial fibrillation in the UK. Heart, (3): p Fedida, D., et al., The mechanism of atrial antiarrhythmic action of RSD1235. J Cardiovasc Electrophysiol, (11): p Le Heuzey, J.Y., et al., Cost of care distribution in atrial fibrillation patients: the COCAF study. Am Heart J, (1): p Coyne, K.S., et al., Assessing the direct costs of treating nonvalvular atrial fibrillation in the United States. Value Health, (5): p Healey, J.S., et al., Canadian Cardiovascular Society atrial fibrillation guidelines 2010: etiology and initial investigations. Can J Cardiol, (1): p Hohnloser, S.H., K.H. Kuck, and J. Lilienthal, Rhythm or rate control in atrial fibrillation--pharmacological Intervention in Atrial Fibrillation (PIAF): a randomised trial. Lancet, (9244): p Wyse, D.G., et al., A comparison of rate control and rhythm control in patients with atrial fibrillation, in N Engl J Med p Mao, Z.L., et al., Pharmacokinetics of novel atrial-selective antiarrhythmic agent vernakalant hydrochloride injection (RSD1235): influence of CYP2D6 expression and other factors. J Clin Pharmacol, (1): p Mao, Z.L., et al., Disposition and mass balance of [14C]vernakalant after single intravenous and oral doses in healthy volunteers. Drug Metab Lett, (2): p Roy, D., et al., Vernakalant hydrochloride for rapid conversion of atrial fibrillation: a phase 3, randomized, placebo-controlled trial. Circulation, (12): p Kowey, P.R., et al., Vernakalant hydrochloride for the rapid conversion of atrial fibrillation after cardiac surgery: a randomized, double-blind, placebo-controlled trial. Circ Arrhythm Electrophysiol, (6): p Van Gelder, I.C., et al., A comparison of rate control and rhythm control in patients with recurrent persistent atrial fibrillation. N Engl J Med, (23): p Pratt, C.M., et al., Usefulness of vernakalant hydrochloride injection for rapid conversion of atrial fibrillation. Am J Cardiol, (9): p Carlsson, J., et al., Randomized trial of rate-control versus rhythm-control in persistent atrial fibrillation: the Strategies of Treatment of Atrial Fibrillation (STAF) study. J Am Coll Cardiol, (10): p Stiell, I.G., et al., A multicenter, open-label study of vernakalant for the conversion of atrial fibrillation to sinus rhythm. Am Heart J, (6): p Camm, A.J., et al., A randomized active-controlled study comparing the efficacy and safety of vernakalant to amiodarone in recent-onset atrial fibrillation. J Am Coll Cardiol, (3): p