Flecainide current role in the treatment of Atrial Fibrillation

1. Flecainide – current role in the treatment of Atrial Fibrillation David Bennett, Marketing Centre Cardiology, MEDA

3. Product History Tambocor™ 100 mg immediate-release tablets was first registered in Germany in June 1982 The Original indication was for Ventricular Arrhythmias which was extended to Supraventricular Arrhythmias from 1986 Tambocor withdrawn from CAST in April 1989 Showed that the number of deaths in patients with asymptomatic or mildly symptomatic ventricular arrhythmias after myocardial infarction was greater in those receiving flecainide or encainide therapy than in those receiving placebo. Subsequent to the CAST trial, a retrospective study was conducted in patients with supraventricular arrhythmias treated with flecainide or encainide. This study showed that neither drugs were shown to be associated with excess mortality. Now available in over 50 countries Sold officially under a specific treatment programme in the Czech Republic since 2008

4. Projected number of people with AF during the next 50 years In this work published by Miyasaka et al in circulation 2006 (Olmsted County study), accordingly to the US population projections by the US Census Bureau, the number of persons with AF is projected to be 12.1 million by 2050, assuming no further increase in age-adjusted incidence of AF, but 15.9 million if the increase in incidence continues.1 The age-adjusted incidence of AF increased significantly in Olmsted County during 1980 to 2000. Whether or not this rate of increase continues, the projected number of persons with AF for the United States will exceed 10 million by 2050.1 It has been estimated that between 2.3 million and 10 and 12 million individuals in USA and European Union, respectively, have AF and it is expected that these numbers will increase 2.5- to 3-fold during the next 50 years.1 Ref : 1.Yoko Miyasaka, Marion E. Barnes et al. Secular Trends in Incidence of Atrial Fibrillation in Olmsted County, Minnesota, 1980 to 2000, and Implications on the Projections for Future Prevalence.Circulation.2006;114:119-125. In this work published by Miyasaka et al in circulation 2006 (Olmsted County study), accordingly to the US population projections by the US Census Bureau, the number of persons with AF is projected to be 12.1 million by 2050, assuming no further increase in age-adjusted incidence of AF, but 15.9 million if the increase in incidence continues.1 The age-adjusted incidence of AF increased significantly in Olmsted County during 1980 to 2000. Whether or not this rate of increase continues, the projected number of persons with AF for the United States will exceed 10 million by 2050.1 It has been estimated that between 2.3 million and 10 and 12 million individuals in USA and European Union, respectively, have AF and it is expected that these numbers will increase 2.5- to 3-fold during the next 50 years.1 Ref : 1.Yoko Miyasaka, Marion E. Barnes et al. Secular Trends in Incidence of Atrial Fibrillation in Olmsted County, Minnesota, 1980 to 2000, and Implications on the Projections for Future Prevalence.Circulation.2006;114:119-125.

5. AF is associated with long-term risk of CV events AF is an independent predictor of all-cause mortality in women and men. AF is associated with an increased long term risk of stroke, heart failure and all-cause mortality, especially in women. Ref: 1. Stewart S, Hart CL, Hole DJ, McMurray JJ. 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 2002113:359-64 AF is an independent predictor of all-cause mortality in women and men. AF is associated with an increased long term risk of stroke, heart failure and all-cause mortality, especially in women. Ref: 1. Stewart S, Hart CL, Hole DJ, McMurray JJ. 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 2002113:359-64

6. AF: an early and late killer Atrial fibrillation can usually be controlled with treatment. However, the natural tendency of atrial fibrillation is to become a chronic condition. Because of the development of serious comorbid diseases such as myocardial infarction, stroke, and heart failure, chronic AF leads to an increased risk of death. People with AF are about twice as likely to die as those in sinus rhythm.1 AF is associated with both early mortality and late mortality. The risk of death is increased within the first year of AF diagnosis and remains high as long as AF is present.1 Ref: 1. Benjamin EJ, Wolf PA, D'Agostino RB, et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study Circulation 1998; 98: 946–952. Atrial fibrillation can usually be controlled with treatment. However, the natural tendency of atrial fibrillation is to become a chronic condition. Because of the development of serious comorbid diseases such as myocardial infarction, stroke, and heart failure, chronic AF leads to an increased risk of death. People with AF are about twice as likely to die as those in sinus rhythm.1 AF is associated with both early mortality and late mortality. The risk of death is increased within the first year of AF diagnosis and remains high as long as AF is present.1 Ref: 1. Benjamin EJ, Wolf PA, D'Agostino RB, et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study Circulation 1998; 98: 946–952.

7. AF impairs QoL The burden of AF extends to the impact of the disease on patients’ quality of life. In addition to physical symptoms of AF and symptoms associated with comorbid disease, patients with AF commonly experience anxiety about their disease and modify their lifestyle to avoid exacerbating their symptoms. Common lifestyle modifications include reduced amount of exercise or travel. This may be particularly relevant for younger patients who may be used to more active lifestyles. Quality of life issues may also extend to the relatives of patients with AF. Quality of life is an important consideration in the treatment of patients with AF and is a common secondary endpoint of clinical trials evaluating antiarrhythmic drugs. Symptoms during arrhythmia were palpitations while exerting (88%), reduced physical ability (87%), palpitations at rest (86%), shortage of breath during exertion (70%) and anxiety (59%). Significant differences between sexes were noted regarding swollen legs (women 21%, men 6%, p=0.027), nausea (women 36%, men 13%, p=0.012) and anxiety (females 79%, males 51%, p=0.014).1 Ref: 1 - Hansson A, Madsen Hardig B, Olsson SB. BMC Cardiovasc Disord. 2004 Aug 3;4(1):13. Epub 2004 Aug 03.Arrhythmia-provoking factors and symptoms at the onset of paroxysmal atrial fibrillation: A study based on interviews with 100 patients seeking hospital assistance. The burden of AF extends to the impact of the disease on patients’ quality of life. In addition to physical symptoms of AF and symptoms associated with comorbid disease, patients with AF commonly experience anxiety about their disease and modify their lifestyle to avoid exacerbating their symptoms. Common lifestyle modifications include reduced amount of exercise or travel. This may be particularly relevant for younger patients who may be used to more active lifestyles. Quality of life issues may also extend to the relatives of patients with AF. Quality of life is an important consideration in the treatment of patients with AF and is a common secondary endpoint of clinical trials evaluating antiarrhythmic drugs. Symptoms during arrhythmia were palpitations while exerting (88%), reduced physical ability (87%), palpitations at rest (86%), shortage of breath during exertion (70%) and anxiety (59%). Significant differences between sexes were noted regarding swollen legs (women 21%, men 6%, p=0.027), nausea (women 36%, men 13%, p=0.012) and anxiety (females 79%, males 51%, p=0.014).1 Ref: 1 - Hansson A, Madsen Hardig B, Olsson SB. BMC Cardiovasc Disord. 2004 Aug 3;4(1):13. Epub 2004 Aug 03.Arrhythmia-provoking factors and symptoms at the onset of paroxysmal atrial fibrillation: A study based on interviews with 100 patients seeking hospital assistance.

8. Paroxysmal Atrial Fibrillation Paroxysmal AF. In patients who have self-limited episodes of AF, antiarrhythmic drugs to prevent recurrence (rhythm control) are not usually given unless AF is associated with severe symptoms related to hypotension, myocardial ischemia, or heart failure. In the absence of heart disease, episodes of AF of less than 48 hours are usually managed conservatively, with rest and or mild sedation.1 Recurrent paroxysmal AF. In these patients, antiarrhythmic drugs may or may not be given, depending on the severity of symptoms The decision as to whether or not anticoagulation is required is individualised for each patient based on the intrinsic risk of thromboembolism.1 The choice as to whether or not to treat depends on the success of previous cardioversion and severity of symptoms. When the decision to treat has been made, the choice of antiarrhythmic drug to maintain sinus rhythm depends on the presence or absence of heart disease. Ref: 1. Fuster V, Ryden LE,Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation. J Am Coll Cardiol 2006;48:149-246. Paroxysmal AF. In patients who have self-limited episodes of AF, antiarrhythmic drugs to prevent recurrence (rhythm control) are not usually given unless AF is associated with severe symptoms related to hypotension, myocardial ischemia, or heart failure. In the absence of heart disease, episodes of AF of less than 48 hours are usually managed conservatively, with rest and or mild sedation.1 Recurrent paroxysmal AF. In these patients, antiarrhythmic drugs may or may not be given, depending on the severity of symptoms The decision as to whether or not anticoagulation is required is individualised for each patient based on the intrinsic risk of thromboembolism.1 The choice as to whether or not to treat depends on the success of previous cardioversion and severity of symptoms. When the decision to treat has been made, the choice of antiarrhythmic drug to maintain sinus rhythm depends on the presence or absence of heart disease. Ref: 1. Fuster V, Ryden LE,Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation. J Am Coll Cardiol 2006;48:149-246.

9. Recurrent persistent AF and permanent AF Persistent AF. Patients with symptoms that would benefit for a return to sinus rhythm should be treated with an antiarrhythmic agent (in addition to medications for rate control and anticoagulation) before cardioversion and following return to sinus rhythm for maintenance. The selection of an antiarrhythmic drug should be based on the same treatment algorithm used for patients with recurrent paroxysmal AF. 1 Permanent AF. In cases where sinus rhythm cannot be sustained after cardioversion or when the patient and physician have decided to allow AF to continue without further efforts to restore sinus rhythm, ventricular rate control and antithrombotic therapy are the main treatments. 1 Ref: Fuster V, Ryden LE,Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation. J Am Coll Cardiol 2006;48:149-246. Persistent AF. Patients with symptoms that would benefit for a return to sinus rhythm should be treated with an antiarrhythmic agent (in addition to medications for rate control and anticoagulation) before cardioversion and following return to sinus rhythm for maintenance. The selection of an antiarrhythmic drug should be based on the same treatment algorithm used for patients with recurrent paroxysmal AF. 1 Permanent AF. In cases where sinus rhythm cannot be sustained after cardioversion or when the patient and physician have decided to allow AF to continue without further efforts to restore sinus rhythm, ventricular rate control and antithrombotic therapy are the main treatments. 1 Ref: Fuster V, Ryden LE,Cannom DS, et al. ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation. J Am Coll Cardiol 2006;48:149-246.

10. ACC/AHA/ESC guidelines Rate control may be a reasonable initial therapy in older patients with persistent AF who have hypertension or heart disease. For younger individuals, especially those with paroxysmal lone AF, rhythm control maybe a better initial approach.

11. AAD therapy to maintain SR in patients with recurrent paroxysmal or persistent AF

12. AAD therapy to maintain sinus rhythm in AF patients with coronary artery disease or heart failure

13. Flecainide is highly effective in the prevention of AF recurrence Flecainide was found to be more effective in maintening SR than other AADs ( i.e: quinidine, sotalol, propafenone, amiodarone) in a publication analysis of AF prevention studies with a follow-up of at least six months.1 Ref: 1. Levy S, Breithardt G, Campbell RW et al. Atrial fibrillation: current knowledge and recommendations for management. Working Group on Arrhythmias of the European Society of Cardiology. Eur Heart J 1998; 19:1294-320.Flecainide was found to be more effective in maintening SR than other AADs ( i.e: quinidine, sotalol, propafenone, amiodarone) in a publication analysis of AF prevention studies with a follow-up of at least six months.1 Ref: 1. Levy S, Breithardt G, Campbell RW et al. Atrial fibrillation: current knowledge and recommendations for management. Working Group on Arrhythmias of the European Society of Cardiology. Eur Heart J 1998; 19:1294-320.

14. Flecainide has a « class I recommendation, A level of evidence » recommendation for pharmacological cardioversion of AF up to 7 days duration. Flecainide has a « class IIb, B level of evidence » recommendation for pharmacological cardioversion of AF longer than 7 days duration. Flecainide has a « class IIa, B level of evidence » Acknowledgement of Flecainide to enhance the success of direct current cardioversion and prevent recurrence of AF. In the ACC/AHA/ESCC 2006 guidelines1 Flecainide has also some other recommendations with different levels of evidence.1 Ref: 1. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC Guidelines for the Management of Patients With Atrial Fibrillation. J Am Coll Cardiol 2006; 48: 149-246. In the ACC/AHA/ESCC 2006 guidelines1 Flecainide has also some other recommendations with different levels of evidence.1 Ref: 1. Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC Guidelines for the Management of Patients With Atrial Fibrillation. J Am Coll Cardiol 2006; 48: 149-246.

15. Flecainide is highly effective in the acute cardioversion of AF The efficacy of Flecainide in cardioversion has been evaluated in a pooled analysis from the Agency for Healthcare Research and Quality ( AHRQ). Fourty six studies of AADs in cardioversion have been selected in this meta-analysis.1 Ref: 1. McNamara RL et al. Management of new onset AF. Evidence Report/Technology assessment N° 12 AHRQ Publication Number 01-E026.2001The efficacy of Flecainide in cardioversion has been evaluated in a pooled analysis from the Agency for Healthcare Research and Quality ( AHRQ). Fourty six studies of AADs in cardioversion have been selected in this meta-analysis.1 Ref: 1. McNamara RL et al. Management of new onset AF. Evidence Report/Technology assessment N° 12 AHRQ Publication Number 01-E026.2001

16. Flecainide produces a low incidence of extra-cardiac adverse events A meta analysis1 of 122 Flecainide studies with a mean exposure time of 241+/- 224 days demonstrated that Flecainide is associated with A lower incidence of diaarrhoea vs controls ( 0.7% vs 2.8%) A lower incidence of headache vs controls (2.0% vs 2.9%) A lower incidence of nausea vs controls (1.6% vs 1.8%). Less than 5% of patients discontinue Flecainide because of Adverse effects. Ref: 1. Wehling M. Meta-analysis of flecainide safety in patients with supraventricular arrhythmias. Arzneimittelforschung 2002;52:507-14A meta analysis1 of 122 Flecainide studies with a mean exposure time of 241+/- 224 days demonstrated that Flecainide is associated with A lower incidence of diaarrhoea vs controls ( 0.7% vs 2.8%) A lower incidence of headache vs controls (2.0% vs 2.9%) A lower incidence of nausea vs controls (1.6% vs 1.8%). Less than 5% of patients discontinue Flecainide because of Adverse effects. Ref: 1. Wehling M. Meta-analysis of flecainide safety in patients with supraventricular arrhythmias. Arzneimittelforschung 2002;52:507-14

17. Flecainide is safe over the long-term in patients without structural heart disease A meta analysis1 of 122 Flecainide studies with a mean exposure time of 241+/- 224 days demonstrated that Flecainide is associated with A lower incidence of proarrhythmic episodes vs controls (2.7% vs 4.8%) A lower incidence of angina vs controls (1% vs 1.3%) A lower incidence of syncope vs controls (0.1% vs 0.2%) A significantly lower incidence of hypotension vs controls (0.8% vs1.3%) Ref: 1. Wehling M. Meta-analysis of flecainide safety in patients with supraventricular arrhythmias. Arzneimittelforschung 2002;52:507-14 A meta analysis1 of 122 Flecainide studies with a mean exposure time of 241+/- 224 days demonstrated that Flecainide is associated with A lower incidence of proarrhythmic episodes vs controls (2.7% vs 4.8%) A lower incidence of angina vs controls (1% vs 1.3%) A lower incidence of syncope vs controls (0.1% vs 0.2%) A significantly lower incidence of hypotension vs controls (0.8% vs1.3%) Ref: 1. Wehling M. Meta-analysis of flecainide safety in patients with supraventricular arrhythmias. Arzneimittelforschung 2002;52:507-14

18. Antiarrhythmic Drug Usage in Western Europe Why is flecainide growing? 3M and now Meda clearly committed to the promotion of the product. Very little promotion by competitors. Plus our ongoing commitment to medical education and supporting physicians.Why is flecainide growing? 3M and now Meda clearly committed to the promotion of the product. Very little promotion by competitors. Plus our ongoing commitment to medical education and supporting physicians.

19. 11th Tambocor Periodic Safety Update Report25 June 2007 - 24 June 2008 The estimated patient exposure for the period of this report is: TOTAL (ESTIMATED): 194 MILLION PATIENT-DAYS Based on the assumption that the patients are treated continuously with Tambocor TOTAL (ESTIMATED): 532 000 PATIENTS WERE EXPOSED TO TAMBOCOR

20. Summary Flecainide is a recommended first line treatment for patients without structural heart disease Flecainide is highly effective for acute cardioversion of AF Flecainide effectively reduces recurrences of AF, maintaining patients in sinus rhythm for longer Flecainide is a well-tolerated AAD for patients without structural heart disease inducing a low incidence of extra-cardiac adverse events After 25 years flecainide still remains an essential part of a physicians toolkit and with new products continuing to fail to meet expectations this looks likely to continue