1. CV/Thrombosis Regional Medical Liaison
DRO
Approved:
Atrial Fibrillation: A Clinical Review of the Disease State and Treatment Options
Lori Arnold, Pharm.D.
CV/Thrombosis Regional Medical Liaison
Sanofi
Atrial Fibrillation: an Escalating Cardiovascular Disease With Significant Clinical and Economic
Consequences

2. Objectives
Understand the economic impact and unmet needs of Atrial Fibrillation
Define the “Burden” of Atrial Fibrillation
Describe the mechanism of Atrial Remodeling and how this contributes to the progression of Atrial Fibrillation
Provide therapeutic management and guideline options for the treatment of Atrial Fibrillation
Atrial Fibrillation Disease State Awareness Objectives

3. Clinical Presentation of Atrial Fibrillation
AF presents with a wide range of symptoms1
May also be asymptomatic
Impact of asymptomatic AF2
Potential for underlying electrical and structural damage to atrial myocardium
While AF symptoms alone may not always be severe, untreated disease can result in significant morbidity and mortality3
LIGHT- HEADEDNESS
PALPITATIONS
DYSPNEA
SYNCOPE
CHEST PAIN
FATIGUE
Clinical Presentation of Atrial Fibrillation
Most patients with AF present with symptoms that include palpitations, chest pain, dyspnea, fatigue, and lightheadedness1
However, symptoms do not always correlate with AF, and some patients have asymptomatic episodes.1 At least one-third of patients report no symptoms of the disease and have no noticeable impairment of quality of life2
Note that even asymptomatic AF can have devastating consequences. The disease can cause electrical and structural damage to the atrial myocardium that can predispose individuals to clinical consequences, such as stroke2-4
References
Fuster V, Ryden LE, Cannon DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (writing committee to revise the 2001 guidelines for the management of patients with atrial fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114:e257-e354.
Page RL, Tilsch TW, Connolly SJ, et al. Asymptomatic or “silent” atrial fibrillation: frequency in untreated patients and patients receiving azimilide. Circulation. 2003;107:
Stewart S, Hart CL, Hole DJ, McMurray JJV. A population-based study of long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study. Am J Med. 2002;113:
Leonardi M, Bissett J. Prevention of atrial fibrillation. Curr Opin Cardiol. 2005;20:
THROMBO- EMBOLISM
DEATH
1. Fuster V et al. Circulation. 2006;114:e257-e Page RL et al. Circulation. 2003;107:
3. Stewart S et al. Am J Med. 2002;113:

4. The ALFA Study Prevalence of Symptoms
Total Population (N=756)
The ALFA Study
Prevalence of Symptoms
Atrial fibrillation (AF) may be symptomatic or asymptomatic. However, the majority of patients seen in general clinical practice are symptomatic.
In the ALFA (Étude en Activité Libérale de la Fibrillation Auriculaire) study, palpitations, dyspnea, and fatigue were found to be the most common symptoms experienced by AF patients.
Chest pain and syncope were present in only 10% of patients.
Reference
Lévy S, Maarek M, Coumel P, et al. Characterization of different subsets of atrial fibrillation in general practice in France: the ALFA study. Circulation. 1999;99:
ALFA = Étude en Activité Libérale de la Fibrillation Auriculaire.
Lévy S et al. Circulation. 1999;99:

5. Burden of Atrial Fibrillation
DRO
Burden of Atrial Fibrillation
Epidemiology and Clinical Impact
Magnitude of the Problem: Epidemiology and Clinical and Economic Impact

6. Epidemiology of Atrial Fibrillation in the US: Rising Prevalence of the Disease
In 2010, 2.66 Million Americans have AF1
Lifetime risk for developing AF is high2
1 in 4 for men and women aged 40 years
Prevalence increases rapidly with age1
3.8% for persons aged 60 years
9% for persons aged 80 years
Predicted Prevalence of AF3
15.9 16
15.2
14.3 14
13.1
11.7 12
10.2
12.1 10
8.9
11.7
11.1
7.7
10.3
Projected No. of Persons With AF (millions) 8
6.7
9.4
5.9
8.4 6
5.1
7.5
6.8
5.6
6.1 4
5.1
Current age-adjusted incidence 2
Increased age-adjusted incidence
2000
2005
2010
2015
2020
2025
2030
2035
2040
2045
2050
Epidemiology of Atrial Fibrillation in the US: Rising Prevalence of the Disease
2.3 Million Americans have atrial fibrillation (AF)1
Lifetime risk for developing AF is high: 1 in every 4 men and 1 in every 4 women aged 40 years will develop AF in their lifetime; thus, both men and women have the same lifetime risk2
The prevalence of AF is increasing, as shown in the graph3
Furthermore, prevalence increases rapidly with age:
3.8% of persons aged 60 years have AF, whereas 9% of persons aged 80 years have the disease1
In other words, AF affects 1 in 25 adults aged >60 years, and 1 in 10 adults aged >80 years1
The rising prevalence may be due to several reasons, including
The aging population1
An increase of predisposing factors for AF (hypertension and diabetes)4
Improved methods of detection
An increasing rate of cardiac surgical procedures
Improved survival with concomitant cardiovascular conditions (myocardial infarction and congestive heart failure)
References
Go AS, Hylek EM, Phillips KA, 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. 2001;285:
Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation. 2004;110:
Miyasaka Y, Barnes ME, Gersh BJ, 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:
Naccarelli GV, Varker H, Lin J, Schulman KL. Increasing prevalence of atrial fibrillation and flutter in the United States. Am J Cardiol. 2009;104:
Year
AF affects 1 in 25 adults aged >60 years and 1 in 10 adults >80 years1
1. Go AS et al. JAMA. 2001;285:
2. Lloyd-Jones DM et al. Circulation. 2004;110:
3. Miyasaka Y et al. Circulation. 2006;114:

7. And These Hospitalization Rates Are Rising…
DRO
And These Hospitalization Rates Are Rising…
Statistics From NHLBI ( )
Hospitalizations for AF by Primary and Secondary Diagnosis, US
Hospitalizations for AF by Age Group, US
100 80 60 40 20
3000
Ages 65 years
2500
2000
Secondary diagnosis
Hospitalizations/10,000 Population
Hospitalizations (Thousands)
1500
1000
Ages years
Primary diagnosis
500
Hospitalization rates for AF are also rising steadily
These graphs illustrate AF hospitalization trends over a 20-year period, with the most recent data from 2006
From 1988 to 2006, hospitalization rates for AF nearly doubled for those aged 45–64 years and slightly more than doubled for those aged 65 years and older
For AF as a primary diagnosis, hospitalizations are 2.5 times higher in 2006 than in 1988.
For AF as a secondary diagnosis, hospitalizations was 3 times higher in 2006 than in 1988.
1982
1987
1992
1997
2000
1980
1985
1990
1995
2000
2005
Year
Year
NHLBI = National Heart, Lung, and Blood Institute.
NHLBI. Accessed June 1, 2009.

8. Atrial Fibrillation Adversely Affects Quality of Life*
DRO
Atrial Fibrillation Adversely Affects Quality of Life* ‡ †
SF-36 Score
Atrial Fibrillation Adversely Affects Quality of Life
This slide summarizes the results of a study comparing quality of life (QOL) in patients with intermittent AF and coronary artery disease patients referred to tertiary care and healthy controls (lower scores = poorer QOL)
Subjective health-related QOL in patients with AF is as impaired as in patients with significant cardiac disease and much worse than in healthy patients
Reference
Dorian P, Jung W, Newman D, et al. The impairment of health-related quality of life in patients with intermittent atrial fibrillation: implications for the assessment of investigational therapy. J Am Coll Cardiol. 2000;36:
SF-36 = 36-question Short-Form health survey.
*Across all scales, both the disease specific and generic QoL was significantly worse in the AF patients compared with the controls (P<0.05 compared with AF patients); †Values represent raw mean scores ± SD; ‡P<0.001 compared with AF patients.
Dorian P et al. J Am Coll Cardiol. 2000;36:

9. Independent Risk Factors for Atrial Fibrillation
Independent Risk Factors for Atrial Fibrillation* Framingham Heart Study
Men† (N=2090)
Women‡ (N=2641)
P0.0001
P0.05
P0.01
Independent Risk Factors for Atrial Fibrillation Framingham Heart Study
95% CI
Men
Women
*2-Year pooled logistic regression; †AF was diagnosed in 226 men in 16,529 follow-up person-examinations; ‡AF was diagnosed in 244 women in 23,763 follow-up person-examinations; §Valvular heart disease was a significantly more potent risk factor for the development of atrial fibrillation in women than in men.
DM = diabetes mellitus; HTN = hypertension; MI = myocardial infarction; CHF = congestive heart failure.
Benjamin EJ et al. JAMA. 1994;271:

10. Impact of Atrial Fibrillation on Mortality. . .Beyond Stroke
3- to 5-fold  in risk of stroke1,2
Stroke severity is worse with AF than without AF3
Hypertension
In the LIFE trial, patients with hypertension and AF had higher rates of CV and all-cause mortality4
Heart failure
Those with AF had a significantly higher mortality than those without AF (SOLVD trial)5
Diabetes
Diabetes is an independent risk factor for AF prevalence and incidence,6,7 and LVH, CHF, and CAD were independently associated with diabetes6
Myocardial infarction
Several studies (eg, GISSI-3, TRACE) have shown that post-MI mortality is higher in those with AF8,9
Sudden cardiac death
AF is an independent risk factor for sudden cardiac death1,10
Impact of Atrial Fibrillation on Mortality. . .Beyond Stroke
Several studies have documented the relationship between AF and other types of cardiovascular disease; the presence of AF with comorbid conditions, such as MI,1,2 hypertension,3 heart failure,4 and diabetes5,6 can increase mortality
Cardiovascular diseases, such as hypertension and ischemic heart disease, often precede AF and are independently associated with increased AF7
Therefore, AF in the presence of underlying cardiovascular disease is among the strongest predictors of worsening disease and mortality8,9
Furthermore, AF is a strong independent predictor of stroke and hospitalization9,10
References
Pizzetti F, Turazza FM, Franziosi MG, et al. Incidence and prognostic significance of atrial fibrillation in acute myocardial infarction: the GISSI-3 data. Heart. 2001;86:
Pedersen OD, Bagger H, Kober L, Torp-Pedersen C, on behalf of the TRACE study group. The occurrence and prognostic significance of atrial fibrillation/flutter following acute myocardial infarction. Eur Heart J. 1999;20:
Wachtell K, Hornestam B, Lehto M, et al. Cardiovascular morbidity and mortality in hypertensive patients with a history of atrial fibrillation. The Losartan Intervention for End Point Reduction in hypertension (LIFE) study. J Am Coll Cardiol. 2005;45:
Middlekauff HR, Stevenson WG, Stevenson LW. Prognostic significance of atrial fibrillation in advanced heart failure. Circulation. 1991;84:40-48.
Movahed MR, Hashemzadeh M, Jamal MM. Diabetes mellitus is a strong, independent risk for atrial fibrillation and flutter in addition to other cardiovascular disease. Int J Cardiol. 2005;105:
Nichols GA, Reinier K, Chugh SS. Independent contribution of diabetes to increased prevalence and incidence of atrial fibrillation. Diabetes Care. 2009;32:
Fuster V, Ryden LE, Cannon DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (writing committee to revise the 2001 guidelines for the management of patients with atrial fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114:e257-e354.
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:
Dries DL, Exner DV, Gersh BJ, et al. Atrial fibrillation is associated with an increased risk for mortality and heart failure progression in patients with asymptomatic and symptomatic left ventricular systolic dysfunction: a retrospective analysis of the SOLVD trials. J Am Coll Cardiol. 1998;32:
Dulli DA, Stanko H, Levine RL. Atrial fibrillation is associated with severe acute ischemic stroke. Neuroepidemiology. 2003;22:
CAD = coronary artery disease; CHF = congestive heart failure; CV = cardiovascular; LVH = left ventricular dysfunction.
1. Benjamin EJ et al. Circulation. 1998;98: Fuster V et al. Circulation. 2006;114:e257-e Dulli DA et al. Neuroepidemiology. 2003;22: Wachtell K et al. J Am Coll Cardiol. 2005;45: Dries DL et al. J Am Coll Cardiol. 1998;32: Movahed MR et al. Int J Cardiol. 2005;105: Nichols GA et al. Diabetes Care. 2009;32: Pizzetti F et al. Heart. 2001;86: Pedersen OD et al. Eur Heart J. 1999;20:
10. Middlekauff HR et al. Circulation. 1991;84:40-48.

11. Atrial Fibrillation is Linked to …
Dementia/Alzheimer’s1
AF patients were 44% more likely to develop dementia
Younger patients with AF are at higher risk of developing all types of dementia, particularly Alzheimer’s
Patients with both AF and dementia were 61% more likely to die during study period than patients without AF
Sleep Apnea2
Arrhythmia risk of older men rises with severity of sleep apnea and other sleep-related breathing disorders
Men with the worst respiratory disturbance at night had 2x more nocturnal AF
Growing evidence for a link between cardiac health and sleep disorders
Obesity3
BMI was associated with short- and long-term increase in AF risk
Women becoming obese in first 60 months of study had 41% increase in risk of developing AF
Short-term elevations in BMI resulted in 18.3% increase in AF incidence
“Weight control may be a reasonable strategy for reducing the growing burden of AF”
1. Bunch J et al. Heart Rhythm. 2010; 7: Mehra R et al. Arch Intern Med. 2009; 169:
3. Tedrow et al. Journal of the American College of Cardiology. 2010; 55; Tedrow et al. 3.

12. DRO
Atrial Fibrillation / Flutter Is Associated with Increased Morbidity and Mortality
Death: 2-fold  in risk
Thromboembolism / stroke: 4.5-fold  in risk
Tachycardia-induced worsening of associated myocardial ischemia or heart failure
Adverse atrial and ventricular remodeling due to tachycardia-induced cardiomyopathy
Cardiovascular hospitalization: 2 to 3-fold  in risk
Krahn AD, et al al. Am J Med. 1995;98: Benjamin EJ, et al. Circulation. 1998;98: 12

13. AF-Attributable Utilization (Annual) of Key Health Care Resources
Coyne KS, Paramore C, Grandy S, Mercader M, Reynolds MR, Zimetbaum P. Assessing the direct costs of treating nonvalvular atrial fibrillation in the United States. Value Health.2006;9:348–356.
Coyne KS, Paramore C, Grandy S, Mercader M, Reynolds MR, Zimetbaum P. Assessing the direct costs of treating nonvalvular atrial fibrillation in the United States. Value Health.2006;9:348–356.

14. Economic Impact and Public Health Burden of Hospitalizations in Those With Atrial Fibrillation
Significant public health burden; total AF-attributable costs estimated at 6.65 billion1-5
Annual cost per patient ~$47005
Associated with more hospitalizations than any other arrhythmia6
Approximately one third for cardiac rhythm disturbances1
Increased hospitalizations impact quality of life and health care costs2,7
Economic Impact and Public Health Burden of Hospitalizations in Those With Atrial Fibrillation
Atrial fibrillation (AF) represents a significant public health burden.1,2 It is the most common arrhythmia in clinical practice and accounts for approximately one-third of hospitalizations for cardiac rhythm disturbances2
Furthermore, hospitalizations for AF have increased substantially (2- to 3-fold).4 The Cost of Care in Atrial Fibrillation (COCAF) study was a prospective survey designed to evaluate the cost of care for patients with AF (N=671) who were treated by cardiologists in an outpatient setting. The costs of care were analyzed from the health care payer and societal perspectives. Compared with patients with paroxysmal AF, those with persistent or permanent AF were hospitalized much more frequently (P<0.05). Additionally, hospitalizations and pharmacotherapy accounted for the majority of costs (52% and 23%, respectively)3
In conclusion, the adverse trend toward hospitalization among an aging population combined with the prevalence of heart failure sets the stage for an enormous burden on the health care system4
References
Fuster V, Ryden LE, Cannon DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (writing committee to revise the 2001 guidelines for the management of patients with atrial fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114:e257-e354.
LeHuezey J-Y, Paziaud D, Piot O, et al. Cost of care distribution in atrial fibrillation patients: the COCAF study. Am Heart J. 2004;147:
Singh SN, Tang XC, Singh BN, et al. Quality of life and exercise performance in patients in sinus rhythm versus persistent atrial fibrillation. J Am Coll Cardiol. 2006;48:
Wattigney WA, Mensah GA, Croft JB. Increasing trends in hospitalization for atrial fibrillation in the United States, 1985 through 1999: implications for primary prevention. Circulation. 2003;108:
1. Fuster V et al. Circulation. 2006;114:e257-e Le Heuzey J-Y et al. Am Heart J. 2004;147: Coyne KS et al. Value Health. 2006;9: Kim MH et al. Adv Ther. 2009;26: Reynolds MR et al. J Cardiovasc Electrophysiol. 2007;18: Singh SN et al. J Am Coll Cardiol. 2006;48: Wattigney WA et al. Circulation. 2003;108:

15. Goals of AF Management and Treatment
DRO
Goals of AF Management and Treatment
Successful management of AF should also aim at further reducing CV morbidity, mortality, and hospitalization1-4
Wolf.Arch Intern Med.February.1998/p234/c2/lines 9-14
Wolf.Stroke.August.1991/p987/c1/lines 53-58
AF management
Prystowsky.J Cardiovasc Electrophysiol September.2006/pS7/c2/lines 5-7
Prevention of thrombo- embolism
Reduction of AF burden*
Reduction of morbidity and mortality
The successful management of AF should include the following goals:
Prevention of thromboembolism (Wolf.Stroke.August.1991/p987/c1/lines 53-58)
Reduction of AF recurrence2 (Prystowsky.J Cardiovasc Electrophysiol.September.2006/pS7/c2/lines 5-7)
Reduction of morbidity and mortality3 (Wolf.Arch Intern Med.February.1998/p234/c2/lines 9-14)
*Total percentage of time a patient has AF as determined by the number and duration of AF episodes.
1. Wolf PA, et al. Stroke. 1991;22: ; 2. Prystowsky EN. J Cardiovasc Electrophysiol. 2006;17(suppl 2):S7-S10; 3. Singh SN, et al. J Am Coll Cardiol. 2006;48: ; 4. Wolf PA, et al. Arch Intern Med. 1998;158:
Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke ;22:
Prystowsky EN. Assessment of rhythm and rate control in patients with atrial fibrillation. J Cardiovasc Electrophysiol. 2006;17 (suppl 2):S7-S10.
Singh SN, Tang XC, Singh BN, et al. Quality of life and exercise performance in patients in sinus rhythm versus persistent atrial fibrillation: a Veterans Affairs Cooperative Studies Program substudy. J Am Coll Cardiol. 2006;48:
Wolf PA, Mitchell JB, Baker CS, Kannel WB, D’Agostino RB. Impact of atrial fibrillation on mortality, stroke, and medical costs. Arch Intern Med. 1998;158:

16. Significant Unmet Needs in the Treatment of Atrial Fibrillation
Summary of AF
Prevalence is rapidly increasing1
Significantly increases CV mortality2,3
Driver of CV hospitalizations and other health care resource utilization4-6
Successful therapy needs reduce both symptoms and AF burden7
AF Unmet Needs
Early restoration and maintenance of sinus rhythm8
Reduction in CV morbidity and mortality2
Reduction in CV events and hospitalizations6
Effective methods to maintain sinus rhythm with fewer side effects8
Significant Unmet Needs in the Treatment of Atrial Fibrillation
Summary of AF
The prevalence of AF is rapidly increasing1
Based on an estimated 61% increase in the number of adults in the United States with AF from 1980 to 2000 (from 3.2 million to 5.1 million), and a population that continues to age, as many as 15.9 million people in the United States could have AF by the year 20501
The presence of AF has been significantly associated with higher mortality rates in patients with cardiovascular disease (CVD)2,3
In a prospective cohort study of patients with AF and 1 other CVD diagnosis, compared with a matched group without AF, the presence of AF increased mortality risk by approximately 20%2
AF is also a driver of CV hospitalizations and other health care resource utilization4-6
Successful therapy needs to reduce both symptoms and AF burden7
AF Unmet Needs
Early restoration and maintenance of sinus rhythm8
Reduction in CV morbidity and mortality2
Reduction in CV events and hospitalizations6
Effective methods to maintain sinus rhythm with fewer side effects8
References
Miyasaka Y, Barnes ME, Gersh BJ, 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:
Wolf PA, Mitchell JB, Baker CS, Kannel WB, D’Agostino RB. Impact of atrial fibrillation on mortality, stroke, and medical costs. Arch Intern Med. 1998;158:
Haywood LJ, Ford CE, Crow RS, et al; for the ALLHAT Collaborative Research Group. Atrial fibrillation at baseline and during follow-up in ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial). J Am Coll Cardiol. 2009;54:
Reynolds MR, Essebag V, Zimetbaum P, Cohen DJ. Healthcare resource utilization and costs associated with recurrent episodes of atrial fibrillation: the FRACTAL registry. J Cardiovasc Electrophysiol. 2007;18:
Kim MH, Lin J, Hussein M, Kreilick C, Battleman D. Cost of atrial fibrillation in Unites States managed care organizations. Adv Ther. 2009;26:
Wattigney WA, Mensah GA, Croft JB. Increasing trends in hospitalization for atrial fibrillation in the United States, 1985 through Circulation. 2003;108:
Prystowsky EN. Assessment of rhythm and rate control in patients with atrial fibrillation. J Cardiovasc Electrophysiol. 2006;17(suppl 2):S7-S10.
Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (writing committee to revise the 2001 guidelines for the management of patients with atrial fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114:e257-e354.
CV = cardiovascular.
1. Miyasaka Y et al. Circulation. 2006;114: Wolf PA et al. Arch Intern Med. 1998;158:
3. Haywood LJ et al. J Am Coll Cardiol. 2009;54: Reynolds MR et al. J Cardiovasc Electrophysiol. 2007;18: Kim MH et al. Adv Ther. 2009;26: Wattigney WA. Circulation. 2003;108: Prystowsky EN. J Cardiovasc Electrophysiol. 2006;17(suppl 2):S7-S Fuster V et al. Circulation. 2006;114:e257-e354. 16

17. Atrial Fibrillation is a Progressive Cardiovascular Disease
DRO
Atrial Fibrillation is a Progressive Cardiovascular Disease
The Need for Early Intervention
Pathophysiology and Underlying Mechanisms of Atrial Fibrillation
Atrial Fibrillation Is a Progressive Cardiovascular Disease

18. What Can Cause Atrial Fibrillation?
Alcohol1
Psychological stress/Anxiety1
Heart stimulating agents: Caffeine, Cold Medications, etc. 1
Heart surgery
Heart attacks
Cardiomyopathy
Heart valve disease (genetic, infectious, degeneration/calcification of the valves)
Pericarditis (inflammation)
Hyperthyroidism
Pulmonary embolism
Hypertension
Atrial flutter
Other heart conditions that stretch, scar or thicken the heart muscle2
Shea, J. A Patient’s Guide to Living with Atrial Fibrillation. Circulation. 2008; 117e340-e343. Available at Last accessed July 3, 2008.
Fuster, V 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. 2011; 123: e269-e367.
1. Shea, J. A Patient’s Guide to Living with Atrial Fibrillation. Circulation. 2008; 117e340-e343. Available at Last accessed July 3, 2008.
2. Fuster, V 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. 2011; 123: e269-e367.

19. 1
In AF, the heart rate may reach 100 to 175 bpm2, and the ventricular rate may accelerate excessively during exercise even when well-controlled at rest3
1. Accessed August 13, 2009.
2. Accessed February 5, Fuster V et al. Circulation. 2006;114:e257-e354.

20. Development of Atrial Fibrillation
RAA
LAA SN
SVC
I A S CT PV
RAFW
CSO
LAFW
IVC
Development of Atrial Fibrillation
Ectopic foci may initiate AF. Frequently, these foci are located in the pulmonary veins or atria. Atrial myocytes that have been identified extending into the pulmonary veins are likely remnants of embryonic development.1 In a study of 79 patients with frequent AF, electrophysiologic and anatomic properties of pulmonary veins were investigated. Sections of the pulmonary veins closest to the atria demonstrated the shortest effective refractory periods (ERPs), and the right superior sections had a higher incidence of intravein conduction block. Ectopic foci were more commonly found in the superior pulmonary veins. Interestingly, superior and left pulmonary veins had longer myocardial sleeves, possibly explaining the greater frequency of ectopic foci2
Once triggered, AF is perpetuated in the form of multiple small wavelets in which the ERP is shorter, allowing reentry of some of the wavelets. Initially, AF activity may occur as large reentrant loops or small circuits. The smaller circuits are more likely to persist. The smallest circuit results from reactivation of a region of atrium recently repolarized. Thus, decreases in atrial effective refractory period (AERP) and dispersion of ERP are factors that perpetuate AF. The circumference of the wavelet may be calculated by conduction velocity times refractory period and is called tissue wavelength3
The concept of triggers, such as ectopic foci and perpetuation of AF by short ERPs, has important implications for AF therapy3
In the 1960s Moe suggested that the atrial activity in AF, rather than being random, proceeds as multiple wavelets that arc around the atrium, some of which circle back on themselves (reentry). For this action to continue, the conduction velocity must be such that the time taken for the wavelet to complete 1 circuit exceeds the time required for an atrial region to recover from its last activation (its refractory period). In AF, the conduction velocity and refractory period vary across the atria (spatial heterogeneity) so that wavelets follow dynamically altering courses and few, in practice, complete a classic reentrant loop.4 This theory has been supported by intraoperative cardiac mapping in human beings and may explain the clinical correlates of AF3
References
Solc D. The heart and heart conducting system in the kingdom of animals: a comparative approach to its evolution. Exp Clin Cardiol. 2007;12:
Chen SA, Hsieh MH, Tai CT. Initiation of atrial fibrillation by ectopic beats originating from the pulmonary veins: electrophysiological characteristics, pharmacological responses, and effects of radiofrequency ablation. Circulation. 1999;100:
Narayan SM, Cain ME, Smith JM. Atrial fibrillation. Lancet. 1997;350:
Moe GK. On the multiple wavelet hypothesis of atrial fibrillation. Arch Intl Pharmacodynam Ther. 1962;140:
Multiple Wavelets1,2
Focal Triggers2,3
CSO = coronary sinus ostium; CT = crista terminalis; IAS = interatrial septum; IVC = inferior vena cava; LAFW = left atrial free wall; RAA/LAA = right/left atrial appendage; RAFW = right atrium free wall; SN = sinus node; SVC = superior vena cava.
1. Narayan SM et al. Lancet. 1997;350: Fuster V et al. Circulation. 2006;114:e257-e Chen SA et al. Circulation. 1999;100:

21. Classification and Patterns of Atrial Fibrillation ACC/AHA/ESC Guidelines
DRO
First detected*
7 d
>7 d
May be recurrent†
Paroxysmal
(self-terminating)
Persistent
(not self-terminating)
Classification and Patterns of Atrial Fibrillation
ACC/AHA/ESC Guidelines
The clinician should distinguish a first-detected episode of symptomatic or self-limited AF, although there may be uncertainty about the duration of the episode and about previous undetected episodes
After 2 or more episodes, AF is considered recurrent. If the arrhythmia terminates spontaneously, recurrent AF is designated paroxysmal; when sustained beyond 7 days, it is termed persistent. First-detected AF may be either paroxysmal or persistent
Both paroxysmal AF and persistent AF are potentially recurrent arrhythmias. Over time, paroxysmal AF may become persistent; likewise, both paroxysmal and persistent AF may become permanent
The category of persistent AF also includes cases of long-standing AF (eg, longer than 1 y), usually leading to permanent AF, in which cardioversion has failed or has been foregone. The definition of permanent AF is often arbitrary, and the duration refers both to individual episodes and to how long the diagnosis has been present in a given patient
ACC/AHA/ESC Guidelines: Recurrent AF
Recent guidelines recommend a classification system based on the temporal pattern of the arrhythmia. When a patient has 2 or more episodes, AF is considered recurrent. If AF terminates spontaneously, it is classified as paroxysmal. If AF is sustained for more than 7 days, it is classified as persistent. The designation does not change if AF ceases with pharmacologic therapy or direct-current cardioversion
Lone AF generally applies to younger individuals (<60 years) without clinical or echocardiographic evidence of cardiopulmonary disease, including hypertension. Patients with lone AF have a favorable prognosis with regard to thromboembolism and mortality. Over time, patients may move out of the lone AF category due to aging or cardiac abnormalities, at which time, risk of thromboembolism and mortality rise accordingly
These categories are not mutually exclusive. A patient may have several episodes of paroxysmal AF and occasionally experience persistent AF, or vice versa
Reference
Fuster V, Ryden LE, Cannon DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (writing committee to revise the 2001 guidelines for the management of patients with atrial fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114:e257-e354.
Permanent
Cardioversion failed or not attempted
Cardioversion failed or not attempted
*Lone AF generally applies to younger individuals (<60 years) without clinical or echocardiographic evidence of cardiopulmonary disease, including hypertension; †Recurrent AF defined as ≥2 episodes; termination with pharmacologic or direct-current cardioversion does not change designation.
Adapted from Fuster V et al. Circulation. 2006;114:e257-e354.

22. AF Disease Progression Can Lead to Cardiac Remodeling
DRO
Electrical1
Shortening of atrial refractory periods2
Loss of normal adaptation of atrial refractoriness to heart rate3
Contractile1
Structural1
Histologic changes4
Left atrium and LA appendage enlargement5
Decrease in cardiac output6
Electrical remodeling (ie, shortening of atrial refractoriness) develops within a few days of the onset of AF. Subsequently, contractile remodeling of the atria leads to a reduction in atrial transport function and loss of contractility. Moreover, the reduction in atrial contractility may enhance atrial dilatation, thus causing AF to persist.
This slide shows the relationship between electrical, contractile, and structural remodeling. It is hypothesized that downregulation of L-type Ca2+ channels initiates both electrical and contractile remodeling. The ensuing “stretching” of the atrial myocardium may cause further loss of contractility, which serves as the primary stimulus for the structural remodeling of the atria. Ultimately, this results in dilated atria and small intra-atrial circuits that have a shortened refractory period. Eventually these changes persist and AF becomes permanent.
Reduced atrial contractility4
1. Allessie M, et al. Cardiovasc Res. 2002;54: ; 2. Prystowsky EN, et al. Circulation. 1996;93: ; 3. Hobbs WJC, et al. Circulation. 2000;101: ; 4. Thijssen VLJL, et al. Cardiovasc Pathol. 2000;9:17-28; 5. Sanfilippo AJ, et al. Circulation. 1990;82: ; 6. Fuster V, et al. Circulation. 2006;114:e257-e354. 22
Allessie M, Ausma J, Schotten U. Electrical, contractile and structural remodeling during atrial fibrillation. Cardiovasc Res. 2002;54:

23. The Chronic Progressive Nature of AF
DRO
The AF Continuum of Disease1
Diagnosis
Paroxysmal AF
AF episodes ≤7days
Spontaneous termination
Persistent AF
AF episodes >7 days
No spontaneous termination
Permanent AF
AF that cannot be converted to SR
AF episode
Sinus rhythm (SR)
It takes an average of 1.7 years before patients are diagnosed,
leaving patients vulnerable2
1. Kirchhof P, et al. Europace. 2007;9:
2. The State of AFib in America Survey. March-April 23

24. Atrial Fibrillation in the Cardiovascular Continuum
Remodeling
Ventricular
dilatation MI HF
LVH and
atherosclerosis
End-stage microvascular and heart disease
AF1,2
Risk factors
(diabetes,
hypertension)
Atrial Fibrillation in the Cardiovascular Continuum
Atrial fibrillation (AF) can be present with, be affected by, and serve as a contributing factor in a wide range of cardiovascular (CVD) conditions
Risk factors for CVD (eg, hypertension and diabetes) also predispose patients to AF
Additionally, AF may increase the risk of CVD1-3
Several renin-angiotensin-aldosterone system pathways are activated in experimental models of AF as well as AF patients. Furthermore, inhibition of angiotensin-converting enzyme and blockade of angiotensin II receptor may potentially prevent AF by reducing fibrosis4,5
Therefore, modification of risk factors for CVD may decrease the incidence of AF5
References
Fuster V, Ryden LE, Cannon DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (writing committee to revise the 2001 guidelines for the management of patients with atrial fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114:e257-e354.
Benjamin EJ, Levy D, Vaziri SM, et al. Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study. JAMA. 1994;271:
Krahn AD, Manfreda J, Tate RB, Mathewson FAL, Cuddy TE. The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-up Study. Am J Med. 1995;98:
Nakashima H, Kumagai K, Urata H, et al. Angiotensin II antagonist prevents electrical remodeling in atrial fibrillation. Circulation. 2000;101:
Tsai C-T, Lai L-P, Lin J-L, et al. Renin-angiotensin system gene polymorphisms and atrial fibrillation. Circulation. 2004;109:
Death
RAAS can impact the progression of AF,
and inhibition of RAAS can have some beneficial effects3,4
HF = heart failure; LVH = left ventricular hypertrophy; MI = myocardial infarction; RAAS = renin-angiotensin-aldosterone system.
1. Fuster V et al. Circulation. 2006;114:e257-e Benjamin EJ et al. JAMA. 1994;271: Krahn AD et al. Am J Med. 1995;98: Nakashima H et al. Circulation. 2000;101: Tsai CT et al. Circulation. 2004;109:

25. DRO
Patients Who Convert to Sinus Rhythm Within 3 Months of Atrial Fibrillation Onset Are More Likely to Remain in Sinus Rhythm
P<0.02
82%
36%
Patients Who Convert to Sinus Rhythm Within 3 Months of Atrial Fibrillation Onset Are More Likely
to Remain in Sinus Rhythm
The 3 groups are divided based on how long the patient was in AF prior to cardioversion: for instance, the orange bars represent patients who were converted to less than 3 months of AF onset, and so forth. The bars represent the percentage of patients who remained in sinus rhythm (SR) after cardioversion at 3 different time points: immediately after, and 1 and 6 months after
Dittrich and colleagues evaluated echocardiographic and clinical features in patients with AF who had been converted to SR (N=85) to determine predictors of success in maintaining SR
Among the patients with AF of less than 3 months’ duration prior to cardioversion, 82% remained in SR 1 month after cardioversion, compared with 36% of those whose AF had been present for more than 12 months (P<0.02)
The investigators found that the duration of AF may predict the maintenance of SR at 1 month after successful cardioversion
Reference
Dittrich HC, Erickson JS, Schneiderman T, Blacky AR, Savides T, Nicod PH. Echocardiographic and clinical predictors for outcome of elective cardioversion of atrial fibrillation. Am J Cardiol. 1989;63:
Dittrich HC et al. Am J Cardiol. 1989;63:

26. Adopt Protocol-Driven AF Management Utilizing 2011 ACCF/AHA/HRS Guidelines
Ventricular Rate Control
Early Restoration of Sinus Rhythm
Stroke & Thromboembolism Prevention
Now we will take a look at the ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation
Classification of Atrial Fibrillation and Therapeutic Options

27. AF Treatment Options Rate Control Rhythm Stroke Prevention
DRO
Rate
Control
Rhythm
Stroke
Prevention

28. Rate Control During Atrial Fibrillation
DRO
Rate Control During Atrial Fibrillation
Rate control usually targets heart rate of bpm at rest and bpm during moderate exercise.
New Recommendations for Rate Control During Atrial Fibrillation:
Treatment to achieve strict rate control of heart rate (<80 bpm at rest or <110 bpm during a 6-minute walk) is not beneficial compared to achieving a resting heart rate of <110 bpm in patients with persistent AF who have stable ventricular function (left ventricular ejection fraction >0.40) and no or acceptable symptoms related to the arrhythmia, though uncontrolled tachycardia may over time be associated with a reversible decline in ventricular performance. (Level of Evidence: B)
Wann LS, et al. Circulation 2011;123:

29. Rhythm Control
DRO
Used to maintain sinus rhythm, suppress symptoms, improve exercise capacity and hemodynamic function, and prevent tachycardia-induced cardiomyopathy due to AF1
Restoration of sinus rhythm may prevent AF progression2
Common agents include amiodarone, dofetilide, dronedarone, flecainide, propafenone, and sotalol
Most AADs have been shown to be 50-65% effective at maintaining sinus rhythm over a 6-12 month period3
1. Fuster V, et al. Circulation 2006;114:
2. Bunch TJ, Gersh BJ. J Gen Intern Med 2011; May;26(5):531-7
3. Naccarelli GV, et al. Am J Cardiol 2003;91(suppl):15D-26D.

30. Maintenance of Sinus Rhythm No (or minimal) heart disease
DRO
2011 ACCF/AHA/HRS Focused Update on the Management of Patients with Atrial Fibrillation
Maintenance of Sinus Rhythm
No (or minimal) heart disease
Hypertension
Coronary Artery
Disease
Heart Failure
Dronedarone
Flecainide
Propafenone
Sotalol
Substantial LVH
Dofetilide
Dronedarone
Sotalol
Amiodarone
Dofetilide No
Yes
Amiodarone
Dofetilide
Catheter
ablation
Amiodarone
Catheter
ablation
Catheter
ablation
Amiodarone
Dofetilide
Catheter
ablation
Dronedarone
Flecainide
Propafenone
Sotalol
Amiodarone
2011 ACCF/AHA/HRS Focused Update on the Management of Patients with Atrial Fibrillation
AADs to Maintain SR in Patients With Recurrent Paroxysmal or Persistent Atrial Fibrillation
The recommendations for drug therapy for patients with recurrent paroxysmal or persistent AF are presented on this slide
For patients with no (or minimal) heart disease, therapy should begin with dronedarone, flecainide, propafenone, or sotalol. If these drugs are not effective, amiodarone or dofetilide may be initiated. If AF persists, treatment with disopyramide, procainamide, or quinidine may be attempted. Nonpharmacologic options may also be considered at this point
Patients with heart disease have a greater risk of adverse events with the use of antiarrhythmic drugs; therapy must be tailored to the type of heart disease and in accordance with safety data in the medical literature. For patients with heart failure, amiodarone and dofetilide are the drugs of choice. For patients with coronary heart disease, a first attempt should be made using sotalol, followed by amiodarone and dofetilide. Disopyramide, procainamide, or quinidine may be used in these patients if the more appropriate drugs fail. Hypertensive patients with left ventricle (LV) hypertrophy of 1.4 cm or greater can be treated with amiodarone. The first choice for hypertensive patients with LV hypertrophy less than 1.4 cm is flecainide or propafenone, followed by amiodarone, dofetilide, or sotalol. If AF persists, these patients can be treated with disopyramide, procainamide, or quinidine
Reference
Wann LS, et al. Circulation 2011;123:
Catheter
ablation
Drugs are listed alphabetically and not in order of suggested use. The seriousness of heart disease progresses from left to right, and selection of therapy in patients with multiple conditions depends on the most serious condition present. LVH indicates left ventricular hypertrophy.
Wann LS, et al. Circulation 2011;123:

31. “In…A Fib, what may matter most to patients is not the risk of stroke or bleeding but rather the risks of functional and cognitive disability.”
Fraenkel L, et al. Individualized Medical Decision Making. Arch Intern Med. 2010; 170:

32. Atrial Fibrillation and Stroke
DRO
Atrial Fibrillation and Stroke
Stroke is the most common and devastating complication of AF1,2
Incidence of all-cause stroke in patients with AF is 5%1
AF is an independent risk factor for stroke2
Approximately 15% of all strokes in the U.S. are caused by AF1
Risk for stroke increases with age1
Ischemic stroke associated with AF is often more severe than stroke from other etiology3
Stroke risk persists even in asymptomatic AF4
AFib is an independent risk factor for stroke; in fact, it increases the risk of stroke approximately 5-fold.1,2 It is estimated that 15% of all strokes in the United States are attributable to AFib, and the proportion increases markedly with age.1 Additionally, ischemic stroke associated with AFib is often more severe than stroke due to other causes.3 A retrospective study determined that those with AFib were more likely than those without AFib to be bedridden following a stroke (41.2% vs 23.7%, P<.0005).3 Finally, asymptomatic, or “silent,” AFib is common and may also increase the risk of stroke.4
1. Fuster V, et al. Circulation 2006;114:e257-e Benjamin EJ, et al. Circulation 1998;98: Dulli DA, et al. Neuroepidemiology 2003;22: Page RL, et al. Circulation 2003;107:

33. CHADS2 Stroke Risk Stratification Scheme for Patients With Nonvalvular AF
DRO
Risk factors
Score C
Recent congestive heart failure 1 H
Hypertension A
Age ≥75 yrs D
Diabetes mellitus S2
History of stroke or transient ischemic attack 2
1.9
2.8
4.0
5.9
8.5
12.5
18.2
0.0
5.0
10.0
15.0
20.0 1 2 3 4 5 6
CHADS
Score
Stroke Rate (%)
Atrial fibrillation (AF) is the most important risk factor for ischemic stroke in the elderly.
Risk stratification schemes that recognize a continuum of stroke risk from AF rather than a simple dichotomy of “low” and “high” risk are more useful to the clinician.1
One such scheme is the recently proposed CHADS2 (Congestive heart failure, Hypertension, Age, Diabetes, Stroke/TIA) risk assessment for nonvalvular AF.2
CHADS2 has been validated and incorporated into a National Registry of AF (NRAF) consisting of 1733 Medicare beneficiaries aged 65 to 95 years who had nonrheumatic AF and were not prescribed warfarin at hospital discharge.
The CHADS2 index was formed by assigning 1 point each for the presence of congestive heart failure, hypertension, age 75 years or older, and diabetes mellitus and by assigning 2 points for history of stroke or transient ischemic attack.
Relationship between CHADS2 score and annual risk of stroke
Adapted from Hersi A, et al. Curr Probl Cardiol. 2005;30:175–234.
1. Hersi A, Wyse DG. Management of atrial fibrillation. Curr Probl Cardiol. 2005;30:
2. Gage B, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke. Results from the National Registry of Atrial Fibrillation. JAMA. 2001;285: . 33

34. Antithrombotic Therapy for AF
DRO
Risk Factors1
Recommended Therapy*
No risk factors
Aspirin, 81 to 325 mg daily
1 moderate-risk factor
Aspirin, 81 to 325 mg daily, or warfarin (INR 2.0 to 3.0, target 2.5)
Any high-risk factor or >1 moderate-risk factor
Warfarin (INR 2.0 to 3.0, target 2.5)
*If mechanical valve, target INR >2.5
Dabigatran is useful as an alternative to warfarin for the prevention of stroke and systemic thromboembolism in patients with paroxysmal to permanent AF and risk factors for stroke or systemic embolization who do not have a prosthetic heart valve or hemodynamically significant valve disease, severe renal failure (creatinine clearance < 15 mL/min), or advanced liver disease (impaired baseline clotting function).2-3 Class 1, Level of evidence B
1. Fuster V, et al. Circulation. 2006;114:e257-e354.
2. Wann LS, et al. Circulation. 2011;123:
3. Connolly SJ, et al. N Engl J Med. 2009;361:1139–1151.

35. Thrombotic Risk Continues in High-Risk Patients Even When SR is Maintained
III
IIb
IIa I B A C
Antithrombotic therapy is recommended for all patients with AF, except those with lone AF or contraindications
Antithrombotic therapy is recommended for patients with atrial flutter as for those with AF
It is reasonable to select antithrombotic therapy using the same criteria irrespective of the pattern (ie, paroxysmal, persistent, or permanent) of AF
In high-risk AF patients, therapeutic anticoagulation should be continued
Thrombotic Risk Continues in High-Risk Patients Even When SR Is Maintained
This slide describes the patients for whom anticoagulation should be considered despite maintenance of sinus rhythm
Factors associated with a high risk of stroke include previous stroke, TIA, or embolism; mitral stenosis; and the presence of prosthetic heart valves
Reference
Fuster V, Ryden LE, Cannon DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (writing committee to revise the 2001 guidelines for the management of patients with atrial fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114:e257-e354.
SR = sinus rhythm.
Fuster V et al. Circulation. 2006;114:e257-e354.

36. Optimal Management Encompasses All Three Components
AF Treatment Options
DRO
Rate
Control
Rhythm
Control
Stroke
Prevention
Optimal Management Encompasses All Three Components

37. Selecting Agents
DRO
Initial therapy may be anticoagulation and rate control, while the long-term goal is to restore sinus rhythm
Restoration of sinus rhythm becomes clear goal when rate control offers inadequate symptomatic relief
Traditional agents have not demonstrated benefits in patient focused outcomes.
Currently published and/or ongoing trials are demonstrating beneficial outcomes in morbidity, mortality and hospitalizations
Wann LS, et al. Circulation 2011;123:

38. Defining Success With Management of Atrial Fibrillation
DRO
Defining Success With Management of Atrial Fibrillation
Early Intervention and Long-Term
Commitment Are Required
Defining Success With Management of Atrial Fibrillation
Early Intervention and Long-Term Commitment Are Required

39. Defining Success With Management of Atrial Fibrillation
Current common measures of success1,2
Any AF recurrence
Time to first recurrence of AF
Reduction of AF burden
Redefining the best measure of success: reduction in AF burden and symptoms
Mortality1
Cardiovascular hospitalization2
Quality of life3
Frequency of episodes
Duration of episodes
Symptoms during episodes
Success in Rhythm Control
Clinical trials comparing rhythm vs rate-control strategies for the management of AF have demonstrated efficacy in terms of clinical outcomes, such as mortality, but have failed to define appropriate measures of treatment “success” in terms of individual patient outcomes1,2
A typical measure of treatment success is the reduction in frequency and duration of AF episodes, and with a few exceptions, most patients can tolerate the occasional AF episode. In these patients, rate control may be considered successful even without complete elimination of all episodes of AF1,2
Successful rate control therapy may be reasonably defined by a 24-hour heart rate that approximates normal sinus rhythm. AF symptoms are minimized, and the risk of tachycardia-mediated cardiomyopathy is reduced when rate adequate control is achieved1,2
A number of measures have been used to gauge the success of antiarrhythmic drug (AAD) therapy1,2
Time to first recurrence of AF
Any AF recurrence
AF burden
Reduction in symptoms
Reduction of AF burden and symptoms may be a better measure of success than reduction in AF burden alone1
Atrial fibrillation burden is defined as the total percentage of time a patient has AF and is determined by the number and duration of AF episodes
A reduction in episodes following initiation of AAD therapy without improvement in symptoms would not be considered clinical success1
Symptoms do not always correlate with AF; many patients have asymptomatic episodes
Further clinically relevant redefinition of success of atrial fibrillation treatment may include CV hospitalizations and quality of life
In the AFFIRM trial, CV hospitalization occurred more frequently than death, and has many attributes of a surrogate for mortality2
Quality of life is as impaired in patients with intermittent AF as in patients with significant structural heart disease, and patient’s perception of quality of life is not dependent on the objective measures of disease severity that are usually emplyed3
References
Prystowsky EN. Assessment of rhythm and rate control in patients with atrial fibrillation. J Cardiovasc Electrophysiol. 2006;17(suppl 2):S7-S10.
Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (writing committee to revise the 2001 guidelines for the management of patients with atrial fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114:e257-e354.
Wyse DG, Slee A, Epstein AE, et al. Alternative endpoints for mortality in studies of patients with atrial fibrillation: the AFFIRM study experience. Heart Rhythm. 2004;1:
Dorian P, Jung W, Newman, et al. The impairment of health-related quality of life in patients with intermittent atrial fibrillation: implications for the assessment of investigational therapy. J Am Coll Cardiol. 2000;36:
1. Prystowsky EN. J Cardiovasc Electrophysiol. 2006;17(suppl 2):S7-S Fuster V et al. Circulation. 2006;114:e257-e Wyse DG et al. Heart Rhythm. 2004;1: Dorian P et al. J Am Coll Cardiol. 2000;36:

40. Conclusion Summary of AF Prevalence is rapidly increasing1
DRO
Summary of AF
Prevalence is rapidly increasing1
Significantly increases CV mortality2,3
Driver of CV hospitalizations and other health care resource utilization4-6
AF Unmet Needs
Early restoration and maintenance of sinus rhythm7
Reduction in CV morbidity and mortality2
Reduction in CV events and hospitalizations6
Significant Unmet Needs in the Treatment of Atrial Fibrillation
Summary of AF
The prevalence of AF is rapidly increasing1
Based on an estimated 61% increase in the number of adults in the United States with AF from 1980 to 2000 (from 3.2 million to 5.1 million), and a population that continues to age, as many as 15.9 million people in the United States could have AF by the year 20501
The presence of AF has been significantly associated with higher mortality rates in patients with cardiovascular disease (CVD)2,3
In a prospective cohort study of patients with AF and 1 other CVD diagnosis, compared with a matched group without AF, the presence of AF increased mortality risk by approximately 20%2
AF is also a driver of CV hospitalizations and other health care resource utilization4-6
AF Unmet Needs
Early restoration and maintenance of sinus rhythm7
Reduction in CV morbidity and mortality2
Reduction in CV events and hospitalizations6
References
Miyasaka Y, Barnes ME, Gersh BJ, 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:
Wolf PA, Mitchell JB, Baker CS, Kannel WB, D’Agostino RB. Impact of atrial fibrillation on mortality, stroke, and medical costs. Arch Intern Med. 1998;158:
Haywood LJ, Ford CE, Crow RS, et al; for the ALLHAT Collaborative Research Group. Atrial fibrillation at baseline and during follow-up in ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial). J Am Coll Cardiol. 2009;54:
Reynolds MR, Essebag V, Zimetbaum P, Cohen DJ. Healthcare resource utilization and costs associated with recurrent episodes of atrial fibrillation: the FRACTAL registry. J Cardiovasc Electrophysiol. 2007;18:
Kim MH, Lin J, Hussein M, Kreilick C, Battleman D. Cost of atrial fibrillation in Unites States managed care organizations. Adv Ther. 2009;26:
Wattigney WA, Mensah GA, Croft JB. Increasing trends in hospitalization for atrial fibrillation in the United States, 1985 through Circulation. 2003;108:
Fuster V, Rydén LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (writing committee to revise the 2001 guidelines for the management of patients with atrial fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006;114:e257-e354.
CV = cardiovascular.
1. Miyasaka Y et al. Circulation. 2006;114: Wolf PA et al. Arch Intern Med. 1998;158:
3. Haywood LJ et al. J Am Coll Cardiol. 2009;54: Reynolds MR et al. J Cardiovasc Electrophysiol. 2007;18: Kim MH et al. Adv Ther. 2009;26: Wattigney WA. Circulation. 2003;108: Fuster V, et al. Circulation. 2006;114:e257-e354. 40