1. Atrial Fibrillation Rate or Rhythm Control
Saeed Oraii MD
Tehran Arrhythmia Clinic
April 2007
Shiraz

2. “Delirium Cordis”
First described by Sir William Harvey in 17th century:
observed chaotic motion of atria in open chest animal
Heart rhythm irregularity first described in 1903 by Hering
ECG findings described in 1909 by Sir Thomas Lewis:
“irregular or fibrillatory waves and irregular ventricular response” or “absent atrial activity with grossly irregular ventricular response”
The irregularity and inequality of heart rhythm associated with atrial fibrillation was first described by Dr. Hering in 1903.
Atrial fibrillation is by far the most common sustained arrhythmia diagnosed and treated by physicians. It may be either paroxysmal or chronic. Paroxysms may be brief or lengthy, frequent or infrequent; they may be benign or result in marked symptoms. 1

3. Atrial fibrillation accounts for 1/3 of all patient discharges with arrhythmia as principal diagnosis
6% PSVT
6% PVCs
18% Unspecified
4% Atrial Flutter
9% SSS
34% Atrial Fibrillation
8% Conduction Disease
10% VT
3% SCD
2% VF
Baily D. J Am Coll Cardiol. 1992;19(3):41A.

4. Incidence and Prevalence
Prevalence increases with age
4.8 % in the age group
Increases to
8.8% in the age group
During the next 7-8 years, the number of people over the age of 80 is expected to quadruple

5. Atrial Fibrillation Demographics by Age
U.S. population x 1000
Population with AF x 1000
30,000
20,000
10,000
Population with atrial fibrillation
500
400
300
200
100
U.S. population
<5
5- 9
10- 14
15- 19
20- 24
25- 29
30- 34
35- 39
40- 44
45- 49
50- 54
55- 59
60- 64
65- 69
70- 74
75- 79
80- 84
85- 89
90- 94
>95
Age, yr
Adapted from Feinberg WM. Arch Intern Med. 1995;155:

6. Projected AF Prevalence:
OLMSTED COUNTY DATA
12% observed increase in AF incidence
between 1980 and 2000
Miyasaka et al, Circulation 2005; 114:119

7. Projections of AF Prevalence in the United States
Adults With AF (millions)
It is expected that as the number of elderly people in the United States increases, diagnoses of AF will increase proportionally. A recent study applied age-specific estimates of the prevalence of AF to US census data to estimate the number of adults who will be diagnosed with AF in the future.
Go and colleagues estimated that the number of patients with AF will approach 3 million within the next 15 years. The authors estimated that in the year 2050, 5.6 million adults in the United States will be diagnosed with AF.
Adapted from Go. JAMA. 2001;285:2370.

8. Complications and Prognosis
5-fold increase in risk of stroke and thromboembolism
Strokes associated with AF are more severe
Death: OR 1.5 –1.9
AF worsens diagnosis in CHD and HF
Impairment in cognitive function
Reduced exercise tolerance

9. The 10,000 Foot View … The prevalence of AF is rapidly increasing
Aging population
True increase in incidence
Lifetime risk of AF at age 40 is 25%
AF is a progressive disorder
Cardiac remodeling due to genetic factors, acquired disease, atrial fibrillation itself
Up to 25% of initially self-terminating AF will become chronic in 5 years, > 50% at 10 years
Associated with substantial risk of adverse outcomes beyond immediate symptoms
Stroke
Congestive heart failure
Death
Associated with substantial increase in health care costs and resource utilization

10. Therapeutic Approaches to Atrial Fibrillation
Anticoagulation
Rate Control (ventricular response)
Pharmacologic
Catheter modification/ablation of AV node
Rhythm Control
Antiarrhythmic suppression
Curative procedures
Catheter ablation
Surgery (maze)

11. Thromboembolic prophylaxis
Thromboembolic events do not just occur in permanent AF
Consider treatment for all patients with AF
Clustering of events at the time of onset
62% RR reduction with adjusted dose Warfarin
22% RR reduction with Aspirin
0.9% absolute risk increase of major haemorrhage with Warfarin

12. Risk Assessment Tools Do not apply to valvular heart disease
Risk of thromboembolism depends on other risk factors in patients with AF
Various risk assessment tools available
There are differences between CHAD2 and the tool favoured in the NICE guidelines

13. CHAD2 Score

14. Therapeutic Approaches to Atrial Fibrillation
Anticoagulation
Rate Control
Pharmacologic
Catheter modification/ablation of AV node
Rhythm Control
Antiarrhythmic suppression
Curative procedures
Catheter ablation
Surgery (maze)

15. AF: Pharmacologic Rate Control
Digitalis
Beta Blockers
Calcium Channel Blockers (verapamil, diltiazem)
Amiodarone (in special settings)

16. Atrial Fibrillation: Rate Control
Essential in all patients
Persistent tachycardia rates can induce cardiomyopathy and heart failure
Occasional follow-up holter monitor to ascertain rate control
Target: bpm rest
bpm with exercise

17. Adequate Rate Control AFFIRM RACE HOT CAFÉ
Average HR of ≤80 beats/min at rest and either a maximum of ≤110 bpm during a 6-minute walk or an average of <100 bpm on 24-hour Holter monitoring, with the rate not exceeding 110% of maximum predicted age-adjusted exercise rate.
RACE
Resting heart rate on a 12-lead ECG of ≤100 beats/min
HOT CAFÉ
A heart rate of 70–90 beats/min on a resting 12-lead ECG and ≤140 beats/min during moderate exercise

18. Digoxin: some words of caution
Oldest and most commonly prescribed drug for control of ventricular rate
Predominant acute effect is mediated by the autonomic nervous system
An important slowing effect of the AV node is mediated by enhanced vagal tone
Not effective during periods of increased sympathetic tone
Not effective in paroxysmal atrial fibrillation

19. AVN Ablation and PPM Paroxysmal AF – DDDR pacing with mode switch
Permanent AF – VVIR pacemaker
Biventricular devices may be better in preserving LV function

20. AVN Ablation and PPM Pros: Controls and regularizes ventricular rate
Effective at improving symptoms, QOL and ? LV function
Cons:
Permanent
Detrimental effects of RV pacing, especially if reduced LV function already
Still have thromboembolic risk
Continue to have loss of atrial contractile function

21. Ablate and pace Suitable for
AF with symptomatic rapid ventricular rate unresponsive to drug Rx, or when drug Rx not tolerated
Curative AF ablation not suitable or not possible
Patients with a bradycardia indication for pacing
More suited to elderly (less requirement for generator changes and lead revision)

22. Therapeutic Approaches to Atrial Fibrillation
Anticoagulation
Rate Control (ventricular response)
Pharmacologic
Catheter modification/ablation of AV node
Rhythm Control
Antiarrhythmic suppression
Curative procedures
Catheter ablation
Surgery (maze)

23. AF: Rhythm Control Options

24. Antiarrhythmic Therapy for Atrial Fibrillation
Advantages
High efficacy for some patients, at least initially (< 50% of all patients)
Low initial cost
Noninvasive
Disadvantages
High recurrence rate
High long-term cost
Non-curative
Adverse effects
Potential proarrhythmia

25. Proarrhythmia Drug-induced Torsade

26. Rhythm vs Rate control Trials
PIAF
Lancet 2000
AFFIRM
NEJM 2002
RACE
STAF
JACC 2003
Hot CAFÉ
Chest 2004

27. Rate vs. Rhythm control
None of the RCTs found rate control inferior in terms of mortality or quality of life.
One study showed rate control reduced the mortality in patients without Heart Failure, in over 65s and in patients with CHD.
Reduced rates of hospitalization and adverse events with rate control
No difference in the rate of thromboembolic or hemorrhagic events
Rate control is more cost effective.

28. AFFIRM: Atrial Fibrillation Follow-up Investigation of Rhythm Management
Design
Multicenter, randomized, open, parallel group
Patients
4060 patients who had atrial fibrillation that was likely to be recurrent, with other risk factors for stroke or death. Patients with contraindications for anticoagulant therapy were excluded
Follow up and primary endpoint
Primary endpoint: all-cause mortality. Mean 3.5 years follow up.
Treatment
Rate control: >1 rate-controlling drugs, plus anticoagulant, or
Rhythm control: >1 antiarrhythmics, plus cardioversion as necessary; anticoagulant encouraged but could be discontinued
Nonpharmacological therapies and changes in pharmacological therapy, including crossover between groups, were permitted.
The AFFIRM Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825–33.

29. AFFIRM Baseline characteristics Overall 70 41 25 5 52 1 13 23
Rate control
(n=2027) 70 38 28 5 50 1 12 23
Rhythm control
(n=2033)
(n=4060)
Age (years) a 70
Female (%) 39
Predominant cardiac diagnosis (%)
Coronary artery disease 26
Cardiomyopathy 5
Hypertension 51
Valvular disease 5
Other 1
No apparent heart disease 12
History of congestive 23
heart failure (%) a
Mean
AFFIRM Investigators.
N Engl J Med
2002;
347
:1825 –
33.

30. AFFIRM Drugs used in rate and rhythm control groups a Rate control
Used drug for
Used drug
Used drug for
Used drug
initial therapy
at any time
initial therapy
at any time
No.
(%)
No.
(%)
No.
(%)
No.
(%)
Rate control:
data available
1957
2027
1266
2033
Digoxin
949
(48.5)
1432
(70.6)
417
(32.9)
1106
(54.4)
Beta-blocker
915
(46.8)
1380
(68.1)
276
(21.8)
1008
(49.6)
Diltiazem
583
(29.8)
935
(46.1)
198
(15.6)
610
(30.0)
Verapamil
187
(9.6)
340
(16.8) 56
(4.4)
204
(10.0)
Rhythm control:
data available
1265
2027
1960
2033
Amiodarone 2
(0.2) b
207
(10.2)
735
(37.2)
1277
(62.8)
Sotalol 1
(0.1) b 84
(4.1)
612
(31.2)
841
(41.4) a
A few patients in the rate and a significant number in the rhythm control groups received other antiarrhythmics b
These patients immediately crossed over to the rhythm control group, a protocol violation
AFFIRM Investigators.
N Engl J Med
2002;
347
:1825 –
33.

31. AFFIRM Goals of AFFIRM Anticoagulate:
Resting HR <80
24 hr Holter average <100 bpm. No HR above 110% of age predicted maximum
HR <110 on a six min walk
Anticoagulate:
-If over 48hrs of AF, must anticoag before cardioversion.
-Warfarin (6-12wks), heparin, LMWH
-Aspirin
-If Lone AF aspirin or nothing

32. AFFIRM - RESULTS -
No significant difference between rate control and rhythm control groups in:
all-cause mortality (25.9 vs. 26.7%, P=0.08)
composite secondary endpoint (death, disabling stroke or anoxic encephalopathy, major bleeding, and cardiac arrest)
total number of central nervous system events (stroke or hemorrhage)
Nonsignificant trends were towards reduction of all- cause mortality and CNS events with rate control, compared with rhythm control
Significantly reduced hospitalization in rate control group compared with rhythm control
Fewer patients initially assigned to rate control crossed over to rhythm control than crossed from rhythm to rate control (15 vs. 38% at 5 years; P<0.001)
NOTE ON LAST POINT: paper shows crossover at 1, 3 and 5 years; have included only the latter here

33. AFFIRM - RESULTS - All-cause mortality Cumulative 30 mortality (%) 2520 15 10
P=0.08 5
Rhythm control
Rate control 1 2 3 4 5
Years after randomization
AFFIRM Investigators.
N Engl J Med
2002;
347
:1825 –
33.

34. AFFIRM - RESULTS - Primary and selected secondary endpoints
Overall
Rate control
Rhythm control
(n=4060)
(n=2027)
(n=2033) P
No.
(%)
No.
(%)
No.
(%)
Primary endpoint:
all-cause mortality
666
(26.3)
310
(25.9)
356
(26.7)
0.08
Secondary endpoint:
861
(32.3)
416
(32.7)
445
(32.0)
0.33
death, disabling stroke,
disabling
encephalopathy, major
bleeding, and cardiac arrest
CNS eventa
211
(8.2)
105
(7.4)
106
(8.9)
0.93
Hospitalization
2594
(76.6)
1220
(73.0)
1374
(80.1)
<0.001
a Ischemic stroke, or primary intracerebral
or subdural/subarachonoid hemorrhage
AFFIRM Investigators.
N Engl J Med
2002;
347
:1825 –
33.

35. AFFIRM - SUMMARY-
In patients who had atrial fibrillation and were at high risk for stroke or death, comparison of rate and rhythm control showed:
No significant difference in all-cause mortality, composite secondary endpoint (death, disabling stroke, disabling anoxic encephalopathy, major bleeding, cardiac arrest) or ischemic stroke
A nonsignificant trend to reduction of all-cause mortality and stroke with rate control
Reduced hospitalization with rate control
Crossover to the other control method was lower in the rate control group

36. RACE Trial Rate Control vs. Electrical Cardioversion
522 patients with persistent atrial fibrillation or atrial flutter (24 hours-1 year)
2 cardioversions within 1 year
Rate control to HR < 100 bpm and no symptoms
Rhythm control: Sotalol followed by Flecainide or Propafenone followed by Amiodarone
Primary endpoint: cardiovascular death, admission or CHF, Thromboembolic events, severe bleeding, pacemaker implantation or severe anti-arrhythmic side effects

37. RACE Study
522 Patients 256 patients – rate control 266 patients – cardioversion Outcome Rate Rhythm Death/Stroke 17.2% 22.6% Mortality 7% 6.7% CHF 3.5% 3.4% Hypertension Subgroup: Combined Endpoints: Mortality/thromboembolism/severe complication Rate Rhythm 19% 31%

38. Rate vs. Pharmacologic Rhythm control
Favor of rate control
Favor of rhythm control
Persistent AF
History of AF more than 1 year
Less symptomatic
> than 65 years of age
History of HTN
Previous AAD failure
LA > 60 mm
No history of CHF
Patient preference
Paroxysmal AF
First episode of AF
More Symptomatic
< than 65 years of age
No history HTN
No Previous AAD failure
LA < 60 mm
History CHF
Patient preference

39. Who is under-represented in AFFIRM?
Young patients
Paroxysmal atrial fibrillation
CHF
Reduced systolic function
Isolated diastolic dysfunction
Disabling symptoms of AF
What therapies are under-represented ?
Other (newer?) drugs
Non-pharmacologic therapies

40. What AFFIRM Does Not Tell Us?
Optimal management for patients with moderate or severe disabling symptoms related to atrial fibrillation
Outcome if better tools to maintain sinus rhythm were available
Long-term implications of rate vs. rhythm control (mean duration of follow-up only 3.5 years)

41. Nonpharmacological Approaches to Atrial Fibrillation
Pacemaker therapy
2. Ablation
3. Surgery

42. Pulmonary Vein Triggers

43. Segmental Ablation

44. Segmental Ablation

45. Circumferential Ablation

46. Circumferential Ablation

47. Circumferential Ablation

48. Randomized Trials of Ablation for PAF
STABILE: EHJ : ; prior AAD failure; 1 episode/mo 6 mo duration; included 32% persistent AF; AAD given to ablation group; PVI+MI+CTI; blanking 1 mo; HM + 3 mo daily event montioring; endpoint 30 sec AF
WANZI: JAMA 2005: 293: ); No prior AAD; 1 episode/mo 3 mo duration; PVAI; blanking 2 mo; HM + 1,3 mo event monitoring; endpoint 15 sec AF. Pilot study for RAAFT (400 pt trial)
JAIS: HRS Scientific Sessions 2006; Prior AAD failure, 2 episodes/mo 6 mo duration; PVI+CTI+lines; blanking 3 mo; HM + symptom diaries; endpoint 3 min AF or palpitations
PAPPONE: JACC 2006 in press, doi 10:1016. Limited prior AAD; 2 episodes /mo 6 mo duration;CPVI+CTI+lines; blanking 6 wks, daily event monitoring; endpoint 30 sec AF
Major complications in 1-4% of ablation groups

49. Can Ablation Improve Survival?
Pappone et al JACC 2003; 42:

50. Catheter ABlation Versus ANtiarhythmic Drug Therapy for Atrial Fibrillation (CABANA)
Randomized trial comparing ablation to best drug therapy (rate or rhythm control)
Primary endpoint: mortality (powered for 30% mortality reduction assuming 12% 3 yr mortality in drug group)
Secondary endpoints:
Composite (death, disabling stroke, serious bleeding, cardiac arrest)
Freedom from AF recurrence (irrespective of symptoms)
Health care costs and resource utilization
Quality of life
Planned 3000 pts, 120 enrolling centers
Pilot phase approved starting late 2006, full study pending approval

51. Catheter ABlation Versus ANtiarhythmic Drug Therapy for Atrial Fibrillation (CABANA)
Enrollment criteria
> age 65, or < 65 with > 1 risk factor for stroke
Eligible for both AF, and at least 2 membrane active drugs or 3 rate control drugs
Paroxysmal (at least 2 episodes in prior 3 mo), persistent or chronic AF
Ablation technique to include PVI + additional procedures (lines, CFAE, ganglionated plexi)
3 month blanking period in both groups (repeat ablation, or change in AAD permitted). Crossover to ablation in drug group strongly discouraged
Follow-up with holter monitor, daily TTM (2 wks every 6 mo), and ILR (proposed 750 pt substudy)

52. Curative AF ablation Potential harm Death Stroke
Exacerbation of arrhythmia (flutters)
Tamponade / PV stenosis
Failure and redo rate
Potential benefits
Symptomatic benefit
No need for AADs ?
Thromboembolic benefit ?
Mortality benefit?

53. Who Should be Offered Ablation Here and Now?
Patients with symptomatic, drug refractory atrial fibrillation, should be judged on an individual basis according to the Ablation Centre’s experience
Ideally, the patient should satisfy the following criteria:
A rhythm control strategy is preferred and other therapeutic options are not as appropriate
Attempts with at least 1 AAD have failed
Preferably <70 (certainly <80!)
Preferably normal heart or mild-moderate structural heart disease (LVEF>45%?)
Preferably not a very dilated left atrium
Prepared to accept risk of stroke (based on patient factors and institution’s results)
Prepared to accept failure (based on institution’s results)
Prepared to accept need for a re-do procedure (based on institution’s results)

54. Points to remember:
Will need Warfarin 1 month before and minimum 3 months after procedure
May require ongoing AA drug Rx
AFib and LA flutter often occur in first few months after procedure. True success should be assessed after 3-6 months
Permanent AFib may be considered, but ~50% success rate

55. Summing up the evidence

56. Who could we offer rhythm control to?P O ?

57. Key Messages All patients with AF need thromboembolic risk assessment.
Rate control will benefit most of our patients but adequate rate control is necessary.
Digoxin is not first line drug for rate control
The plethora of antiarrhythmic drugs currently available for the treatment of AF is a reflection that none is wholly satisfactory, each having limited efficacy combined with poor safety and tolerability.
Catheter ablation considered a Class 2a indication for patients with symptomatic persistent or paroxysmal AF after failure of an initial trial of AAD therapy (AHA/ACC/ESC Guidelines)

58. Tehran Arrhythmia Clinic
Tehran Arrhythmia Center