1. RATE CONTROL V/S RHYTHM CONTROL IN AF
JOURNAL REVIEW
RAJESH K F

2. Basic strategies for treatment of AF
Restoration & maintenance of sinus rhythm(rhythm control)
Regulation of ventricular rate during AF (rate control)

3. Advantages of rhythm control
Physiological rhythm
Normal dromotropic response
AV synchrony
Maintained atrial contribution to ventricular filling
No need for long-term anticoagulation
Better hemodynamics, exercise tolerance
Better prevention of complications
Thrombo–embolic events
Structural and electrical remodeling
Better symptom relief

4. Disadvantages Adverse effects of medication Proarrhythmia
Sinus node, AV node dysfunction, pacemaker
Worsening of heart failure
Gastrointestinal, thyroid dyfunction
More hospital admissions and higher costs
Risks of interventions
Electrical and chemical cardioversions
Ablation, MAZE surgery
Low success and high recurrence rates

5. Determinants of long-term success in maintaining sinus rhythm
Duration of AF
Increased left atrial size
Older age
Poor left ventricular function
Poor functional class
Cardiol Clin 22 (2004) 63–69

6. Trials comparing of rate control and rhythm control
PIAF-Pharmacological Intervention in Atrial Fibrillation (2000)
STAF - Strategies of Treatment of Atrial Fibrillation study(2003)
RACE-Rate Control vs Electrical cardioversion for persistent AF(2002)
AFFIRM-AF follow–up investigation of rhythm management (2002)
HOT CAFÉ- - How to Treat Chronic Atrial Fibrillation(2004)
AF CHF-Atrial Fibrillation and Congestive Heart Failure(2007)
J RHYTHM- Japanese Rhythm Management Trial for AF(2009)

7. PIAF
Rrandomized 252 patients with symptomatic and persistent AF (7 to 360 days)
Rate control (125 patients) - diltiazem and if necessary additional therapy
Rhythm control (127 patients) - amiodarone(600 mg X 3 weeks) -> electrical cardioversion
Anticoagulation (INR 2.0 to 3.0)
1 year follow-up
Sinus rhythm in 10% of rate control vs 56% of rhythm-control patients(P<.001)

9. Primary endpoint-Improvement in symptoms related to AF
Improvement in 61% of rate vs 56% of rhythm controlled patients(P-0.317)

10. Secondary endpoints
6-minute walking distance -Better in rhythm controlled patients (p=0·008)
Quality of life - no differences
Incidence of hospital admissions (69% vs 24%) (P-0.001) higher in rhythm-controlled
Adverse drug effects (25% vs 14%) - higher in rhythm-controlled (P0.036)

11. STAF trial Randomized 200 patients (100 /group) with persistent AF
AF duration > 4 wks in 78% pts and mean duration months
Rate control - BBs, digitalis, CCB, or AV nodal ablation/modification with or without pacemaker
Rhythm control - Repeated cardioversions and prophylactic use of class I agents or sotalol
CAD or LV dysfunction -beta-blocker and/or amiodarone
Oral anticoagulation in both arms of study

13. 2 years of follow-up
Sinus rhythm -26% of rhythm Vs 11% of rate controlled patients (P-0.99)
Primary endpoint -Combination of death, stroke or TIA, TE and cardiac resuscitation
No difference - rhythm control (9/100; 5.54%/year) and rate-control (10/100; 6.09%/year; p 0.99)
18 of 19 of events occurred during AF(p 0.049)
No significant differences in quality of life score, AF-related symptoms and echo parameters

14. P = 0.99
P-0.99
<0.01

15. RACE 522 patients with persistent AF or AFl(duration 1 to 399 day)
Rate control (256 patients)with digoxin, CCB, and/or BB
Rhythm control (266 patients) with serial cardioversions and antiarrhythmic drug
Sotalol , if unsuccessful flecainide or propafenone amiodarone
Oral anticoagulation with warfarin was used (INR 2.5 to 3.5)
In cases of SR warfarin stopped /replaced by aspirin

16. Mean follow-up of 2.3 years (plus or minus 0.6 years)
Sinus rhythm -10% of rate-controlled and 39% of rhythm-controlled patients
Primary endpoint-composite of death from CVD, HF, TE complications, bleeding, need for pacemaker,or severe adverse drug effects
No significant difference (rate-control 17.2% versus rhythm-control 22.6%)

18. HF, TE events, adverse drug effects, and pacemaker implantations - more frequent in rhythm-control patients, Bleeding - more frequent in rate-control patients (Not statistically significant)
35 cases with TE complications - 29 occurred after cessation or during inadequate anticoagulant therapy (INR < 2.0)
17 of 21 significant bleeding occurred at an INR > 3.0

19. AFFIRM trial
Screened 7401 patients with paroxysmal or persistent AF > 65 yrs OR >1 RF for stroke or death
RF – H/O HTN,DM, CHF , stroke, TIA or TE, LA >50mm or LV SF < 25% or LVEF < 0.40
4060 patients - randomized to rate or rhythm control strategies
Digoxin, CCB, and/or BB were used for rate control(2027 patients)
Electrical cardioversions, class IA, IC, and III drugs to rhythm-control arm (2033 )
Oral anticoagulation adjusted to maintain INR of 2.0 to 3.0
Could be stopped if SR > 4 weeks

20. Base -line characteristics of patients

21. Mean followup - 3.5 yrs (max 6 yrs)
At 5 yrs, sinus rhythm - 35% of rate Vs 63% of rhythm-controlled patients
Primary endpoint - Total mortality
356/2033 (17.5%) for rhythm control and 310/2027 (15.3%) for rate control hazard ratio, 1.15 [95 % CI , 0.99 to 1.34]; P=0.08)

22. Secondary endpoint composite (death, disabling stroke or anoxic encephalopathy, major bleeding or cardiac arrest) (No difference P-0.33)
Rhythm-controlled pts hospitalized more frequently (P < 0.001) and had more adverse drug effects (P = 0.004)
No differences in quality of-life measures between two arms

23. HOT CAFÉ Randomized multicenter prospective trial
205 Patients with clinically overt persistent first episode AF
Follow up of 1.7yrs

25. Primary endpoint –Composite of all cause mortality,TE,bleeding
No difference (p 0.71)
No significant difference in secondary endpoints except
Incidence of hospitalization 74% vs 12% in Rhy vs rate control(p<0.001)
Better exercise tolerance (p<.001)
Smaller LA size in rhythm control group
Better LV function in rhythm control group

26. AF CHF Randomized open label trial
1376 pts EF< 35% and NYHA II–IV HF
Follow up of 3.1 years
Rhythm control-Amiodarone, in selected cases sotalol and dofetilide, electrical cardioversion
Primary endpoint –cardiovascular mortality
No difference- 182 (27%) vs 175(25%) in rhythm vs rate control(HR 1.06; 95% CI, 0.86 to 1.30; P = 0.59 by log-rank test)

27. Secondary end points-Total mortality ,stroke,HF
Hospitalizations in first yr 46% in rhythm vs 39% in rate control group (0.0063)
On treatment analysis no survival benefit from maintenance of SR (HR 1.11;95% CI ,0.78 – 1.58; p=0.568)

29. J RHYTHM
Randomized, multicenter comparison of rate control vs rhythm control in Japanese patients with PAF
823 Patients
Follow up 1.6 yrs
Primary endpoint -Composite of total mortality, symptomatic cerebral infarction, systemic embolism, major bleeding, hospitalization for HF or physical/psychological disability requiring alteration of treatment strategy

31. Primary endpoint occurred in 64 patients (15
Primary endpoint occurred in 64 patients (15.3%) rhythm control and 89 (22.0%) to rate control (P=0.0128)

33. Comparison of adverse outcomes in rhythm control and rate control trials in patients with AF

34. CONCLUSION Rhythm control is not superior to rate control
Rhythm-control therapies show trend toward increased mortality and morbidity caused by the adverse effects of antiarrhythmic drugs and need for cardioversions
Conclusions of trials should not be generalized
Patients included in trials had average age of 60 to 70 years
Most had persistent AF
Success rate of rhythm control was poor
They could not benefit from possible advantages of sinus rhythm while being exposed to possible hazards and disadvantages of frequent cardio versions and antiarrhythmic drugs

35. ESC 2012

36. Catheter ablation
Antiarrhythmic drugs are commonly used for prevention of recurrent AF despite inconsistent efficacy and frequent adverse effects
Catheter ablation has been proposed as an alternative treatment for paroxysmal AF

37. PAF2
Permanent AF develops in many patients after ablation and pacing therapy
Multicentre randomized controlled trial
68 patients affected by severely symptomatic paroxysmal AF were assigned, after successful AV junction ablation and pacing treatment, to antiarrhythmic drug therapy with amiodarone, propafenone, flecainide or sotalol
Compared with 69 patients assigned, after successful AV junction ablation and pacing treatment to no antiarrhythmic drug therapy

39. Followed-up for 12 to 24 months (mean 16+4)
Drug arm patients had 57% reduction in the risk of developing permanent AF (21% vs 37%, P=0·02)
Similar quality of life scores and echocardiographic parameters in the two groups
Drug arm patients had more episodes of HF and hospitalizations (P=0·05)
Conventional antiarrhythmic therapy reduces risk of development of permanent AF after ablation and pacing therapy

41. RACE II
Prospective, multicenter, randomized, open-label, noninferiority trial
614 patients with permanent AF
Lenient rate control (resting HR <110 /min) or strict rate control strategy (resting HR <80/ min and HR during moderate exercise <110 /min)
One or more negative dromotropic drugs (BBs, CCB, and digoxin) used alone or in combination and at various doses
Follow-up at least 2 years, with a maximum of 3 years

42. Primary outcome - composite of death from CV causes, hospitalization for HF & stroke, life-threatening arrhythmia & adverse effects of drugs, TE , bleeding
Primary outcome at 3 years % in lenient and 14.9% in strict-control group (90% CI −7.6 to 3.5; P<0.001 for prespecified noninferiority margin)

44. Frequencies of symptoms and adverse events similar in two groups
Secondary outcomes- Components of primary outcome, death from any cause, symptoms and functional status
In patients with permanent AF lenient rate control is as effective as strict rate control and is easier to achieve

45. PHARMACOLOGICAL CARDIOVERSION IN AF

46. ACC/AHA 2011
Pharmacological Cardioversion of Atrial Fibrillation of Up to 7-d Duration

47. ACC/AHA 2011

49. DOFETILIDE
DIAMOND AF
SAFIRE D
DDAFFS
EMERALD

50. DIAMOND-AF Substudy of 506 HF patients who had baseline AF or flutter
Pharmacological or spontaneous cardioversion occurred in 112 (44%) dofetilide and 35 (14%) placebo (P,0.001)
Probability of maintaining sinus rhythm for 1 year - 79% with dofetilide versus 42% with placebo (P,0.001)
Dofetilide had no effect on all-cause mortality

51. Restoration and maintenance of SR associated with significant reduction in mortality (RR 0.44; 95% CI, 0.30 to 0.64; P,0.0001)
Dofetilide therapy- significantly lower risk ratio versus placebo for rehospitalization
All-cause (RR, 0.70; 95% CI, 0.56 to 0.89; P 0.005)
CHF(RR, 0.69; 95% CI, 0.51 to0.93; P-0.02)

52. SAFIRE D Double-blind, multicenter, placebo-controlled study
Determined efficacy and safety of dofetilide in converting AF or Afl to SR and maintaining SR for 1 year
325 patients were randomized to 125, 250, or 500 microg dofetilide or placebo twice daily

53. Pharmacological cardioversion rates - 6. 1%, 9. 8%, and 29. 9% vs 1
Pharmacological cardioversion rates - 6.1%, 9.8%, and 29.9% vs 1.2% for placebo (250 and 500 mg versus placebo; P and P,0.001, respectively)
70% cardioversions with dofetilide - achieved in 24 hours and 91% in 36 hours

54. For 250 patients who successfully cardioverted pharmacologically or electrically
Probability of remaining in SR at 1 year -0.40, 0.37, 0.58 for 125, 250, and 500 mg dofetilide and 0.25 for placebo (500 mg versus placebo,P-0.001)
Two cases of TDPs ,1 SCD

55. FLECAINIDE &PROPAFENONE
PILL IN POCKET
PAFIT 2
PAFIT 3

56. 268 patients
AF of recent onset,hemodynamically well tolerated,with mild or no heart disease in emergency room
Administered either flecainide or propafenone orally to restore sinus rhythm
58 (22 percent) were excluded - Treatment failure or side effects
Out-of-hospital self-administration of flecainide or propafenone - After onset of palpitations was evaluated in remaining 210 patients

57. Mean follow-up of 15±5 months
165 patients (79 percent) had a total of 618 episodes
569 (92 percent) were treated 36±93 minutes after the onset of symptoms
Successful in 534 episodes (94 percent)
Time to resolution of symptoms was 113±84 minutes
Drug was effective during all the arrhythmic episodes in 139 patients (84 percent)

58. Adverse effects - during one or more arrhythmic episodes by 12 patients (7 percent)
Atrial flutter at rapid ventricular rate in 1 patient and noncardiac side effects in 11 patients

59. IBUTILIDE
IBUTILIDE REPEAT DOSE STUDY
VOLGMAN etal RCT

60. IBUTILIDE REPEAT DOSE STUDY
Multicentre double-blind placebo-controlled, RCT
266 patients with sustained AF (n=133) or AFl (n=133) duration of 3 hours to 45 days
Randomized to receive up to two 10-minute infusions, separated by 10 minutes of ibutilide (1.0 and 0.5 mg or 1.0 and 1.0 mg or placebo)
Conversion rate was 47% after ibutilide and 2% after placebo (P<.0001)
Two ibutilide dosing regimens did not differ in conversion efficacy (44% versus 49%)
Efficacy was higher in Afl than AF (63% versus 31%, P<.0001)

61. In AF conversion rates were higher with shorter arrhythmia duration or normal LA size
Arrhythmia termination occurred a mean of 27 minutes after start of the infusion
Of 180 ibutilide-treated patients, 15 (8.3%) developed polymorphic VT during or soon after infusion
Required cardioversion in 3 patients (1.7%)

62. Multicenter double-blind RCT
Compared efficacy and safety of ibutilide vs procainamide for conversion of recent onset Afl or AF
178 (age range 22 to 92 years) with Afl or AF of 3 h to 90 days’ (mean 21 days) - randomized to either two 10-min IV infusions of 1 mg of ibutilide, separated by a 10-min infusion of 5% dextrose or three successive 10-min IV infusions of 400 mg of procainamide

63. 120 were evaluated for efficacy
35 (58.3%) of 60 in ibutilide group compared with 11 (18.3%) of 60 in procainamide group had successful termination within 1.5 h (p < )
In AF group ibutilide had a significantly higher success rate than procainamide (51% [22 of 43] vs. 21% [8 of 38] p )
*p , **p ***p

64. Study establishes the superior efficacy of ibutilide over procainamide
low incidence of serious proarrhythmia was seen with ibutilide occurring at end of infusion

65. AMIODARONE
META ANALYSIS JACC 2003 CHEVALIER
CHF STAT
SAFE T

66. Recent-onset AF defined as lasting less than 7 days
Primary end point-rate of conversion at 24 h
Secondary end points -Rates of cardioversion at 1 to 2 h, 3 to 5 h, and 6 to 8 h,mortality, proarrhythmia, and other adverse effects
Six studies randomizing amiodarone versus placebo (595 patients) and seven studies versus class Ic drugs (579 patients)

67. Efficacy of Amiodarone Versus Placebo

70. No significant difference between amiodarone and placebo at 1 to 2 h
Significant efficacy after 6 to 8 h (relative risk [RR] 1.23, p ) and at 24 h (RR 1.44, p )
Amiodarone is superior to placebo for cardioversion of AF even though onset of conversion is delayed

71. Efficacy of Amiodarone Versus Class Ic Drugs

74. Efficacy with amiodarone - inferior to class Ic drugs for up to 8 h (RR 0.67, p ) but no difference seen at 24 h (RR 0.95, p 0.50)
No major adverse effects
Its efficacy is similar at 24 h compared with class Ic drugs

75. SAFE-T Double-blind, placebo-controlled trial
665 patients with persistent AF receiving anticoagulants
Received amiodarone (267 patients), sotalol (261 patients), or placebo (137 patients)
Monitored them for 1 to 4.5 years
Primary end point-time to recurrence of AF beginning on day 28
Spontaneous conversion % amiodarone, 24.2 % sotalol and 0.8 % of placebo group

76. Median times to recurrence of AF days amiodarone,74 sotalol and 6 in placebo group according to intention to treat and 809, 209, and 13 days according to treatment received respectively
Amiodarone superior to sotalol (P<0.001) and to placebo (P<0.001)
Sotalol was superior to placebo (P<0.001)

77. In IHD patients - median time to a recurrence of AF days with amiodarone therapy and 428 days with sotalol therapy (P=0.53)
Restoration and maintenance of sinus rhythm significantly improved quality of life and exercise capacity
No significant differences in major adverse events among three groups

78. VERNAKALANT
CRAFT
ACT I
ACT II
ACT III
ACT IV
AVRO
Scene 2

81. Effective in cardioversion with AF ≤7 days or AF ≤3 days after cardiac surgery
10-minute infusion of 3 mg/kg and if AF persists after 15 minutes, a second infusion of 2 mg/kg
Provides rapid effect with 50% convertion within 90 min after start of treatment
Median time to conversion of 8–14 min
Contraindicated in hypotension< 100 mmHg, recent (30 days) ACS,NYHA class III and IV HF, severe AS and uncorrected QT> .440 ms

82. AF PREVENTION

83. ESC 2012

84. DRONEDARONE

87. Multichannel blocker inhibits sodium and potassium channels shows noncompetitive antiadrenergic activity and calcium antagonist properties
Maintain sinus rhythm in patients with paroxysmal or persistent AF
Should not be given to patients with moderate or severe heart failure
Monitoring of liver function tests

88. RATE CONTROL DRUGS

89. ACUTE-AHA/ESC 2011

91. THANK U