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

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Presentation on theme: "RATE CONTROL V/S RHYTHM CONTROL IN AF JOURNAL REVIEW RAJESH K F."— Presentation transcript:

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 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 Advantages of rhythm control

4 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 Disadvantages

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  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) Trials comparing of rate control and rhythm control

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)

8

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  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 STAF trial

12

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  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 RACE

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%)

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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  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 AFFIRM trial

20 Base -line characteristics of patients

21  Mean followup 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

24

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)

28

29  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 J RHYTHM

30

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

32

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

34  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 CONCLUSION

35 ESC 2012

36  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 Catheter ablation

37  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 PAF2

38

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

40

41  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 RACE II

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)

43

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

48

49  DIAMOND AF  SAFIRE D  DDAFFS  EMERALD DOFETILIDE

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 1.2% 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  PILL IN POCKET  PAFIT 2  PAFIT 3 FLECAINIDE &PROPAFENONE

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 REPEAT DOSE STUDY  VOLGMAN etal RCT IBUTILIDE

60  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) IBUTILIDE REPEAT DOSE STUDY

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  META ANALYSIS JACC 2003 CHEVALIER  CHF STAT  SAFE T AMIODARONE

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

68

69

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 0.022) and at 24 h (RR 1.44, p 0.001)  Amiodarone is superior to placebo for cardioversion of AF even though onset of conversion is delayed

71 Efficacy of Amiodarone Versus Class Ic Drugs

72

73

74  Efficacy with amiodarone - inferior to class Ic drugs for up to 8 h (RR 0.67, p 0.001) 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  CRAFT  ACT I  ACT II  ACT III  ACT IV  AVRO  Scene 2 VERNAKALANT

79

80

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.440 ms

82 AF PREVENTION

83 ESC 2012

84 DRONEDARONE

85

86

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

90

91 THANK U


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