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RATE CONTROL V/S RHYTHM CONTROL IN AF
JOURNAL REVIEWRAJESH K F
Basic strategies for treatment of AF Restoration & maintenance of sinus rhythm(rhythm
control) Regulation of ventricular rate during AF (rate control)
Physiological rhythm Normal dromotropic response AV synchrony Maintained atrial contribution to ventricular fillingNo need for long-term anticoagulationBetter hemodynamics, exercise toleranceBetter prevention of complications Thrombo–embolic events Structural and electrical remodelingBetter symptom relief
Advantages of rhythm control
Adverse effects of medication Proarrhythmia Sinus node, AV node dysfunction, pacemaker Worsening of heart failure Gastrointestinal, thyroid dyfunctionMore hospital admissions and higher costsRisks of interventions Electrical and chemical cardioversions Ablation, MAZE surgeryLow success and high recurrence rates
Disadvantages
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
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
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)
Primary endpoint-Improvement in symptoms related to AF
Improvement in 61% of rate vs 56% of rhythm controlled patients(P-0.317)
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)
Randomized 200 patients (100 /group) with persistent AF AF duration > 4 wks in 78% pts and mean duration-6 + 3
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
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
P-0.99
P = 0.99
<0.01
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
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%)
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
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
Base -line characteristics of patients
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)
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
HOT CAFÉ
Randomized multicenter prospective trial
205 Patients with clinically overt persistent first episode AF
Follow up of 1.7yrs
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
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)
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)
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
Primary endpoint occurred in 64 patients (15.3%) rhythm control and 89 (22.0%) to rate control (P=0.0128)
Comparison of adverse outcomes in rhythm control and rate control trials in patients with AF
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
ESC 2012
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
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
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
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
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 - 12.9% in lenient and 14.9% in strict-control group (90% CI −7.6 to 3.5; P<0.001 for prespecified noninferiority margin)
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
PHARMACOLOGICAL CARDIOVERSION IN AF
ACC/AHA 2011Pharmacological Cardioversion of Atrial Fibrillation of Up to 7-d Duration
ACC/AHA 2011
DIAMOND AF SAFIRE D DDAFFS EMERALD
DOFETILIDE
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
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)
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
Pharmacological cardioversion rates - 6.1%, 9.8%, and 29.9% vs 1.2% for placebo (250 and 500 mg versus placebo; P 0.015 and P,0.001, respectively)
70% cardioversions with dofetilide - achieved in 24 hours and 91% in 36 hours
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
PILL IN POCKET PAFIT 2 PAFIT 3
FLECAINIDE &PROPAFENONE
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
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)
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
IBUTILIDE REPEAT DOSE STUDY VOLGMAN etal RCT
IBUTILIDE
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
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%)
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
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 < 0.0001)
In AF group ibutilide had a significantly higher success rate than procainamide (51% [22 of 43] vs. 21% [8 of 38] p 5 0.005)
*p , 0.0001 **p 5 0.0001***p 5 0.005.
Study establishes the superior efficacy of ibutilide over procainamide
low incidence of serious proarrhythmia was seen with ibutilide occurring at end of infusion
META ANALYSIS JACC 2003 CHEVALIER CHF STAT SAFE T
AMIODARONE
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)
Efficacy of Amiodarone Versus Placebo
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
Efficacy of Amiodarone Versus Class Ic Drugs
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
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 -27.1 %
amiodarone, 24.2 % sotalol and 0.8 % of placebo group
Median times to recurrence of AF - 487 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)
In IHD patients - median time to a recurrence of AF - 569 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
CRAFT ACT I ACT II ACT III ACT IV AVRO Scene 2
VERNAKALANT
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
AF PREVENTION
ESC 2012
DRONEDARONE
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
RATE CONTROL DRUGS
ACUTE-AHA/ESC 2011
THANK U