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

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

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

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

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

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)

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)

STAF trial 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

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

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

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

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

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)

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

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)

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

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

ESC 2012

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

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

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

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

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 2011 Pharmacological Cardioversion of Atrial Fibrillation of Up to 7-d Duration

ACC/AHA 2011

DOFETILIDE DIAMOND AF SAFIRE D DDAFFS EMERALD

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 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

FLECAINIDE &PROPAFENONE PILL IN POCKET PAFIT 2 PAFIT 3

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 IBUTILIDE REPEAT DOSE STUDY VOLGMAN etal RCT

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)

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

AMIODARONE META ANALYSIS JACC 2003 CHEVALIER CHF STAT SAFE T

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

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

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

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