Transcript Rate control v/s Rhythm control in AF

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
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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 endpointImprovement 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 ratecontrolled and 39% of rhythmcontrolled patients
 Primary endpoint-composite of
death from CVD, HF, TE
complications, bleeding, need for
pacemaker,or severe adverse drug
effects
 No significant difference (ratecontrol 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 P0.33)
 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
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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
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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 (15.3%) 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
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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 allcause 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
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
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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
THANK U