Atrial Fibrillation: Is is time for a change of pace?

Atrial Fibrillation:Is is time for a change of

pace?

Resident Grand RoundsDr. Lee Graham

Emergency Medicine R2November 19, 2009

Disclosure

•Be prepared to be Dazzled!

•I just got KEYNOTE.

Scenario #1• 76 year old Female

• Chronic paroxysmal A Fib X 6 years

• Meds: include Diltiazem / Coumadin

• CAD / Stroke / COPD / DM / OA

• Presents to ED with recurrent palpitations / presyncope

• Been to Emerg 3 times in the last 3 months

• HR ~135 / BP 115/76

Question

•“Is there a role for long-term anti-arrhythmic medications in this patient?”

Scenario #2•52 yr old Male

•Sudden onset palpitations - 6 hrs ago

•Feels weak / No CP / NO dyspnea

•PMed Hx - Nil

•Meds - Nil

•HR~140

Question

•“What is the evidence for chemical cardioversion for acute Atrial Fibrillation?”

So why should we talk about this?

Objectives.

•What is the role of rhythm control in Atrial Fibrillation? Dronedarone?

•Should we attempt to be getting patients back into sinus rhythm in Emerg?

•If time...at the end A Fib Potpourri

Atrial Fibrillation is Bad.

What is Atrial Fibrillation?

•Risk Factor •(causative)

•Risk Marker• (bystander)

Terminology•Acute - <48hrs after onset

•Paroxysmal - intermittent / recurrent / self-terminating

•Persistent - will not self-terminate / can cardiovert to sinus rhythm

•Permanent - cannot be terminated by cardioversion or only terminates for brief intervals

•Lone - <60yrs and no heart or lung disease

First First DetecteDetecte

dd

First First DetecteDetecte

dd

PermanePermanentnt

PermanePermanentnt

ParoxsymalParoxsymal(Self-(Self-

terminating)terminating)

ParoxsymalParoxsymal(Self-(Self-

terminating)terminating)

PersistentPersistent(Non self-terminating)(Non self-terminating)

PersistentPersistent(Non self-terminating)(Non self-terminating)

SecondarySecondarySecondarySecondary

X

The great debate...•“Rate” vs “Rhythm”

“Rate” vs “Rhythm”

•5 RCTS

AFFIRM

RACE

PIAF

STAF

HOT CAFE

•Meta-analysis

Closer look at AFFIRM

•Foundation of our management of A Fib

•Randomized / Multi-center

•4060 patients

Inclusion

•Age > 65 years old

•Other risk factors for death

•“likely to be recurrent”

•“likely to cause illness or death”

•“treatment warranted”

Groups

•RHYTHM

•Use what you want

•Could use Cardioversion

•RATE

•Use what you want

•Goal HR 80 at rest. 110 during activity.

Anti-coagulation

•RATE

•Continuous

•RHYTHM

•“Encouraged” = could be stopped

• > 4 weeks

• >12 weeks (preferably)

Rhythm Control Drugs

“almost significant trend in mortality”

CNS EVENT

RATE RHYTHM

NO WARFBad INR

441725w/ Afib

2725

42

•AFFIRM

•NEJM 2002 = Intention to treat

•Circulation 2006 = “In treatment” analysis

Covariate Analysis

0.53

1.49

Sinus rhythm

Rhythm-control

AFFIRM

•Rate

• =

•Rhythm

POSITIVE “side effects”+

NEGATIVE “side effects”



ACTUAL

ACTUAL

control

control

AFFIRM

•Rate

• =

•Rhythm




“side effects”

ACTUAL

ACTUAL

control

control

NEGATIVE

Why is everyone getting so excited?

•First “A Fib” Drug approved in last 10 years

•First drug to show effect on hard outcomes (other than atrial fibrillation recurrence)

Dronedarone

•SR33589 / Multaq

•Noniodinated benzofuran

•Electrophysiologic effects similar to AMIODARONE

•Na, K, Ca currents, acteylcholine-activated potassium currents, anti-adrenergic

Amiodarone Side Effects

•Iodine

•Pulmonary

•Hepatitis

•Thyroid

•Eye

• MAY have fewer side effects

X

Long lost brothers????

A T H E N A

• rial with dronedarone to prevent ospitalization or d ath in patie ts with trial fibrillation

A TH E NA

•4628 patients with ATRIAL FIBRILLATION and ADDITIONAL RF for death

•Dronedarone 400mg BID vs PLACEBO

Outcomes• Primary Outcome

• COMPOSITE of:

•cardiovascular hospitalization

• +

• death

• Secondary Outcome

i) death any cause

ii) death from CV cause

iii) hosptilalization due to CV

Inclusion•Paroxysmal or persistent A Fib or A Flutter

•+ one of

•>70 years old

•Hypertension (> 2 meds)

•DM

•previous stroke / TIA / embolism

•Left atrial diameter > 50mm

•LVEF <40%

•EKGs within 6 months (one in sinus / one in afib)

Inclusion•Paroxysmal or persistent A Fib or A Flutter

•+ one of

•>70 years old

•Hypertension (> 2 meds)

•DM

•previous stroke / TIA / embolism

•Left atrial diameter > 50mm

•LVEF <40%

•EKGs within 6 months (one in sinus / one in afib)

>75<70 excluded

Inclusion Criteria

Changed During Study

Exclusion• Permanent atrial fibrillation

• Decompensated heart failure within 4 weeks

• NYHA class IV CHF

• Acute MI

• Planned major surgery

• HR <50

• PR 0.28

• Previous sinus-node disease not with a pacemaker

• NON CARDIAC

• GFR <10ml/min

• K < 3.5 mmol if currently not being corrected

• going to die / pregnant / breast feeding

Exclusion• Permanent atrial fibrillation

• Decompensated heart failure within 4 weeks

• NYHA class IV CHF

• Acute MI

• Planned major surgery

• HR <50

• PR 0.28

• Previous sinus-node disease not with a pacemaker

• NON CARDIAC

• GFR <10ml/min

• K < 3.5 mmol if currently not being corrected

• going to die / pregnant / breast feeding

Patient Characteristics

•Mean age 71.6

•46.9% female

•Hypertension 59.6%

•LVEF < 35% (3.9%), LVEF <45% (11.9%)

•Hx of NYHA II - 17.1%

• III - 4.4%

ATHENA•Follow-up - mean 21 +- 5 months

•Study drug discontinued prematurely in:

•Dronedarone - 30.2%

•Placebo - 30.8%Anti-arrhythmic drug

Intolerance

Side Effects•Bradycardia

•QT - prolongation

•Gastrointestinal (26.2% vs 22.0%) P<0.001

•Nausea

•Rash

•Increase in serum creatinine

Outcomes• Primary Outcome

• COMPOSITE of:

•cardiovascular hospitalization

• +

• death

• Secondary Outcome

i) death any cause

ii) death from CV cause

iii) hosptilalization due to CV

Primary Outcome

•Dronedarone 31.9%

•Placebo 39.4%

Death 2.6% Hospitalization 29.3%

Death 2.5% Hospitalization 36.9%

Hazard ratio 0.76 (0.69 - 0.84)

Secondary Outcomes

i)death any cause

•Dronedarone 5.0%

• Placebo 6.0%

ii)death from CV cause

•Dronedarone 2.7%

• Placebo 3.9%

iii)first hosptilalization due to CV

• Dronedarone 29.3%

• Placebo 36.9%

HR 0.71 (0.51 - 0.98)

HR 0.84 (0.66 - 1.08)

HR 0.74 (0.67 - 0.82)

First Hospitalization

Dronedarone

Placebo P - value

A Fib 335 (14.6) 510 (21.9) <0.001

CHF112 (4.9)

132 (5.7) 0.22

ACS 62 (2.7) 89 (3.8) 0.03

Syncope 27 (1.2) 32 (1.4) 0.54

Ventricular arrhythmia

13 (0.6) 12 (0.3) 0.83

Contribution of A Fib

Hospitalization

•CV Hospitalization = 7.6

•Primary Outcome = 7.5

Dronedarone Placebo

A Fib 335 (14.6) 510 (21.9) = 7.3

Limitations

•High rate of discontinuing study drug

•No comparison to other anti-arrhythmic

•Importance of primary outcome?

A N D R O M E AD

• tiarrhythmic trial with nedarone in oderate-to-severe Congestive Heart Failure valuating Morbidity ecre se

AN DROME AD

•Multi-center / Double-blind design

•1000 patients hospitalized for symptomatic heart failure and severe left ventricular systolic failure

•After 627 patients (310 dronedarone)

•Prematurely stopped

Mortality

•Dronedarone 8.1%

•Placebo 3.8%

“related to worsening heart failure”

So where does Dronedarone fit in?

•First trial of an anti-arrhythmic to show a reduction in an endpoint other than RECURRENCE of A Fib

•Effect of trial or drug?

✓Dronedarone in context of Rate vs Rhythm

✓Dronedarone compared to other AAR

Text


•Not published, or presented

•504 patients randomized• Documented AF (not continuous)

• “need for cardioversion and antiarrhythmic treatment”

• On anticoagulants

• Not in “clinically overt” NYHA 3-4

Primary Endpoint

•1) AF recurrence

•or

•II) premature drug discontinuation for intolerance of lack of efficacy

COMPOSITE:

Primary Outcome

•Dronedarone 73.9%

•Amiodarone 55.3%

A Fib 36.5% Stopped Drug 10.4%

A Fib 24.3% Stopped Drug 13.3%

P < 0.001

•Systematic overview of RCTs

•INDIRECT META-ANALYSIS

•Drugs have not been compared Head to Head

“Dronedarone is LESS effective for maintaining SINUS RHYTHM, but has FEWER adverse effects”

Weakness of analysis

•All Dronedarone studies have EXCLUDED PERMANENT A Fib

•Amiodarone pts more likely to have persistent/permanent A Fib and STRUCTURAL Heart Disease

Odds Ratios

A Fib

Death

Adverse

Dronedarone Amiodarone

Dronedarone Amiodarone

Study Conclusions

•For every 1000 patients treated with Dronedarone instead of Amiodarone

•228 MORE recurrences of A Fib

•9.6 FEWER deaths

•62 FEWER adverse events requiring stoppage

X

So where does Dronedarone fit in?

•First trial of an anti-arrhythmic to show a reduction in an endpoint other than RECURRENCE of A Fib

•Effect of trial or drug?




•Multicenter / Randomized

•1376 pts

•Rhythm vs Rate

• LVEF < 35%

•Symptoms of CHF

•Atrial Fibrillation

Survival

% in A Fib

Canadian Trial of Atrial Fibrillation

Dronedarone

NYHA1 2 3 4

Mortality

No Heart Failure

DronedaroneINCREASEDMortality

Dronedarone

Benefit

ATHENA ANDROMEDA

✓ ? “POTENTIAL”

Amiodarone

Thoughts...

•STILL no studies showing RHYTHM superior to RATE

•If sinus rhythm is important for mortality

• ...Amiodarone would be superior to Dronedarone

My take...

•Dronedarone not ready for prime time

•Rate and Rhythm are STILL equivalent

•Anti-coagulation! ANTI-COAGULATION!

Indications for Rhythm

•Symptomatic

•Secondary cause

•Failed Rate control

•Patient preference

Chance at sinus...

FAVORS RATEFAVOR

RHYTHMPersistent - Recurrent Paroxysmal AF

History Afib > 1yr First Episode of AF>65 years of age <65 yrs of age

HTN NO HTNAAD failure No AAD failureLA > 60cm LA < 60cm

No previous CHF History of CHFPatient Preference

So what about in the ED?

•Retrospective chart-review (5 yrs) all patients who received IV Procainamide

•“Routine Care”

•169 pts

•Chemical Electrical

Sinus

A Fib

DC w/ no meds+- Cardiology FU

RateAnticoagulaion

Exclusion

•>48 hrs (unless anticoagulated)

•Permanent or Long standing A Fib

•Another dx requiring admission (CHF etc..)

•Unknown duration


•Age, median 68

•Previous A Fib 65.4%

•HTN 32.8%

•CAD 24.9%

•CHF 5.3%

•Thromboembolic 5.0%

Outcomes• SBP < 100mg

• Bradycardia

• Syncope

• Heart Block

• VT

• Torsades

• CVA

• Death

• Recurrence of A Fib

(within 6hrs)

(within 7 days)

Results

•Chemical cardioversion

•Electrical cardioversion

•Discharge home

•Discharge in sinus

50.4%

91.0%

94.4%

88.9%

Median conversions time = 55 minutes (2 - 390)

Adverse events

•Hypotension 28 (8.5%)

•Bradycardia 2 (0.6%)

•Ventricular arrhythmia 1 (0.3)

•Death / Badness 0 (0.0%)

•Relapse within seven days 10 (2.9%)

Limitations

•Retrospective

•Short term follow-up

•Generalizability

•No telephone or death registry review

How effective is Procainamide?

Is converting these patients doing anything?

•Retrospective chart review of patient presenting with Atrial Fibrillation to the ED as the primary diagnosis

24hrs

50%

Procainamide 50.4%


NO IV available Black Box

PO

xx

xx Slow / Ineffective

Vernelakant

Limitations

•Retrospective

•Short term follow-up

•Generalizability

•No telephone or death registry review



•Prospective / randomized / OPEN

•2 X 2 design

•144 pt randomized - trans-telephonic monitoring BID

•DIGOXIN vs VERAPAMIL

•ACUTE (<24hrs) vs ROUTINE electrical cardioversion


•“Acute cardioversion did not improve long term rhythm control”

•Retrospective review of:

•1950 pts receiving 2630 DC Cardioversions

•4 week post chart follow + contacted treating physician

•258 pts Afib < 2 days

Coumadin PRE / POST - 60

NO Coumadin PRE / POST - 198

# Stroke

1

0

0.3%

•“New-onset AF is associated with a significantly higher risk for death compared with no AF or persistent AF”

•Mortality

•<4 months HR 9.62 (8.93 - 10.32)

•>4 months HR 1.66 (1.59 - 1.73)

•“Through safe in these studies, it may be prudent to perform TEE (or delay cardioversion for 1 month) Even without use of TEE, anticoagulation with heparin immediately prior to cardioversion may be appropriate.” Grade 2C

•NO RCT’s <48hrs


•Age, median 68


•HTN 32.8%

•CAD 24.9%

•CHF 5.3%


C H A SD


•Age, median 68


•HTN 32.8%

•CAD 24.9%

•CHF 5.3%


C

H

A

S

Paroxysmal

Conclusions

•Procainamide - moderately efficacious

•Cardioversion “helping” pts with secondary atrial fibrillation

•Decision to start ANTI-COAGULATION and RATE/RHYTHM needs to be patient SPECIFIC

Questions?

Documents

Atrial Fibrillation: Is is time for a change of pace?