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Atrial Fibrillation: Is is time for a change of pace? Resident Grand Rounds Dr. Lee Graham Emergency Medicine R2 November 19, 2009 Disclosure • I just got KEYNOTE. • Be prepared to be Dazzled! 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 longterm 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 Secondary First Detected Paroxsymal (Self-terminating) Persistent (Non self-terminating) Permanen t 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” RATE RHYTHM CNS EVENT NO WARF Bad INR w/ Afib 25 27 42 44 17 25 • AFFIRM • NEJM 2002 • Circulation 2006 analysis = Intention to treat = “In treatment” Covariate Analysis Sinus rhythm 0.53 Rhythm-control 1.49 AFFIRM •Rate • = •Rhythm ACTUAL POSITIVE “side effects” + NEGATIVE “side effects” control ACTUAL control POSITIVE “side effects” + NEGATIVE “side effects” AFFIRM •Rate • = •Rhythm ACTUAL POSITIVE “side effects” + NEGATIVE “side effects” control ACTUAL control POSITIVE “side effects” + NEGATIVE“side effects” 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, acteylcholineactivated potassium currents, antiadrenergic Amiodarone • IodineSide Effects X • Pulmonary • Hepatitis • Thyroid • Eye • effects MAY have fewer side Long lost brothers???? A T H E N A • A T rial with dronedarone to prevent d ath in patie H ospitalization or E N ts with A trial fibrillation • 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 Inclusion Criteria Changed During Study • Paroxysmal or persistent A Fib or A Flutter • + one of • >70 years old >75 • Hypertension (> 2 meds) • DM <70 excluded • previous stroke / TIA / embolism • Left atrial diameter > 50mm • LVEF <40% • EKGs within 6 months (one in sinus / one in afib) 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 •MeanCharacteristics 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% Intolerance Anti-arrhythmic drug 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% Hospitalization Death 2.6% 29.3% Placebo • Death 2.5% 36.9% 39.4% Hospitalization Hazard ratio 0.76 (0.69 - 0.84) Secondary Outcomes i) death any cause •Dronedarone 5.0% • Placebo HR 0.84 (0.66 - 1.08) 6.0% ii) death from CV cause •Dronedarone 2.7% • Placebo HR 0.71 (0.51 - 0.98) 3.9% iii) first hosptilalization due to CV HR 0.74 (0.67 - 0.82) • Dronedarone 29.3% • Placebo 36.9% First Hospitalization A Fib CHF Dronedaron e Placebo P - value 335 (14.6) 510 (21.9) <0.001 132 (5.7) 0.22 112 (4.9) 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 A Fib Dronedarone Placebo 335 (14.6) 510 (21.9) = 7.3 • CV Hospitalization = 7.6 • Primary Outcome = 7.5 Limitations • High rate of discontinuing study drug • No comparison to other anti-arrhythmic • Importance of primary outcome? A N D R O M E D A •A N tiarrhythmic trial withDRO nedarone in Moderate-to-severe Congestive Heart A se EFailure valuating Morbidity D ecre • 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 compared to other AAR ✓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 COMPOSITE: • 1) AF recurrence • or • II) premature drug discontinuation for intolerance of lack of efficacy Primary Outcome P < 0.001 • Dronedarone 73.9% A Fib 36.5% Stopped Drug 10.4% • Amiodarone 55.3% A Fib 24.3% Stopped Drug 13.3% • 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 Dronedarone Amiodarone A Fib Adverse Death Dronedarone Amiodarone Study Conclusions • For every 1000 patients treated with Dronedarone instead of Amiodarone • 228 • 9.6 X • 62 MORE recurrences of A Fib FEWER deaths FEWER adverse events requiring stoppage 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 compared to other AAR ✓Dronedarone in context of Rate vs Rhythm ✓Dronedarone in context of Rate vs Rhythm • Multicenter / Randomized • 1376 pts • Rhythm vs Rate • LVEF < 35% • Symptoms of CHF • Atrial Fibrillation Survival % in A Fib Canadian Trial of Atrial Fibrillation Dronedarone Amiodarone Mortality ? ✓ Dronedarone “POTENTIAL” Benefit ANDROMEDA ATHENA No Heart Failure 1 Dronedarone INCREASED Mortality 2 NYHA 3 4 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! ANTICOAGULATION! Indications for Rhythm • Symptomatic • Secondary cause • Failed Rate control • Patient preference Chance at sinus... FAVORS RATE FAVOR RHYTHM Persistent - Recurrent History Afib > 1yr >65 years of age HTN AAD failure LA > 60cm No previous CHF Patient Preference Paroxysmal AF First Episode of AF <65 yrs of age NO HTN No AAD failure LA < 60cm History of CHF So what about in the ED? • Retrospective chart-review (5 yrs) all patients who received IV Procainamide • “Routine Care” • 169 pts Sinus • Chemical ElectricalA Fib DC w/ no meds +- Cardiology FU Rate Anticoagulaion Exclusion • >48 hrs (unless anticoagulated) • Permanent or Long standing A Fib • Another dx requiring admission (CHF etc..) • Unknown duration Patient Characteristics • Age, median 68 • Previous A Fib • HTN • CAD • CHF • Thromboembolic 65.4% 32.8% 24.9% 5.3% 5.0% • • • • • • • • • Outcomes (within 6hrs) SBP < 100mg Bradycardia Syncope Heart Block VT Torsades CVA Death Recurrence of A Fib (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 • Bradycardia • Ventricular arrhythmia • Death / Badness • Relapse within seven days 28 (8.5%) 2 (0.6%) 1 (0.3) 0 (0.0%) 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? How effective is Procainamide • Retrospective 50% 24hrs Procainamide50.4% chart review of patient presenting with Atrial Fibrillation to the ED as the primary diagnosis x x NO IV available Black Box x x PO Slow / Ineffective Vernelakant Limitations • Retrospective • Short term follow-up • Generalizability • No telephone or death registry review How effective is Procainamide? Is converting these patients doing anything? Is converting these patients doing anything? • Prospective / randomized / OPEN • 2 X 2 design • 144 pt randomized - trans-telephonic monitoring BID • DIGOXIN • ACUTE (<24hrs) vs vs VERAPAMIL 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 0 1 0.3% •“New-onset AF is associated with a significantly higher risk for death compared with no AF or persistent AF” •Mortality 9.62 (8.93 - 10.32) •>4 months HR 1.66 (1.59 - 1.73) •<4 months HR • “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 Patient Characteristics C H A D S • Age, median 68 • Previous A Fib • HTN • CAD • CHF • Thromboembolic 65.4% 32.8% 24.9% 5.3% 5.0% A H C S Patient Characteristics • Age, median 68 • Previous A Fib • HTNParoxysmal • CAD • CHF • Thromboembolic 65.4% 32.8% 24.9% 5.3% 5.0% 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?