Atrial Fibrillation Rate or Rhythm Control Saeed Oraii MD Tehran Arrhythmia Clinic April 2007 Shiraz

“Delirium Cordis” First described by Sir William Harvey in 17th century: observed chaotic motion of atria in open chest animal Heart rhythm irregularity first described in 1903 by Hering ECG findings described in 1909 by Sir Thomas Lewis: “irregular or fibrillatory waves and irregular ventricular response” or “absent atrial activity with grossly irregular ventricular response” The irregularity and inequality of heart rhythm associated with atrial fibrillation was first described by Dr. Hering in 1903. Atrial fibrillation is by far the most common sustained arrhythmia diagnosed and treated by physicians. It may be either paroxysmal or chronic. Paroxysms may be brief or lengthy, frequent or infrequent; they may be benign or result in marked symptoms. 1

Atrial fibrillation accounts for 1/3 of all patient discharges with arrhythmia as principal diagnosis 6% PSVT 6% PVCs 18% Unspecified 4% Atrial Flutter 9% SSS 34% Atrial Fibrillation 8% Conduction Disease 10% VT 3% SCD 2% VF Baily D. J Am Coll Cardiol. 1992;19(3):41A.

Incidence and Prevalence Prevalence increases with age 4.8 % in the 70-79 age group Increases to 8.8% in the 80-89 age group During the next 7-8 years, the number of people over the age of 80 is expected to quadruple

Atrial Fibrillation Demographics by Age U.S. population x 1000 Population with AF x 1000 30,000 20,000 10,000 Population with atrial fibrillation 500 400 300 200 100 U.S. population <5 5- 9 10- 14 15- 19 20- 24 25- 29 30- 34 35- 39 40- 44 45- 49 50- 54 55- 59 60- 64 65- 69 70- 74 75- 79 80- 84 85- 89 90- 94 >95 Age, yr Adapted from Feinberg WM. Arch Intern Med. 1995;155:469-473.

Projected AF Prevalence: OLMSTED COUNTY DATA 12% observed increase in AF incidence between 1980 and 2000 Miyasaka et al, Circulation 2005; 114:119

Projections of AF Prevalence in the United States Adults With AF (millions) It is expected that as the number of elderly people in the United States increases, diagnoses of AF will increase proportionally. A recent study applied age-specific estimates of the prevalence of AF to US census data to estimate the number of adults who will be diagnosed with AF in the future. Go and colleagues estimated that the number of patients with AF will approach 3 million within the next 15 years. The authors estimated that in the year 2050, 5.6 million adults in the United States will be diagnosed with AF. Adapted from Go. JAMA. 2001;285:2370.

Complications and Prognosis 5-fold increase in risk of stroke and thromboembolism Strokes associated with AF are more severe Death: OR 1.5 –1.9 AF worsens diagnosis in CHD and HF Impairment in cognitive function Reduced exercise tolerance

The 10,000 Foot View … The prevalence of AF is rapidly increasing Aging population True increase in incidence Lifetime risk of AF at age 40 is 25% AF is a progressive disorder Cardiac remodeling due to genetic factors, acquired disease, atrial fibrillation itself Up to 25% of initially self-terminating AF will become chronic in 5 years, > 50% at 10 years Associated with substantial risk of adverse outcomes beyond immediate symptoms Stroke Congestive heart failure Death Associated with substantial increase in health care costs and resource utilization

Therapeutic Approaches to Atrial Fibrillation Anticoagulation Rate Control (ventricular response) Pharmacologic Catheter modification/ablation of AV node Rhythm Control Antiarrhythmic suppression Curative procedures Catheter ablation Surgery (maze)

Thromboembolic prophylaxis Thromboembolic events do not just occur in permanent AF Consider treatment for all patients with AF Clustering of events at the time of onset 62% RR reduction with adjusted dose Warfarin 22% RR reduction with Aspirin 0.9% absolute risk increase of major haemorrhage with Warfarin

Risk Assessment Tools Do not apply to valvular heart disease Risk of thromboembolism depends on other risk factors in patients with AF Various risk assessment tools available There are differences between CHAD2 and the tool favoured in the NICE guidelines

CHAD2 Score

Therapeutic Approaches to Atrial Fibrillation Anticoagulation Rate Control Pharmacologic Catheter modification/ablation of AV node Rhythm Control Antiarrhythmic suppression Curative procedures Catheter ablation Surgery (maze)

AF: Pharmacologic Rate Control Digitalis Beta Blockers Calcium Channel Blockers (verapamil, diltiazem) Amiodarone (in special settings)

Atrial Fibrillation: Rate Control Essential in all patients Persistent tachycardia rates can induce cardiomyopathy and heart failure Occasional follow-up holter monitor to ascertain rate control Target: 60-80 bpm rest 90-115 bpm with exercise

Adequate Rate Control AFFIRM RACE HOT CAFÉ Average HR of ≤80 beats/min at rest and either a maximum of ≤110 bpm during a 6-minute walk or an average of <100 bpm on 24-hour Holter monitoring, with the rate not exceeding 110% of maximum predicted age-adjusted exercise rate. RACE Resting heart rate on a 12-lead ECG of ≤100 beats/min HOT CAFÉ A heart rate of 70–90 beats/min on a resting 12-lead ECG and ≤140 beats/min during moderate exercise

Digoxin: some words of caution Oldest and most commonly prescribed drug for control of ventricular rate Predominant acute effect is mediated by the autonomic nervous system An important slowing effect of the AV node is mediated by enhanced vagal tone Not effective during periods of increased sympathetic tone Not effective in paroxysmal atrial fibrillation

AVN Ablation and PPM Paroxysmal AF – DDDR pacing with mode switch Permanent AF – VVIR pacemaker Biventricular devices may be better in preserving LV function

AVN Ablation and PPM Pros: Controls and regularizes ventricular rate Effective at improving symptoms, QOL and ? LV function Cons: Permanent Detrimental effects of RV pacing, especially if reduced LV function already Still have thromboembolic risk Continue to have loss of atrial contractile function

Ablate and pace Suitable for AF with symptomatic rapid ventricular rate unresponsive to drug Rx, or when drug Rx not tolerated Curative AF ablation not suitable or not possible Patients with a bradycardia indication for pacing More suited to elderly (less requirement for generator changes and lead revision)

Therapeutic Approaches to Atrial Fibrillation Anticoagulation Rate Control (ventricular response) Pharmacologic Catheter modification/ablation of AV node Rhythm Control Antiarrhythmic suppression Curative procedures Catheter ablation Surgery (maze)

AF: Rhythm Control Options

Antiarrhythmic Therapy for Atrial Fibrillation Advantages High efficacy for some patients, at least initially (< 50% of all patients) Low initial cost Noninvasive Disadvantages High recurrence rate High long-term cost Non-curative Adverse effects Potential proarrhythmia

Proarrhythmia Drug-induced Torsade

Rhythm vs Rate control Trials PIAF Lancet 2000 AFFIRM NEJM 2002 RACE STAF JACC 2003 Hot CAFÉ Chest 2004

Rate vs. Rhythm control None of the RCTs found rate control inferior in terms of mortality or quality of life. One study showed rate control reduced the mortality in patients without Heart Failure, in over 65s and in patients with CHD. Reduced rates of hospitalization and adverse events with rate control No difference in the rate of thromboembolic or hemorrhagic events Rate control is more cost effective.

AFFIRM: Atrial Fibrillation Follow-up Investigation of Rhythm Management Design Multicenter, randomized, open, parallel group Patients 4060 patients who had atrial fibrillation that was likely to be recurrent, with other risk factors for stroke or death. Patients with contraindications for anticoagulant therapy were excluded Follow up and primary endpoint Primary endpoint: all-cause mortality. Mean 3.5 years follow up. Treatment Rate control: >1 rate-controlling drugs, plus anticoagulant, or Rhythm control: >1 antiarrhythmics, plus cardioversion as necessary; anticoagulant encouraged but could be discontinued Nonpharmacological therapies and changes in pharmacological therapy, including crossover between groups, were permitted. The AFFIRM Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002;347:1825–33.

AFFIRM Baseline characteristics Overall 70 41 25 5 52 1 13 23 Rate control (n=2027) 70 38 28 5 50 1 12 23 Rhythm control (n=2033) (n=4060) Age (years) a 70 Female (%) 39 Predominant cardiac diagnosis (%) Coronary artery disease 26 Cardiomyopathy 5 Hypertension 51 Valvular disease 5 Other 1 No apparent heart disease 12 History of congestive 23 heart failure (%) a Mean AFFIRM Investigators. N Engl J Med 2002; 347 :1825 – 33.

AFFIRM Drugs used in rate and rhythm control groups a Rate control Used drug for Used drug Used drug for Used drug initial therapy at any time initial therapy at any time No. (%) No. (%) No. (%) No. (%) Rate control: data available 1957 2027 1266 2033 Digoxin 949 (48.5) 1432 (70.6) 417 (32.9) 1106 (54.4) Beta-blocker 915 (46.8) 1380 (68.1) 276 (21.8) 1008 (49.6) Diltiazem 583 (29.8) 935 (46.1) 198 (15.6) 610 (30.0) Verapamil 187 (9.6) 340 (16.8) 56 (4.4) 204 (10.0) Rhythm control: data available 1265 2027 1960 2033 Amiodarone 2 (0.2) b 207 (10.2) 735 (37.2) 1277 (62.8) Sotalol 1 (0.1) b 84 (4.1) 612 (31.2) 841 (41.4) a A few patients in the rate and a significant number in the rhythm control groups received other antiarrhythmics b These patients immediately crossed over to the rhythm control group, a protocol violation AFFIRM Investigators. N Engl J Med 2002; 347 :1825 – 33.

AFFIRM Goals of AFFIRM Anticoagulate: Resting HR <80 24 hr Holter average <100 bpm. No HR above 110% of age predicted maximum HR <110 on a six min walk Anticoagulate: -If over 48hrs of AF, must anticoag before cardioversion. -Warfarin (6-12wks), heparin, LMWH -Aspirin -If Lone AF aspirin or nothing

AFFIRM - RESULTS - No significant difference between rate control and rhythm control groups in: all-cause mortality (25.9 vs. 26.7%, P=0.08) composite secondary endpoint (death, disabling stroke or anoxic encephalopathy, major bleeding, and cardiac arrest) total number of central nervous system events (stroke or hemorrhage) Nonsignificant trends were towards reduction of all- cause mortality and CNS events with rate control, compared with rhythm control Significantly reduced hospitalization in rate control group compared with rhythm control Fewer patients initially assigned to rate control crossed over to rhythm control than crossed from rhythm to rate control (15 vs. 38% at 5 years; P<0.001) NOTE ON LAST POINT: paper shows crossover at 1, 3 and 5 years; have included only the latter here

AFFIRM - RESULTS - All-cause mortality Cumulative 30 mortality (%) 25 20 15 10 P=0.08 5 Rhythm control Rate control 1 2 3 4 5 Years after randomization AFFIRM Investigators. N Engl J Med 2002; 347 :1825 – 33.

AFFIRM - RESULTS - Primary and selected secondary endpoints Overall Rate control Rhythm control (n=4060) (n=2027) (n=2033) P No. (%) No. (%) No. (%) Primary endpoint: all-cause mortality 666 (26.3) 310 (25.9) 356 (26.7) 0.08 Secondary endpoint: 861 (32.3) 416 (32.7) 445 (32.0) 0.33 death, disabling stroke, disabling encephalopathy, major bleeding, and cardiac arrest CNS eventa 211 (8.2) 105 (7.4) 106 (8.9) 0.93 Hospitalization 2594 (76.6) 1220 (73.0) 1374 (80.1) <0.001 a Ischemic stroke, or primary intracerebral or subdural/subarachonoid hemorrhage AFFIRM Investigators. N Engl J Med 2002; 347 :1825 – 33.

AFFIRM - SUMMARY- In patients who had atrial fibrillation and were at high risk for stroke or death, comparison of rate and rhythm control showed: No significant difference in all-cause mortality, composite secondary endpoint (death, disabling stroke, disabling anoxic encephalopathy, major bleeding, cardiac arrest) or ischemic stroke A nonsignificant trend to reduction of all-cause mortality and stroke with rate control Reduced hospitalization with rate control Crossover to the other control method was lower in the rate control group

RACE Trial Rate Control vs. Electrical Cardioversion 522 patients with persistent atrial fibrillation or atrial flutter (24 hours-1 year) 2 cardioversions within 1 year Rate control to HR < 100 bpm and no symptoms Rhythm control: Sotalol followed by Flecainide or Propafenone followed by Amiodarone Primary endpoint: cardiovascular death, admission or CHF, Thromboembolic events, severe bleeding, pacemaker implantation or severe anti-arrhythmic side effects

RACE Study 522 Patients 256 patients – rate control 266 patients – cardioversion Outcome Rate Rhythm Death/Stroke 17.2% 22.6% Mortality 7% 6.7% CHF 3.5% 3.4% Hypertension Subgroup: Combined Endpoints: Mortality/thromboembolism/severe complication Rate Rhythm 19% 31%

Rate vs. Pharmacologic Rhythm control Favor of rate control Favor of rhythm control Persistent AF History of AF more than 1 year Less symptomatic > than 65 years of age History of HTN Previous AAD failure LA > 60 mm No history of CHF Patient preference Paroxysmal AF First episode of AF More Symptomatic < than 65 years of age No history HTN No Previous AAD failure LA < 60 mm History CHF Patient preference

Who is under-represented in AFFIRM? Young patients Paroxysmal atrial fibrillation CHF Reduced systolic function Isolated diastolic dysfunction Disabling symptoms of AF What therapies are under-represented ? Other (newer?) drugs Non-pharmacologic therapies

What AFFIRM Does Not Tell Us? Optimal management for patients with moderate or severe disabling symptoms related to atrial fibrillation Outcome if better tools to maintain sinus rhythm were available Long-term implications of rate vs. rhythm control (mean duration of follow-up only 3.5 years)

Nonpharmacological Approaches to Atrial Fibrillation Pacemaker therapy 2. Ablation 3. Surgery

Pulmonary Vein Triggers

Segmental Ablation

Segmental Ablation

Circumferential Ablation

Circumferential Ablation

Circumferential Ablation

Randomized Trials of Ablation for PAF STABILE: EHJ 2006 27:216-221; prior AAD failure; 1 episode/mo 6 mo duration; included 32% persistent AF; AAD given to ablation group; PVI+MI+CTI; blanking 1 mo; HM + 3 mo daily event montioring; endpoint 30 sec AF WANZI: JAMA 2005: 293:2634-2640); No prior AAD; 1 episode/mo 3 mo duration; PVAI; blanking 2 mo; HM + 1,3 mo event monitoring; endpoint 15 sec AF. Pilot study for RAAFT (400 pt trial) JAIS: HRS Scientific Sessions 2006; Prior AAD failure, 2 episodes/mo 6 mo duration; PVI+CTI+lines; blanking 3 mo; HM + symptom diaries; endpoint 3 min AF or palpitations PAPPONE: JACC 2006 in press, doi 10:1016. Limited prior AAD; 2 episodes /mo 6 mo duration;CPVI+CTI+lines; blanking 6 wks, daily event monitoring; endpoint 30 sec AF Major complications in 1-4% of ablation groups

Can Ablation Improve Survival? Pappone et al JACC 2003; 42:186-197

Catheter ABlation Versus ANtiarhythmic Drug Therapy for Atrial Fibrillation (CABANA) Randomized trial comparing ablation to best drug therapy (rate or rhythm control) Primary endpoint: mortality (powered for 30% mortality reduction assuming 12% 3 yr mortality in drug group) Secondary endpoints: Composite (death, disabling stroke, serious bleeding, cardiac arrest) Freedom from AF recurrence (irrespective of symptoms) Health care costs and resource utilization Quality of life Planned 3000 pts, 120 enrolling centers Pilot phase approved starting late 2006, full study pending approval

Catheter ABlation Versus ANtiarhythmic Drug Therapy for Atrial Fibrillation (CABANA) Enrollment criteria > age 65, or < 65 with > 1 risk factor for stroke Eligible for both AF, and at least 2 membrane active drugs or 3 rate control drugs Paroxysmal (at least 2 episodes in prior 3 mo), persistent or chronic AF Ablation technique to include PVI + additional procedures (lines, CFAE, ganglionated plexi) 3 month blanking period in both groups (repeat ablation, or change in AAD permitted). Crossover to ablation in drug group strongly discouraged Follow-up with holter monitor, daily TTM (2 wks every 6 mo), and ILR (proposed 750 pt substudy)

Curative AF ablation Potential harm Death Stroke Exacerbation of arrhythmia (flutters) Tamponade / PV stenosis Failure and redo rate Potential benefits Symptomatic benefit No need for AADs ? Thromboembolic benefit ? Mortality benefit?

Who Should be Offered Ablation Here and Now? Patients with symptomatic, drug refractory atrial fibrillation, should be judged on an individual basis according to the Ablation Centre’s experience Ideally, the patient should satisfy the following criteria: A rhythm control strategy is preferred and other therapeutic options are not as appropriate Attempts with at least 1 AAD have failed Preferably <70 (certainly <80!) Preferably normal heart or mild-moderate structural heart disease (LVEF>45%?) Preferably not a very dilated left atrium Prepared to accept risk of stroke (based on patient factors and institution’s results) Prepared to accept failure (based on institution’s results) Prepared to accept need for a re-do procedure (based on institution’s results)

Points to remember: Will need Warfarin 1 month before and minimum 3 months after procedure May require ongoing AA drug Rx AFib and LA flutter often occur in first few months after procedure. True success should be assessed after 3-6 months Permanent AFib may be considered, but ~50% success rate

Summing up the evidence

Who could we offer rhythm control to? P O ?

Key Messages All patients with AF need thromboembolic risk assessment. Rate control will benefit most of our patients but adequate rate control is necessary. Digoxin is not first line drug for rate control The plethora of antiarrhythmic drugs currently available for the treatment of AF is a reflection that none is wholly satisfactory, each having limited efficacy combined with poor safety and tolerability. Catheter ablation considered a Class 2a indication for patients with symptomatic persistent or paroxysmal AF after failure of an initial trial of AAD therapy (AHA/ACC/ESC 2006 Guidelines)

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