Stuart Beldner, MD, FHRS Assistant Professor NSLIJ Hofstra School of Med

Stuart Beldner, MD, FHRS Assistant Professor NSLIJ Hofstra School of Med

None

There s no reason to panic. While it is true that one of the crew members is ill, slightly.

Absence of discrete P waves Chaotic atrial activity Ventricular rate irregularity

Mechanisms of AF. AF indicates atrial fibrillation; Ca++, ionized calcium; and RAAS, reninangiotensin-aldosterone system. January C T et al. Circulation. 2014;130:e199-e267 Copyright American Heart Association, Inc. All rights reserved.

Term Paroxysmal AF Definition AF that terminates spontaneously or with intervention within 7 d of onset. Episodes may recur with variable frequency. Persistent AF Continuous AF that is sustained >7 d. Longstanding persistent AF Permanent AF Nonvalvular AF Continuous AF >12 mo in duration. The term permanent AF is used when the patient and clinician make a joint decision to stop further attempts to restore and/or maintain sinus rhythm. Acceptance of AF represents a therapeutic attitude on the part of the patient and clinician rather than an inherent pathophysiological attribute of AF. Acceptance of AF may change as symptoms, efficacy of therapeutic interventions, and patient and clinician preferences evolve. AF in the absence of rheumatic mitral stenosis, a mechanical or bioprosthetic heart valve, or mitral valve repair.

Rate versus Rhythm Trials Trial Year n PIAF 3 2000 252 Primary End Point Improvement AF symptoms HR (Rate vs Rhythm Control) P 1.10 0.31 AFFIRM 1 2002 4060 Overall mortality 0.87 0.08 RACE 2 2002 522 Composite 0.73 0.11 STAF 4 2003 200 Composite 1.09 0.99 HOT CAFE 5 2004 205 Composite 1.98 >0.71 AF-CHF 6 2008 1376 Cardiovascular mortality 0.94 0.59 PABA- CHF 15 2008 81 Composite Multiple <0.001

Trials such as AFFIRM and RACE, did NOT prove that rate-controlled and anticoagulated AF is as good as NSR. They show that a rhythm control strategy using an ITT analysis, suggests equivalence in at least some populations. These trials do NOT disprove that sinus rhythm would be better than AF in regard to QOL if one were to actually attain and maintain it with a safe and effective therapy.

Patients in Sinus Rhythm, % 100 90 80 70 60 50 40 30 20 10 0 Rate Arm Rhythm Arm R 2 Mo 4 Mo 1 Yr 2 Yr 3 Yr 4 Yr 5 Yr Time The AFFIRM Investigators. NEJM: 2002; 347: 1828-1833

5 fold increase in risk for stroke * AF strokes are usually more severe than nonaf strokes 3 fold risk of heart failure ** 2 fold risk of dementia *** and mortality * *Kannel et al. Am J of Coll. 1998 **Wang et al. Circu. 2003 *** Ott et al. Stroke 1997.

Time dependant, on treatment, Multivariate Analysis of Survival HR (99%) 1.06 (1.05 1.08) 1.56 (1.20 2.04) 1.57 (1.18 2.09) 1.56 (1.17 2.07) 1.78 (1.25 2.53) 1.70 (1.24 2.33) 0.74 (0.55 0.98) 1.36 (1.03 1.80) 0.50 (0.37 0.69) 1.42 (1.09 1.86) 0.53 (0.39 0.72) 1.49 (1.11 2.01) Factor Age (per year) CAD CHF Diabetes Smoking Stroke/TIA Normal LVEF Mitral Regurg Warfarin Digoxin Sinus Rhythm AA drug 0. 2 0. 4 0. Better 6 0. 8 1. 0 1. 2 1. Worse 4 1. 6

Singh BN, et al, NEJM 2005; 352:1861-72. 80 SF-36 Change in One Year 4 3 2 1 0-1 -2-3 -4-5 -6 Physical Fx General Health Social Fx Vitality NSR AF 60 40 20 0-20 -40-60 HR Rest Exercise Duration HR Peak

Class I: Class IC: propafenone (also very weak β-blocker), flecainide (no β-blockade effects) Sustained-release propafenone (Rythmol SR) and flecainide are bid; Propafenone appears to be less proarrhythmic Class IA: disopyramide, quinidine, procainamide No longer included in the ACC/AHA/ESC algorithm Disopyramide may be useful in vagally induced AF Class III: Sotalol (class III plus β-blocker) Dofetilide (pure class III) Amiodarone (class III plus class I, II, IV); highly overused Dronedarone (similar to amiodarone with different pharmacokinetics and markedly reduced organ toxic potential)

Trial Study Design Dronedarone Effects ERATO Dronedarone vs placebo Significant decrease in ventricular rates (24-hr Holter and maximal exercise) DAFNE Dronedarone vs placebo Efficacy vs placebo in time to first AF recurrence with 400 mg bid dose EURIDIS and ADONIS ANDROMEDA DIONYSOS ATHENA PALLAS Dronedarone vs placebo in 1237 patients with AF/AFL Dronedarone vs placebo in 627 patients with severe HF Dronedarone vs amiodarone in 504 patients with persistent AF Dronedarone vs placebo in 4628 high-risk AF patients Dronedarone vs placebo in 3236 patient with permanent AF Significant and consistent reduction in first recurrence of AF/AFL; comparable safety vs placebo Excess mortality risk vs placebo (n=25 vs n=12; HR, 2.13; P=.03); trial stopped early Mixed observations Efficacy against AF Reduction in CV mortality and hospitalization Reduction in additional end points a 2.29-fold increase in the coprimary end point of stroke, MI, embolism, or cardiovascular death events, compared to placebo, and led to a halt in a planned 10,800-patient international randomized trial

Results show dronedarone significantly prolongs the time to AF recurrence compared with placebo No significant difference was found between placebo and dronedarone in all-cause mortality Dronedarone reduced CV mortality, CV hospitalizations, ACS, arrhythmic deaths, and stroke Adverse events occurring significantly more frequently with dronedarone than with placebo included bradycardia, QTinterval prolongation, diarrhea, nausea, rash, and an increase in the serum creatinine level Total discontinuation rates for dronedarone and placebo were identical, no pulmonary or thyroid toxicity was evident, and there were no TDP/VF deaths in the high-risk AF population in dronedarone-treated patients Hohnloser SH, et al. N Engl J Med. 2009;360(7):668-678.

Efficacy of Antiarrhythmic Drug Therapy for A Fib Gold Standard for Judging Ablative Therapy % Patients Free of Symptomatic AF 100 Arm Overestimate AF control 80 with drug (No Sxs) Increased Mortality? (The prevalence of sinus rhythm in the rhythmcontrol group at follow-up was 82.4 percent, 73.3 percent, and 62.6 percent at one, three, and RATE VS RHYTHM CONTROL 60 AFFIRM 40 20 * Roy et al NEJM, 2000 **Antman et al, JACC 1990 ***Crijns et al, AJC 1991 #Natale et al JACC 2001 AFFIRM TRIAL Rhythm Control five years, respectively.) Propafenone** 2 4 6 8 10 12 Months Amiodarone* Sotalol** Hx of Two Failed Drugs*** # Atrial Flutter

Ranalozine (Ranexa) Has a greater effect on the late sodium current (late > peak) which should make it more effective in ischemic patients. Vernakalat Ikur Blocker

Approved for the treatment of chronic stable angina An atrially effective compound, substantially inhibiting peak Na + current mainly in the atria and has been shown to decrease the incidence of atrial fibrillation in an in vitro model. MERLIN TIMI 36 1 (Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes) 6,560 patients with prior chronic angina A neutral effect on overall mortality Suggested (P= 0.08) a 26% reduction in new onset atrial fibrillation. The incidence of significant arrhythmias was screened with holter monitoring 100 50 0 P= 0.08 75 (2.3%) 55 (1.7%) Placebo Ranolazine JACC 2009;53:1510-6

Burashnikov A et al. JACC 2010

A Phase 2, Proof of Concept, Randomized, Placebo- Controlled, Parallel Group Study to Evaluate the Effect of Ranolazine and Dronedarone When Given Alone and in Combination on Atrial Fibrillation Burden in Subjects With Paroxysmal Atrial Fibrillation Primary endpoint The effect of ranolazine and of low dose dronedarone when given alone and in combination at different dose levels on atrial fibrillation burden (AFB) over 12 weeks of treatment the combination of ranolazine (Ranexa, Gilead Sciences) and dronedarone (Multaq, Sanofi) appeared to lower the burden of atrial fibrillation (AF) by >70% over three months in 45% to 60% of patients with the paroxysmal form of the arrhythmia Kowey et al. Presented at HRS 2014

A 59-year-old woman is referred to you for management of permanent atrial fibrillation that she has had for three years. The referring physician reports that recently performed echocardiography revealed normal findings. The patient's current medications are dabigatran and metoprolol, 50 mg daily. During your initial evaluation, the patient says she feels well and has no symptoms. A 12-lead electrocardiogram shows a resting heart rate of 100 beats per minute (bpm). (A) Continue the current drug regimen and schedule follow-up evaluation (B) Increase metoprolol dosage and obtain a 24-hour ambulatory electrocardiographic recording; adjust metoprolol dosage to achieve a heart rate of less than 70 bpm during rest and less than 120 bpm during moderate exercise (C) Increase metoprolol dosage and obtain a 24-hour ambulatory electrocardiographic recording; adjust metoprolol dosage to achieve a heart rate of less than 80 bpm during rest and less than 110 bpm during moderate exercise (D) Increase metoprolol dosage and obtain a 24-hour ambulatory electrocardiographic recording; adjust metoprolol dosage to achieve a heart rate of less than 80 bpm during rest and less than 130 bpm during moderate exercise

2006 guidelines for AF recommended target heart rates of 60 to 80 bpm at rest and 90 to 115 bpm during moderate exercise AFFIRM no higher than 80 bpm at rest and no higher than 110 bpm during a 6-minute walk test, and an average heart rate no higher than 100 bpm over 18+ hours of Holter monitoring with no rates >100% of maximal age-predicted heart rate, as well RACE Resting heart rate < 100 bpm

Trial design: Patients with permanent AF were randomized to lenient (resting heart rate [HR] <110 bpm) or strict rate control (resting HR <80 bpm). Patient follow-up was 3 years. % 3 0 2 0 (p = 0.001)* 12.9 14.9 % 30 2 0 (p = NS) Results Primary outcome was similar in lenient and strict control arms (12.9% vs. 14.9%) Stroke with lenient control (1.6% vs. 3.9%, p< 0.05) CHF (3.8% vs. 4.1%), CV death, PPM implantation (0.8% vs. 1.4%) were similar Conclusions 1 0 0 Primary endpoint Lenient control (n = 311) 1 0 0 * For noninferiority 2.9 3.9 CV mortality Strict control (n = 303) Lenient rate control easier to achieve than strict control, and noninferior for clinical outcomes Most patients had lower CHADS 2 score. Safety and efficacy in patients with higher CHADS 2 score will need to be explored Needs to be tested in patients with significant LV dysfunction Van Gelder IC, et al. N Engl J Med 2010;Mar 15:[Epub]

CHADS 2 Risk Criteria Score Prior stroke or TIA 2 Age > 75 1 Hypertension 1 Diabetes Mellitus 1 Heart Failure 1 Patients Adjusted Stroke Risk CHADS 2 Score 120 468 528 337 65 5 1.9 (1.2 3.0) 2.8 (2.0-3.8) 4.0 (3.1 5.1) 8.5 (6.3-11.1) 12.5 (8.2-17.5) 18.2 (10.5-27.4 0 1 2 3 4 5

CHA 2 DS 2 -VASc Risk Factor Score C ongestive heart failure/lv dysfunction 1 H ypertension 1 A ge > 75 y 2 D iabetes mellitus 1 S troke/tia/te 2 V ascular disease 1 A ge 65-74 y 1 S ex category (ie female gender) 1

Summary of Recommendations for Risk-Based Antithrombotic Therapy. January C T et al. Circulation. 2014;130:e199-e267 Copyright American Heart Association, Inc. All rights reserved.

Primary Endpoint stroke or systemic embolism INR D150 VKA (RELY) Rivaroxaban VKA (ROCKET AF) Apixaban VKA (ARISTOLE) Quartlie 1 1.10% 1.7% (HR= 0.61) 1.5 2 (HR= 0.48) 1.72 2.36 (HR= 0.73) 2 1.10% 2.2% (HR- 0.48) 1.5 2.6 (HR= 0.61) 1.61 1.72 (HR=0.94) 3 1.10% 1.4% (HR= 0.76) 1.5 2.6 (HR= 0.66) 0.86 1.35 (HR= 0.64) 4 1.30% 1.4% (HR= 0.88) 1.2 2.3 (HR= 0.58) 0.91 1.04 (HR= 0.88) Major bleeding INR D150 VKA (RELY) Rivaroxaban* VKA (ROCKET AF)* Apixaban VKA (ARISTOLE) Quartlie 1 2.40% 3.3% (HR= 0.74) 11.3 14.12 (HR= 0.80) 1.44 2.89 (HR= 0.5) 2 3.20% 3.9% (HR= 0.84) 11.72 12.21 (HR= 0.81) 1.97 3.07 (HR= 0.64) 3 3.60% 3.2% (HR= 1.12) 15.1 14.88 (HR= 1.03) 2.61 3.06 (HR= 0.85) 4 3.20% 3% (HR= 1.08) 20.61 16.72 (HR= 1.25) 2.48 3.31 (HR=0.75) * Event rate (100 pt years)

There is evidence from meta-analyses of RCTs that home monitoring of VKA therapy reduces thromboembolic events by 42% compared with usual monitoring. THIS IS SIMILAR TO THE 33% relative risk reduction with dabigatran 150 mg Bid!!!

Dose adjusted VKA therapy + ASA is not recommended in stable coronary artery disease SPORTIF Associated with a nearly 2 fold increase in bleeding with NO significant reduction in stroke or MI. RE-LY Major bleeding was twice as high in patients on aspirin AND either dabigatran or wafarin

No increase in death Nonfatal stroke CHADS 2 = 0 2 fewer strokes/1000 CHADS 2 = 1 6 fewer strokes/1000 CHADS 2 = 2 11 fewer strokes/1000 CHADS 2 = 3 6 24 fewer strokes/1000 Nonfatal MI 21 fewer/1000 Nonfatal Major Extracranial Bleed 26 more bleeds/1000 (RR= 2.37) CHEST February 2012

WOEST Primary Endpoint: Total number of TIMI bleeding events Cumulative incidence of bleeding 50 % 40 % 30 % 20 % Triple therapy group Double therapy group 44.9% 19.5% 10 % 0 % p<0.001 HR=0.36 95%CI[0.26-0.50] 0 30 60 90 120 180 270 365 Days n at risk: 284 210 194 186 181 173 159 140 279 253 244 241 241 236 226 208

WOEST Secondary Endpoint (Death, MI,TVR, Stroke, ST) 20 % Triple therapy group Double therapy group 17.7% Cumulative incidence 15 % 10 % 11.3% 5 % 0 % p=0.025 HR=0.60 95%CI[0.38-0.94] 0 30 60 90 120 180 270 365 Days n at risk: 284 272 270 266 261 252 242 223 279 276 273 270 266 263 258 234

The primary purpose of this study is to evaluate the safety for 2 different rivaroxaban treatment strategies and one Vitamin K Antagonist (VKA) treatment strategy utilizing various combinations of dual antiplatelet therapy (DAPT) or low-dose aspirin (ASA) or clopidogrel (or prasugrel or ticagrelor).

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