TermDefinition Paroxysmal AFAF that terminates spontaneously or with intervention within 7 d of onset. Episodes may recur with variable frequency. Persistent AFContinuous AF that is sustained >7 d. Longstanding persistent AF Continuous AF >12 mo in duration. Permanent AFThe 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. Nonvalvular AFAF in the absence of rheumatic mitral stenosis, a mechanical or bioprosthetic heart valve, or mitral valve repair.
65 year old man presents to his doctor’s office for his routine physical and is found to be in atrial fibrillation. ◦ 1. rate control and anticoagulation ◦ 2. electrical cardioversion ◦ 3. electrical cardioversion plus antiarrhythmic therapy ◦ 4. ablation
TrialYearn Primary End Point HR (Rate vs Rhythm Control) P PIAF 3 2000252 Improvement AF symptoms 1.100.31 AFFIRM 1 20024060Overall mortality0.870.08 RACE 2 2002522Composite0.730.11 STAF 4 2003200Composite1.090.99 HOT CAFE 5 2004205Composite1.98>0.71 AF-CHF 6 20081376 Cardiovascular mortality 0.940.59 PABA- CHF 15 200881CompositeMultiple<0.001 Rate versus Rhythm Trials
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, % 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.
HR Peak SF-36 Change in One Year Singh BN, et al, NEJM 2005; 352:1861- 72.
Antiarrhythmic Drugs for AF 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)
Dronedarone Clinical Trials TrialStudy DesignDronedarone Effects ERATODronedarone vs placeboSignificant decrease in ventricular rates (24-hr Holter and maximal exercise) DAFNEDronedarone vs placeboEfficacy vs placebo in time to first AF recurrence with 400 mg bid dose EURIDIS and ADONIS Dronedarone vs placebo in 1237 patients with AF/AFL Significant and consistent reduction in first recurrence of AF/AFL; comparable safety vs placebo ANDROMEDADronedarone vs placebo in 627 patients with severe HF Excess mortality risk vs placebo (n=25 vs n=12; HR, 2.13; P=.03); trial stopped early DIONYSOSDronedarone vs amiodarone in 504 patients with persistent AF Mixed observations ATHENA PALLAS Dronedarone vs placebo in 4628 high-risk AF patients Dronedarone vs placebo in 3236 patient with permanent AF ● 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
ATHENA: Summary 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, QT- interval 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.
RATE VS RHYTHM CONTROL 100 80 20 40 % Patients Free of Symptomatic AF 24681012 Months 60 Amiodarone* Sotalol** Propafenone** Hx of Two Failed Drugs*** * Roy et al NEJM, 2000 **Antman et al, JACC 1990 ***Crijns et al, AJC 1991 #Natale et al JACC 2001 Atrial Flutter # Efficacy of Antiarrhythmic Drug Therapy for A Fib Gold Standard for Judging Ablative Therapy AFFIRM AFFIRM TRIAL – Rhythm Control Arm Overestimate AF control with drug (No Sxs) Increased Mortality? (The prevalence of sinus rhythm in the rhythm- control group at follow-up was 82.4 percent, 73.3 percent, and 62.6 percent at one, three, and five years, respectively.)
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 JACC 2009;53:1510-6 75 (2.3%) 55 (1.7%) P= 0.08
Synergistic Effect of the Combination of Ranolazine and Dronedarone to Suppress AF Burashnikov A et al. JACC 2010
HARMONY 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
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 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. Results Conclusions Van Gelder IC, et al. N Engl J Med 2010;Mar 15:[Epub] (p = 0.001)* Lenient control (n = 311) Strict control (n = 303) Primary endpoint 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 0 1010 3030 % 12.9 14.9 % (p = NS) 2020 * For noninferiority 2.9 3.9 30 2020 1010 0 CV mortality
1. Nothing 2. ASA 3. ASA + Plavix 4. NOAC or Vit K antagonist 5. NOAC + ASA
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
Re-LY ◦ 18,113 patients randomized to dabigatran 110, 150, or warfarin ◦ 1983 cardioversions in 1270 patients Antecedent TEE (% thrombus) Continuous therapy for > 3 weeks pre DCCV Stroke/systemic embolism D11025.5 (1.8%)76.40.8 D15024.1 (1.2%)79.20.3 Warfarin13.3 (1.1%)85.50.6 Nagarakanti et al. Circ 2011
Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation ◦ 1504 patients (2:1 randomisation rivaroxaban Vs warfarin ◦ TEE guided DCCV versus 3 weeks of oral AC at the discretion of the treating physician For early cardioversion rivaroxaban was started at least 4 hours prior to cardioversion. ◦ composite of stroke, transient ischaemic attack, peripheral embolism, myocardial infarction, and cardiovascular 5 (two strokes) of 978 patients (0.51%) in the rivaroxaban group 5 (two strokes) of 492 patients (1.02%) in the VKA group [risk ratio 0.50; 95% confidence interval (CI) 0.15–1.73]. ◦ Major bleeding ◦ 6 patients (0.6%) in the rivaroxaban group ◦ 4 patients (0.8%) in the VKA group (risk ratio 0.76; 95% CI 0.21– 2.67 Cappato et al. European Heart Journal. 2014
In ARISTOTLE ◦ 743 cardioversions in 540 patients and thromboembolic complications similar to warfarin
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
| Primary Endpoint: Total number of TIMI bleeding events WOEST Days Cumulative incidence of bleeding 0306090120180270365 0 % 10 % 20 % 30 % 40 % 50 % 284210194186181173159140n at risk: 279253244241 236226208 Triple therapy group Double therapy group 44.9% 19.5% p<0.001 HR=0.36 95%CI[0.26-0.50]
Secondary Endpoint (Death, MI,TVR, Stroke, ST) WOEST Days Cumulative incidence 0306090120180270365 0 % 5 % 10 % 15 % 20 % 284272270266261252242223n at risk: 279276273270266263258234 17.7% 11.3% p=0.025 HR=0.60 95%CI[0.38-0.94] Triple therapy group Double therapy group
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).