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Medical Management Atrial Fibrillation
Stuart Beldner, MD, FHRSAssistant Professor NSLIJ Hofstra School of Med
None
Disclosures
“There’s no reason to panic. While it is true that one of the crew members is ill, slightly ….”
A-Fib
ECG Recognition
Absence of discrete P waves Chaotic atrial activity Ventricular rate irregularity
Mechanisms of AF. AF indicates atrial fibrillation; Ca++, ionized calcium; and RAAS, renin-angiotensin-aldosterone system.
January C T et al. Circulation. 2014;130:e199-e267
Copyright © American Heart Association, Inc. All rights reserved.
Term Definition
Paroxysmal AF •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
•Continuous AF >12 mo in duration.
Permanent AF •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.
Nonvalvular AF •AF in the absence of rheumatic mitral stenosis, a mechanical or bioprosthetic heart valve, or mitral valve repair.
2014 AF guidelines classification of AF
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
Trial Year nPrimary End
Point
HR (Rate vs Rhythm Control)
P
PIAF3 2000 252 Improvement AF symptoms
1.10 0.31
AFFIRM1 2002 4060 Overall mortality 0.87 0.08
RACE2 2002 522 Composite 0.73 0.11
STAF4 2003 200 Composite 1.09 0.99
HOT CAFE5 2004 205 Composite 1.98 >0.71
AF-CHF6 2008 1376 Cardiovascular mortality
0.94 0.59
PABA-CHF15 2008 81 Composite Multiple <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.
Should We Truly Believe that AF and NSR are really equal?
0
10
20
30
40
50
60
70
80
90
100
R 2 Mo 4 Mo 1 Yr 2 Yr 3 Yr 4 Yr 5 Yr
Rate Arm
Rhythm Arm
AFFIRM: Prevalence of Sinus Rhythm at Follow-up
Pati
en
ts in
Sin
us
Rh
yth
m,
%
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 *
Atrial Fibrillation Complications
*Kannel et al. Am J of Coll. 1998**Wang et al. Circu. 2003*** Ott et al. Stroke 1997.
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)
Atrial Fibrillation: Follow-up Investigation of Rhythm Management
Time dependant, on treatment, Multivariate Analysis of Survival
FactorAge (per year)CADCHFDiabetes SmokingStroke/TIANormal LVEFMitral RegurgWarfarinDigoxinSinus RhythmAA drug
0.2
0.4
0.6
1.2
1.0
0.8
1.4
1.6Better Worse
-6
-5
-4
-3
-2
-1
0
1
2
3
4
Physical Fx GeneralHealth
Social Fx Vitality
NSR
AF
-60
-40
-20
0
20
40
60
80
HR Rest ExerciseDuration
Effects on Maintaining Sinus Rhythm on QOL and Exercise Capacity: SAFE-T Investigators
HR Peak
SF-3
6 C
han
ge in
On
e Y
ear
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 TrialsTrial 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
Dronedarone vs placebo in1237 patients with AF/AFL
Significant and consistent reduction in first recurrence of AF/AFL; comparable safety vs placebo
ANDROMEDA Dronedarone vs placebo in627 patients with severe HF
Excess mortality risk vs placebo (n=25 vs n=12; HR, 2.13; P=.03); trial stopped early
DIONYSOS Dronedarone vs amiodarone in 504 patients with persistent AF
Mixed observations
ATHENA
PALLAS
Dronedarone vs placebo in4628 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 pointsa 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
% P
atie
nts
Fre
e of
S
ympt
omat
ic A
F
2 4 6 8 10 12
Months
60Amiodarone*
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
New Pharmacologic Rhythm Control Agents
Ranexa (ranolazine) 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 361 (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
0
50
100
Placebo Ranolazine
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
Rate control
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
RACE II
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 CHADS2 score. Safety and efficacy in patients with higher CHADS2 score will need to be explored
• Needs to be tested in patients with significant LV dysfunction
0
10
30
% 12.9
14.9
%
(p = NS)
20
* For noninferiority
2.9 3.9
30
20
10
0CV mortality
1. Nothing2. ASA3. ASA + Plavix4. NOAC or Vit K antagonist5. NOAC + ASA
62 year old female has symptomatic paroxysmal atrial fibrillation. History is negative for hypertension, heart failure, diabetes mellitus, vascular disease, or prior stroke. You reccomend:
CHADS2 Scorestroke risk patients with nonvalvular AF not treated with Anticoagulation According to CHADS index
CHADS2 Risk Criteria Score
Prior stroke or TIA
Age > 75
Hypertension
Diabetes Mellitus
Heart Failure
2
1
1
1
1
Patients Adjusted Stroke RiskCHADS2 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
Refining Risk Stratification in AF
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.
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)
Primary Endpoint – stroke or systemic embolism
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)
Major bleeding
* 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!!!
Home monitoring of AC
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
ASA + Coumadin
No increase in death Nonfatal stroke
◦ CHADS2= 0 2 fewer strokes/1000
◦ CHADS2= 1 6 fewer strokes/1000
◦ CHADS2= 2 11 fewer strokes/1000
◦ CHADS2= 3 – 6 24 fewer strokes/1000
Nonfatal MI◦ 21 fewer/1000
Nonfatal Major Extracranial Bleed◦ 26 more bleeds/1000 (RR= 2.37)
Triple threat(ASA + Plavix + VKA vs ASA+Plavix)
CHEST February 2012
|
Primary Endpoint: Total number of TIMI bleeding events
WOEST
Days
Cum
ula
tive inci
dence
of
ble
edin
g
0 30 60 90 120 180 270 365
0 %
10 %
20 %
30 %
40 %
50 %
284 210 194 186 181 173 159 140n at risk: 279 253 244 241 241 236 226 208
Triple therapy groupDouble 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
Cum
ula
tive inci
dence
0 30 60 90 120 180 270 365
0 %
5 %
10 %
15 %
20 %
284 272 270 266 261 252 242 223n at risk: 279 276 273 270 266 263 258 234
17.7%
11.3%
p=0.025
HR=0.60 95%CI[0.38-0.94]
Triple therapy groupDouble 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).
PIONEER AF
Thank you