Atrial fibrillation in advanced heart failure role of rate control

1. Atrial Fibrillation in Advanced Heart Failure -
Role of Rate Control and Antiarrhythmic Drugs
Disclosures: Lab funded by NIH (HL83359, HL103800, HL122384), Fellowship
Support from British Heart Foundation, Fulbright Foundation. SMN is a co-
inventor of IP owned by UC Regents. Consulting: Abbott EP, Medtronic, ACC
Sanjiv M. Narayan, MD, PHD
Professor of Medicine
Stanford University

2. Treating AF In CHF Patients
• Epidemiology, Mechanisms
• Rate vs Rhythm Control
• Rate Control; Hazards
• Rhythm Control; Hazards
✔

3. Shared Risk Factors for AF and CHF (Systolic)
Trulock KM, Narayan SM and Piccini JP. J Am Coll Cardiol. 2014;64:710-21.
Proportion of AF Patients in CHF Trials

4. Paroxysmal AFPermanent AFNormal
Over Time, AF Becomes a Structural Disease
Myocyte atropy, residual hypertrophy, adiposis; Myocarditis in 66% with lone AF
Frustaci, Circulation 1997; 96: 1180-4
Jahangir et al., Circulation 2007; 115: 3050-3056
Abed, Sanders et al.: Effect of weight reduction on AF. JAMA 2013; 310:2050-2060
May
i.e. Structural change may not ‘condemn’ electrical phenotype

5. Treating AF In CHF Patients
• Epidemiology, Mechanisms
• Rate vs Rhythm Control
• Rate Control; Hazards
• Rhythm Control; Hazards
✔
✔

6. Rate Versus Rhythm Control in HF
Rose-Jones, Heart Failure Clin 10 (2014) 635–652
 Tested medical therapeutic strategies (not rate vs rhythm control)
 Suboptimal efficacy of drugs
 Adverse effects of drugs

7. AF-in-CHF
Roy et al., AF-in-CHF, New Engl J Med 2008; 358: 2667-77
1376 patients, LVEF 27±6%, 67% persistent AF; Amiodarone vs rate control
40% ‘Rhythm
Controlled’
>20% ‘rate
Controlled’

8. Treating AF In CHF Patients
• Epidemiology, Mechanisms
• Rate vs Rhythm Control
• Rate Control; Hazards
• Rhythm Control; Hazards
✔
✔
✔

9. Rate Control
*Power: …. primary outcome of 25% at 2.5Y …80% power to rule out an increase of 10%
Van Gelder et al., RACE 2. N Engl J Med. 2010;362:1363-73

10. Does Lenient Rate Control Apply to HF?
Few patients
with HF symptoms
Few patients
with NYHA Class
II,III
Few patients
with HFREF
(LVEF≤40%)

11. Supporting RACE-II: In HF patients, Elevated HR
Predicts Adverse Outcomes – Not if they have AF!
CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality
and morbidity) Program; 7,599 patients with HFREF or HFPEF
Assessed impact of candesartan (ARB) on CV mortality and morbidity
Heart Rate, Increased Mortality Same for HFREF, HFPEFNo Relationship in AF
Castagno, Granger et al. CHARM. J Am Coll Cardiol. 2012;59:1785-95
T1: 60 (57–64); T2: 72 (70–75): T3: 85 (80–91)
Beats/min at rest

12. RACE-II: Lessons Learned
Actual HR Targets Achieved; Composite Endpoint
Heart Rate
Target <110 vs <80 (rest)/110 (ex)
Lenient Strict
End Dose
adjustment
93±9 76±12
1Y 86±15 75±12
2Y 84±14 75±12
End Follow-up 85±14 76±14
Endpoint: Many Components
Guidelines
US: Lenient IIB
European: Lenient IIA
How Achieved?
Strict (%)
Beta-Block+Digoxin 37.3
Beta-Blockers 20.1
Ca-Channel B+BB 12.5

13. TREAT-AF: Harm from Digoxin?
Turakhia MP, et al. TREAT-AF J Am Coll Cardiol. 2014;64:660-8.
Well Characterized Registry
New Onset AF
On digoxin: 26,703; Propensity matched
Not on digoxin: 26,703

14. Sinus Rhythm Atrial Fibrillation
Is Beta-Blockade Ideal (for Rate Control) in AF/HF?
Kotecha, Lip, Coats et al. Efficacy of β blockers in patients with
heart failure plus AF. Lancet. 2014;384:2235-43.
Individual patient data level meta-analysis
N=18254; 10 HFREF studies randomizing BB/placebo
‘mortality’ as outcome
Sinus Rhythm, BB Good
Atrial Fibrillation, BB equivocal
Atrial Fibrillation

15. Non-Pharmacological Rate Control
Ablate and Pace (<2% in RACE-II)
ACC/AHA/ESC Guidelines, JACC 2014
Ozcan, NEJM 2001; 344:1043-51
Ozcan Am J Cardiol. 2003;92:33-7
N=56 Patients, LVEF 26+8 %, NYHA 1.7+0.8
LVEF Normalized in 29 %

16. Treating AF In CHF Patients
• Epidemiology, Mechanisms
• Rate vs Rhythm Control
• Rate Control; Hazards
• Rhythm Control; Hazards
✔
✔
✔
✔

18. Parameter P HR Lower Upper
Age at enrollment* <0.0001 1.06 1.05 1.08
Coronary artery disease <0.0001 1.56 1.20 2.04
Congestive heart failure <0.0001 1.57 1.18 2.09
Diabetes <0.0001 1.56 1.17 2.07
Stroke or transient ischemic attack <0.0001 1.70 1.24 2.33
Smoking <0.0001 1.78 1.25 2.53
Left ventricular dysfunction 0.0065 1.36 1.02 1.81
Mitral regurgitation 0.0043 1.36 1.03 1.80
Sinus rhythm <0.0001 0.53 0.39 0.72
Warfarin use <0.0001 0.50 0.37 0.69
Digoxin use 0.0007 1.42 1.09 1.86
Rhythm-control drug use 0.0005 1.49 1.11 2.01
Indications for Rhythm Control
(Some) Subgroup Analyses of Rate/Rhythm Control
AFFIRM, Circulation 2004; 109:1509-1513

19. Anti-Arrhythmic Drugs Are Not Ideal
Singh et al., SAFE-T. NEJM 2005; 352(18): 1861-1872
Saksena et al., AFFIRM Substudy J Am Coll Cardiol 2011; 58(19): 1975-1985
Monthly transtelephonic ECG monitoring
AAD Increase CV Death
/Hospitalization
DO NOT USE: Dronedarone (ANDROMEDA), Sotalol (only with ICD)

20. Newer Rhythm Control Agents
Ranolazine
Late sodium-channel antagonist; decreases intracellular calcium
Reduces atrial and ventricular arrhythmias (1)
Synergistic adjunct to amiodarone, dofetilide for AF (2)
Budiodarone
Amiodarone analogue with a shorter half-life and alternative metabolism
Investigated for AF rhythm control, hopefully with fewer side effects (3)
No studies aimed primarily at an HF population.
Genotype-directed therapy
E.g. Beta-blocker therapy. HF patients who are b₁ adrenergic receptor
389 Arg homozygotes exhibit significant reduction in new-onset AF if
treated with bucindolol (vs placebo) (HR: 0.26, 95% CI : 0.12-0.57)
compared with b₁389 Gly carriers (HR: 1.01) (4). Also, GENETIC-AF Trial.
Scirica. MERLIN-TIMI 36. Circulation 2007;116:1647–52
Fragakis. Ranolazine plus amiodarone. Am J Cardiol 2012;110: 673–7
Ezekowitz. Randomized trial of budiodarone. J Interv Cardiac Electrophysiol 2012;34:1–9
Aleong et al. J Am Coll Cardiol Heart Fail 2013;1: 338–44.

21. AF Rhythm Control by Ablation
Any Ablation PVI (Traditional) Newer (e.g. Rotors)
2.4±1.1 per patient, biatrial
Computational

22. Summary
• The standard dichotomy of rate vs rhythm control exists to the
current day for patients with AF and HF;
• Moderate rate-control is key, and new data re-iterate that the
relationship of increased heart rate to mortality in HF patients is
lost in AF patients;
• Rate-control and rhythm control drugs may have hazards
• Unmet needs:
• Preventing progression of paroxysmalpersistent AF
• Pharmacogenomics
• Better non-pharmacological rhythm control