Atrial fibrillation in advanced heart failure role of rate control

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

Treating AF In CHF Patients

• Epidemiology, Mechanisms

• Rate vs Rhythm Control

• Rate Control; Hazards

• Rhythm Control; Hazards

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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

Paroxysmal AF Permanent AF Normal

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






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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

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’






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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

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%)

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, HFPEF No 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

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

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

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

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 %






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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

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)

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.

AF Rhythm Control by Ablation

Any Ablation PVI (Traditional) Newer (e.g. Rotors)

2.4±1.1 per patient, biatrial

Computational

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 paroxysmalpersistent AF • Pharmacogenomics • Better non-pharmacological rhythm control

Healthcare

Atrial fibrillation in advanced heart failure role of rate control