Early Management of Atrial Fibrillation to Prevent Cardiovascular Complications

Supported by an unrestricted educational grant from Sanofi

Contributing Authors

Stanley Nattel MD1, Eduard Guasch MD1, Irina Savelieva MD2, Francisco G Cosio MD3, Irene Valverde MD3, Jonathan L Halperin MD4, Jennifer M Conroy MD4, Sana M Al-Khatib MD MHS5, Paul L Hess MD5, Paulus Kirchhof MD8, 9, 10, Joseph De Bono DPhil7, Gregory Y H Lip MD6, Amitava Banerjee DPhil6, Jeremy Ruskin MD11, Dan Blendea MD11, A John Camm MD2*

1Montreal Heart Institute, Montreal, QC, Canada; 2Division of Clinical Sciences, Cardiovascular Science, St George’s University of London, London, UK; 3Cardiología Department, Hospital Universitario de Getafe, Madrid, Spain; 4Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, USA (affiliation at the time of initial manuscript development); 5Department of Medicine, Cardiology Division, Duke University Medical Center, Durham, NC, USA; 6University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, UK; 7University Hospitals Birmingham NHS Trust, Birmingham, UK; 8University of Birmingham Centre for Cardiovascular Sciences, University of Birmingham and Sandwell and West Birmingham NHS Trust, Birmingham, UK; 9Department of Cardiology and Angiology, Hospital of the University of Münster, Münster, Germany; 10German Atrial Fibrillation Competence NETwork (AFNET), Münster, Germany 11Department of Medicine, Massachusetts General Hospital, Boston, MA, USA

INTRODUCTION

Introduction

• AF is a progressive disease that evolves from paroxysmal through persistent to “permanent” forms.

• Some data suggest that persistent AF is presentin 40% of cases at diagnosis.1

• Earlier diagnosis and treatment may limit progression.

• Personalized treatment may improve outcomes through analysis of each individual’s pathophysiology, risk factors, and genetic predisposition.

1. Panizo JG et al. Conference of the World Society of Arrythmias 2011;34:1307-61

PREDICTING SHORT-TERM RISK AND PROGRESSION OF AF

Registry Data

• Studies have been undertaken to evaluate the clinical progression of AF.

• The prevalence of progression varies with patient population and duration of follow-up, but is as high as 77% over 14 years.1

• The overall progression rate is ~5% per annum (excluding younger patients without CV disease).1

• Older patients and those with underlying heart disease have faster progression rates.

• Risk of AF is exacerbated by obesity, diabetes, and lack of exercise, however, extreme training can predispose other healthy individuals to AF.2

1. Kato T et al. Circulation Journal 2004;68:568-572.2. Kirchhof P et al. Thrombosis and Haemostasis 2011;106:1012-1019.

Abbreviation: CV, cardiovascular

Registry StudiesStudy No. of

patientsAge

(years)Follow-

up(years)

Progression of AF (%)

Predictors of progression Reference

Osaka, 1997 122 61 ±12 2.16Sustained AF

≥6 months: 11.5Left atrial size, abnormal P-signal-averaged ECG

Abe Y et al. Circulation 1997;96:2612-2616

Durham, 2000 23160 ±13

48 at 1 year

18 at 4 yearsAge, AF at presentation Al-Khatib SM et al. American Heart

Journal 2000;140:142-145

Nashville, 2013

253 67 (55–78) 1 24 HATCH scoreBarrett TW et al. American Journal

of Emergency Medicine 2013;8:792-797

Belgrade Atrial Fibrillation study, 2012

346 43.2 ± 9.9 12

Overall:33.5 Paroxysmal AF: 19.1

10-year cumulative rate of progression: 26.1

Overall: age, development of heart failure and hypertension

Paroxysmal: age, development of heart failure and hypertension

Potpara TS et al. CHEST 2012;141:339-347

CARAF, 2005 75764

(median) 88.6 at 1 year 24.7 at 5

years Any recurrent AF: 63.2 at 5 years

Age, cardiomyopathy, mitral regurgitation, left atrial

enlargement

Kerr CR et al. American Heart Journal 2005;149:489-496

Danish Study, 1986

42666

(median)9

(median)33.1

Underlying heart disease, thromboembolism

Petersen P and J Godtfredsen. Stroke 1986;17:622-626

European Heart Survey, 2012

1219 64 ± 13 115

(Permanent: 8Other: 7)

Age, heart failure, hypertension, stroke/TIA, COPD

De Vos CB et al. Am Heart J. 2012 May;163:887-93

Tours, 2010 2167 71 ± 13 2.6 14.1

Age, heart failure, hypertension, COPD, number of electrical

cardioversions, dilated cardiomyopathy, prosthetic valve

Fauchier L et al. Circulation 2010;122:A18129

Abbreviations: AF, atrial fibrillation; CARAF, Canadian Registry of Atrial Fibrillation; COPD, chronic obstructive pulmonary disease; ECG, electrocardiogram; TIA, transient ischemic attack.

Registry StudiesStudy No. of

patientsAge

(years)Follow-

up(years)

Progression of AF (%)

Predictors of progression Reference

Tokyo, 2004 17158.3 ± 11.8

1457 at 10 years77 at 15 years

Age, myocardial infarction, valvular heart disease, left atrial enlargement

Kato T et al. Circ J 2004;68:568-572.

Olmsted County, 1987

88 14 14.8 Recurrent paroxysmal: 58 – Kopecky S et al. N Engl J Med 1987;317:669-674.

Olmsted County, 2007

71 44.2 ±11.7 25.231 (30-year

probability:29)Age, QRS abnormalities Jahangir A et al. Circulation

2007;115:3050-3056.

RECORD-AF, 2011

5171 66 ± 11.9 131 Rhythm vs rate control: 13 vs 54

Age, AF ≥3 months, persistent vs paroxysmal AF, rhythm control,

sinus rhythm, heart failure

Camm AJ et al. J Am Coll Cardiol 2011;58:493-501.

RECORD-AF, 2012

2137 65.1 ±12 1 15Heart failure, hypertension,

rate controlDe Vos CB et al. Am Heart J

2012;163:887-893.

Florence, 1995

10663 ± 11

6Recurrent paroxysmal: 55.6 Sustained: 4.7%

– Rostagno C et al. Am J Cardiol 1995;76:837-839.

Tokyo, 1995 137

62.4 ± 11(70.1 ± 8.2

with progression)

1Sustained AF ≥6 months:

22

Age, heart failure, CTR ≥50%, diabetes, LA ≥38 mm, LVEF ≤0.76, f

waves in V1 ≥2 mm

Sakamoto H et al. Jpn Heart J 1995;36:191-199.

Tokyo, 1981 94 60 >6Sustained AF ≥6 months:

20.2–25.3Rheumatic valvular disease;

frequency of paroxysmsTakahashi N et al. Jpn Heart J

1981;22:143-149.

UK GPRD, 2005

418 70 ±14 2.711 at 1 year

17 at 2.7 yearsValvular heart disease, moderate to

high alcohol intakeRuigomez A et al. BMC

Cardiovasc Disord 2005;5:20.

Abbreviations: AF, atrial fibrillation; RECORD-AF, REgistry on Cardiac rhythm disORDers assessing control of Atrial Fibrillation.

Basic Mechanisms of AF-related Remodelling

‘AF begets AF’• AF induces mechanisms for self-perpetuation.

• The arrhythmia induces structural, electrical, and autonomic remodelling upon pre-existing abnormalities to increase susceptibility to recurrentand more persistent AF.

Clinical observations• Prevalence of AF is higher in older age groups.

• There is an age-dependent loss of cardiomyocytes in the heart.

Basic Mechanisms Contributing to AF• Conditions that improve AF: atrial structural, electrical, and autonomic abnormalities

and/or remodelling that lead to re-entry or triggered activity.

• Slow conduction velocities and short refractory periods allow the establishment and stabilization of re-entrant circuits.

• Delayed after-depolarizations emerge from abnormal Ca2+ release from the sarcoplasmic reticulum during diastole, acting as triggers for re-entry or, when sustained, as a focal source for AF.

Mechanistic Details of AF Remodelling

• Within hours of AF-onset, the refractory period during AF heterogeneously shortens in response to electrical and autonomic remodelling.

• Tachycardia-induced Ca2+ accumulation activates α1-subunit mRNA down-regulation.

• PKC isoform-switch activates the ion channel (see right) leading to decreased atrial conduction velocity by impairing cellular coupling.

Abbreviations: PKC, protein-kinase C; CaMKII, Ca2+-/calmodulin-dependent kinase-II; Ryr2, type 2 ryanodine receptorFigure taken from Xander HT et al. Circulation Research.2004; 94: e61-e70

• The importance of Ca2+-handling is increasingly recognized:– Rapid atrial activation rates stimulate CaMKII.– This phosphorylates the Ca2+-release channel (Ryr2), increasing its Ca2+- sensitivity

and facilitating diastolic Ca2+-leakage events.– Ca2+- leak events cause delayed afterdepolarizations that induce atrial premature beats

and/or tachycardias.– Intracellular calcium oscillations might also induce atrial repolarization heterogeneity,

favoring re-entry.

Mechanistic Details of AF Remodelling (cont…)

• Autonomic tone-remodelling also contributes to the AF-induced arrhythmia substrate.

– Short periods of atrial tachycardia (3 hours) increase discharge-rates in the intracardiac ganglionated plexi.

– Ablation of the intracardiac autonomic ganglia blunts tachycardia-induced refractoriness shortening and AF-susceptibility, demonstrating a role for autonomic tone in AF-induced remodelling.

– Spatially-heterogeneous sympathetic hyper-innervation results from longer-lasting AF.

– Arrhythmogenic structural remodelling develops after longer-term AF-induced remodelling, and uncontrolled ventricular rates accelerate structural remodelling by inducing myocardial dysfunction.

• Cardiomyocyte-fibroblast interactions consequent to sustained atrial tachycardia also promote fibrosis.

– Cardiac fibrosis, a hallmark of the structural AF substrate, could be responsible for the atrial endo-epicardial electrical dissociation that underlies complex intra-atrial re-entry.

• Electrical remodelling and AF-inducibility develop rate-dependently in dogs, and are almost negligible at rates ≤200 beats/minute.1

• Atrial ectopic activity and AF often coexist, and patients with frequent atrial tachyarrhythmias, even of relatively short duration, are at increased risk of AF.

• The association between AF and atrial tachyarrhythmias could be due to common underlying conditions, to atrial tachycardias acting as a repetitive trigger for AF, or to the induction of AF-promoting remodelling by tachycardias.

• These explanations are by no means mutually exclusive and might all apply, to some extent, in many cases.

Mechanistic Details of AF Remodelling (cont…)

1 Shiroshita-Takeshita A et al. Cardiovasc Res 2009;81:90-97

Relationship Between Basic Mechanisms and Clinical Forms

• AF occurrence requires the presence of both triggers and substrate for the arrhythmia.

• Changes in substrate are believed to contribute to AF progression.

• Progression rate is affected by the frequency, duration, and time between paroxysmal AF episodes.

• AF episodes become more persistent when the substrate is highly developed.

Figure modified from Cosio FG et al. Europace 2008;10:21-27.

Relationship Between Basic Mechanisms and Clinical Forms (cont…)

• Ongoing triggers may also contribute to the maintenance of sustained AF. – Some patients do not progress to “permanent” forms,

presumably because of limited development of the primary condition, resistance to AF-induced remodelling, or genetically-determined patient-specific protective factors.

– Patients without structural remodelling progress more gradually than those with heart disease.

• Prospective studies with careful clinical, biomarker, genetic, and atrial-imaging assessment are needed to better understand the basic determinants of AF-progression.

Anti-remodelling Therapy

• Classic AADs aim to prevent AF recurrences, however, there are no firm data to substantiate positive results the efficacy.

• Anti-modelling success has been with amiodarone – the current forerunner in treatment for long-term SR maintenance.

Abbreviations: AAD, anti-arrhythmic drug; SR, sinus rhythm

• Targeting primary disease and AF-induced remodelling may increase therapeutic efficacy.

• Anti-remodelling therapy is directed at potentially preventable causes of AF-promoted remodelling (see right, represented by the red zones).

Anti-remodelling Therapy (cont…)

• Relieving hemodynamic overload may prevent AF recurrence:– Mitral commissurotomy may alter atrial electrophysiology and help restore SR by

electrical cardioversion.

– Reversal of experimental left atrium volume overload reverts electrophysiological remodelling, even when hypertrophy persists.

– Treatment of left ventricular dysfunction by cardiac resynchronization therapy may decrease the incidence of AF.

• These observations suggest that treatment of the underlying condition, rather than pharmacological targets alone, may be an important component of any anti-remodelling approach.

• The benefits of preventing remodelling with RAAS-inhibitors are well-established in experimental models, however, RAAS blockers have not prevented AF in large, randomized prospective trials.

• Inability to reverse advanced substrate or insufficient duration of therapy may explain negative outcomes.

Abbreviation: RAAS, renin-angiotensin-aldosterone system

Anti-remodelling Therapy (cont…)

• Recently-developed MRI-imaging techniques may provide new insights by directly assessing effects of RAAS-blockers and other anti-remodelling therapies on myocardial fibrosis.

• MicroRNAs are evolving as important regulators of pathology. Atrial-selective inhibition of microRNA-21 prevented AF by suppressing fibrosis in a rat model, microRNA-26 restoration reversed K+-current upregulation and AF-promotion in a mouse-model, and microRNA-29 restoration may reverse AF-promoting profibrotic changes.

• MicroRNA-modulation may provide new therapeutic strategies for remodelling-prevention. Heat-shock protein-inducers, in development to prevent remodeling, antioxidant-agents, and compounds targeting Ca2+-handling, are attractive new therapeutic modalities.

Anti-remodelling Therapy (cont…)

• Autonomic modulation via sub-threshold, low-level vagal stimulators blunts autonomic remodelling and prevents AF-inducibility in animal models.

• Vagus nerve stimulators are widely used, with few side-effects, to treat refractory epilepsy, and their benefits in heart failure are under study, but their potential role in AF-prevention has not been elucidated. Intracardiac ganglion ablation might contribute to the success of AF ablation by suppressing autonomic remodelling.

• Renal denervation may also prevent AF-progression; whether this effect is mediated by autonomic changes or suppression of hypertension-induced remodelling remains to be established.

• Further studies are needed to identify effective approaches to preventing AF-progression and enable individualized therapy based on patient-specific pathophysiological processes.

CYCLE OF AF PROGRESSION

Completed Rhythm Control Trials: Evidence I

Maintaining SR from the onset is one approach to preventing AF progression. Several trials have investigated positive outcomes using this method and all but one have shown little improvement with rhythm control compared to rate control:

Study name Outcome

AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) study Trend towards increased mortality with rhythm control

RACE (RAte Control vs. Electrical cardioversion) No survival benefit when using rhythm control strategies

PIAF (Pharmacological Intervention in Atrial Fibrillation) No survival benefit when using rhythm control strategies

STAF (Score for the Targeting of Atrial Fibrillation) No survival benefit when using rhythm control strategies

HOT CAFE (HOw to Treat Chronic Atrial Fibrillation) No survival benefit when using rhythm control strategies

RHYTHM Significant reduction in CV events associated with rhythm rather than rate control

Completed Rhythm Control Trials: Problems

• Low rate of restoration and maintenance of SR.

• Patients at last stage of the disease process.

• The STAF, PIAF, and RACE trials patients had persistent AF.

• PIAF median duration was 103-118 days prior to entry.

• STAF recruited patients with higher risk of AF recurrence.

• Two thirds of AF-CHF study patients had persistent AF. 46% had AF for ≥6 months and all had structural disease.

• AFFIRN recruited persistent and paroxymal AF, 65% had more than one AF episode and most had structural cardiac abnormalities, including dilated left atria 65% at the time of recruitment.

• J-RHYTHM is the only trial to demonstrate an advantage of rhythm control over rate control and was restricted to patients with paroxysmal AF with a low underlying disease burden.

Completed Rhythm Control Trials: Evidence II

ATHENA PALLAS

Patient recruitment • High incidence of cardiac structural abnormalities (60%)

• Eligible participants had SR within 6 months of study entry (25% were in AF at randomization)

• Patients had permanent AF(6-months’ continuous AF, 60% had continuous AF ≥2 years)

Dronedarone group Significant reduction in CV deaths Increased mortality

CV hospitalization Reduction in CV hospitalization Increase in CV hospitalization in the dronedarone-treated group

• The balanced risks and benefits of rhythm control in AF may depend not only on the agents used, but on the stage of the disease process at which treatment is initiated, as demonstrated by these studies with patients at different stages of disease progression:

ATHENA, A placebo-controlled, double-blind, parallel arm Trial to assess the efficacy of dronedarone 400 mg bid for the prevention of cardiovascular Hospitalization or death from any cause in patiENts with Atrial fibrillation/atrial flutterPALLAS (Permanent Atrial fibriLLAtion outcome Study using dronedarone on top of standard Therapy)

Development in Trials of Aggressive Early Rhythm Control

• A greater understanding of the remodelling induced by AF has led to the development of new treatment strategies to actively maintain sinus rhythm early in the course of AF:

– Individualized use of novel antiarrhythmic drugs, early catheter ablation, and ‘upstream’ therapy to prevent the development of the AF substrate.

• Better classification of AF might lead to more effectively directed therapy.– Current classification systems have major limitations.– Etiologically-based classifications have been suggested and are in active development.

• Evaluation of atrial structural remodelling should include assessment of left atrial function, biomarkers, and/or late enhancement MRI.

– Re-assessment of these markers after SR recovery for remodelling and re-classification of AF would be advantageous.

• Catheter ablation offers a greater chance of achieving and maintaining SR, but this requires further evaluation.

Ongoing Trials of Aggressive Early Rhythm Control

These studies investigate whether early and active rhythm control of AF with a strategy involving catheter ablation can break the cycle of progression of AF and improve outcomes compared to standard therapies.

CABANA (NCT00911508) EAST (NCT01288352)

Main aim Compares ablation versus antiarrhythmic drugs

Evaluates rhythm control with ablation and antiarrhythmic drugs against guideline-mandated initial rate control

Patients Aged ≥65 yrs, or aged <65 yrs with one or more of the following risk factors for stroke: Hypertension, Diabetes, Congestive heart failure, Prior stroke or TIA

Recent onset AF and aged >75 yrs or prior stroke, or two AF risk factors

Endpoints Mortality, disabling stroke, serious bleeding, cardiac arrest, CV hospitalization, cost effectiveness, quality of life

CV death, stroke, CV hospitalization, time to recurrent AF, quality of life, cognitive function

Estimated study completion date

September 2015 July 2018

CABANA, Catheter ABlation vs ANti-Arrhythmic drug therapy for atrial fibrillationEAST, Early treatment of Atrial fibrillation for Stroke prevention Trial

CAN MORE INTENSIVE MONITORING TO DETECT AND TREAT AF EARLIER PREVENT COMPLICATIONS?

AF in the Acute Setting

• AF is associated with considerable morbidity and mortality.

• Patients who develop post-operative AF after cardiac surgery have a 3-fold higher risk of stroke and a 2-fold higher risk of in-hospital and 6-month mortality compared with those without AF.1

• Risks of stroke and mortality are increased when AF complicates myocardial infarction and sepsis.2

• Rates of stroke, but not death, are elevated among patients who develop AF after trans-catheter aortic valve replacement for severe aortic stenosis.3

• The pathophysiology of transient AF varies with the type of clinical event.

• Inflammation has been linked to AF during sepsis.4

• Transient AF complicating acute clinical conditions may be a sentinel event, identifying patients at risk for developing subsequent AF and its complications.

• Risk factors for the development of AF in the acute setting are similar to those for developing paroxysmal, persistent, or “permanent” AF unassociated with acute conditions.

1 Echahidi N et al. J Am Coll Cardiol 2008;51:793-8012 Walkey AJ et al. JAMA 2011;306:2248-22543 Amat-Santos IJ et al. J Am Coll Cardiol 2012;59:178-1884 Meierhenrich R et al. Crit Care 2010;14:R108

AF in the Acute Setting

• Patients with acute clinical events may be at high risk of developing longer-term AF.

• More intensive monitoring to detect subclinical AF is therefore needed, as suggested by this figure.

• Arrhythmias can be detected by simple pulse-check or ECG rhythm-recording, or via a variety of advanced types of monitoring equipment.

• Post-MI arrhythmias were detected using implantable loop recorders in the CARISMA Study.

• New-onset AF was detected using implantable devices in the ASSERT and was found to identify increased stroke risk.

• These studies await confirmation before the clinical relevance of intensive ECG monitoring can be established. Other ongoing studies are CRYSTAL-AF (NCT00924638) and REVEAL-AF (NCT01727297).

CARISMA, Cardiac Arrhythmias and RIsk Stratification after acute MyocArdial infarction,ASSERT, ASymptomatic atrial fibrillation and Stroke Evaluation in pacemaker patients and the atrial fibrillation Reduction atrial pacing Trial

CONCLUSIONS

Conclusions

• Both primary disease and AF-induced structural, electrical, and autonomic remodelling contribute to AF progression.

• Earlier intervention may interrupt this progression, improving outcomes and reducing morbidity and mortality.

• Available drug therapies have not yet been shown to prevent progression, either because they are ineffective or because we are giving them too late or to the wrong patients.

• Ongoing basic research has identified some potentially interesting novel drug-development targets.

• The failure of rhythm-control therapy to improve outcomes in most previous large clinical trials may have been due to testing too late in the natural history of the disease, and the results of ongoing studies involving earlier and more active intervention are anticipated with interest.

Conclusions (cont…)

• Despite abundant evidence regarding both the increasing prevalence of AF and the associated risk of thromboembolism, many individuals with AF worldwide remain undiagnosed or undertreated, including many at high risk for stroke.

• Existing practice guidelines for management of patients with AF provide valuable clinical pathways for the treatment of newly discovered AF.

• Integrated care pathways would aid medical providers in the earlier identification of patients with AF, rapid assessment of thromboembolism risk and appropriate selection of anticoagulant therapy.

• Radical improvement of AF management will result if ongoing and future research demonstrates that such approaches facilitate earlier and possibly more effective interventions to restore and/or maintain SR.