Early Management of Atrial Fibrillation to Prevent Cardiovascular Complications

Supported by an unrestricted educational grant from Sanofi

Contributing Authors

Stanley Nattel MD 1 , Eduard Guasch MD 1 , Irina Savelieva MD 2 , Francisco G Cosio MD 3 , Irene Valverde MD 3 , Jonathan L Halperin MD 4 , Jennifer M Conroy MD 4 , Sana M Al-Khatib MD MHS 5 , Paul L Hess MD 5 , Paulus Kirchhof MD 8, 9, 10 , Joseph De Bono DPhil 7 , Gregory Y H Lip MD 6 , Amitava Banerjee DPhil 6 , Jeremy Ruskin MD 11 , Dan Blendea MD 11 , A John Camm MD 2*

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

Study

Osaka, 1997 Durham, 2000 Nashville, 2013 Belgrade Atrial Fibrillation study, 2012 CARAF, 2005 Danish Study, 1986 European Heart Survey, 2012 Tours, 2010

No. of patients

122 231 253 346 757 426 1219 2167

Age (years)

61 60 67 (55 43.2 ± ± –78) ± 64 12 13 9.9

(median)

Follow up (years)

2.16

4 1 12 8 66 (median) 9 (median) 64 71 ± ± 13 13 1 2.6

Progression of AF (%) Predictors of progression Reference

Sustained AF ≥6 months: 11.5

8 at 1 year 18 at 4 years 24 Left atrial size, abnormal P-signal-averaged ECG Age, AF at presentation HATCH score Abe Y

et al

. Circulation 1997;96:2612-2616 Al-Khatib SM

et al

. American Heart Journal 2000;140:142-145 Barrett TW

et al

. American Journal of Emergency Medicine 2013;8:792-797 Overall:33.5 Paroxysmal AF: 19.1

10-year cumulative rate of progression: 26.1

8.6 at 1 year 24.7 at 5 years Any recurrent AF: 63.2 at 5 years 33.1

Overall: age, development of heart failure and hypertension Paroxysmal: age, development of heart failure and hypertension Age, cardiomyopathy, mitral regurgitation, left atrial enlargement Underlying heart disease, thromboembolism 15 (Permanent: 8 Other: 7) Age, heart failure, hypertension, stroke/TIA, COPD Potpara TS

et al

. CHEST 2012;141:339-347 Kerr CR

et al

. American Heart Journal 2005;149:489-496 Petersen P and J Godtfredsen. Stroke 1986;17:622-626 De Vos CB

et al.

Am Heart J. 2012 May;163:887-93 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 Studies

Study

Tokyo, 2004 Olmsted County, 1987 Olmsted County, 2007 RECORD-AF, 2011 RECORD-AF, 2012 Florence, 1995 Tokyo, 1995 Tokyo, 1981 UK GPRD, 2005

No. of patients

171 88 71 5171 2137 106 137 94 418

Age (years)

58.3 ± 11.8

14 44.2 ± 11.7

66 ± 11.9

65.1 ± 12 63 ± 11 62.4 ± (70.1 ± 11 8.2 with progression) 60 70 ± 14

Follow up (years)

14 14.8

25.2

1 1 6 1 >6 2.7

Progression of AF (%) Predictors of progression Reference

57 at 10 years 77 at 15 years Recurrent paroxysmal: 58 31 (30-year probability:29) 31 Rhythm vs rate control: 13 vs 54 15 Recurrent paroxysmal: 55.6 Sustained: 4.7% Age, myocardial infarction, valvular heart disease, left atrial enlargement – Age, QRS abnormalities Kato T

et al.

Circ J 2004;68: 568-572.

Kopecky S e

t al.

N Engl J Med 1987;317:669-674.

Jahangir A

et al.

Circulation 2007;115:3050-3056.

Age, AF ≥3 months, persistent vs paroxysmal AF, rhythm control, sinus rhythm, heart failure Heart failure, hypertension, rate control – Camm AJ

et al.

J Am Coll Cardiol 2011;58:493-501.

De Vos CB

et al.

Am Heart J 2012;163:887-893.

Rostagno C

et al.

Am J Cardiol 1995;76:837-839.

Sustained 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.

Sustained AF ≥6 months: 20.2

–25.3

11 at 1 year 17 at 2.7 years Rheumatic valvular disease; frequency of paroxysms Valvular heart disease, moderate to high alcohol intake Takahashi N

et al.

Jpn Heart J 1981;22:143-149.

Ruigomez 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 recurrent and 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 Ca 2+ 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 Ca 2+ 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.

The importance of Ca 2+ -handling is increasingly recognized: – – Rapid atrial activation rates stimulate CaMKII.

This phosphorylates the Ca 2+ -release channel (Ryr2), increasing its Ca 2+ - sensitivity – and facilitating diastolic Ca 2+ -leakage events.

Ca 2+ - 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.

Abbreviations

: PKC, protein-kinase C; CaMKII, Ca 2+ -/calmodulin-dependent kinase-II; Ryr2, type 2 ryanodine receptor Figure taken from Xander HT et al.

Circulation Research

.2004; 94: e61-e70

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.

Mechanistic Details of AF Remodelling (cont …)

• • • • 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.

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.

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).

Abbreviations:

AAD, anti-arrhythmic drug; SR, sinus rhythm

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 Ca 2+ 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

AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) study RACE (RAte Control vs. Electrical cardioversion) PIAF (Pharmacological Intervention in Atrial Fibrillation) STAF (Score for the Targeting of Atrial Fibrillation) HOT CAFE (HOw to Treat Chronic Atrial Fibrillation) RHYTHM

Outcome

Trend towards increased mortality with rhythm control No survival benefit when using rhythm control strategies No survival benefit when using rhythm control strategies No survival benefit when using rhythm control strategies No survival benefit when using rhythm control strategies 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

• 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:

Patient recruitment ATHENA

• High incidence of cardiac structural abnormalities (60%) • Eligible participants had SR within 6 months of study entry (25% were in AF at randomization)

PALLAS

• 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 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 flutter PALLAS (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.

Main aim Patients Endpoints Estimated study completion date CABANA (

NCT00911508) Compares ablation versus antiarrhythmic drugs 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 Mortality, disabling stroke, serious bleeding, cardiac arrest, CV hospitalization, cost effectiveness, quality of life September 2015

EAST (

NCT01288352) Evaluates rhythm control with ablation and antiarrhythmic drugs against guideline mandated initial rate control Recent onset AF and aged >75 yrs or prior stroke, or two AF risk factors CV death, stroke, CV hospitalization, time to recurrent AF, quality of life, cognitive function July 2018 CABANA, Catheter ABlation vs ANti-Arrhythmic drug therapy for atrial fibrillation EAST, 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 2 Echahidi N et al.

J Am Coll Cardiol

2008

;51

:793-801 Walkey AJ et al.

JAMA

2011;

306

:2248-2254 3 Amat-Santos IJ et al.

4 Meierhenrich R et al.

J Am Coll Cardiol Crit Care

2010;

14

2012; :R108

59

:178-188

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.