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 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 No. of patients Age (years) Followup (years) Osaka, 1997 122 61 ±12 Durham, 2000 231 Nashville, 2013 253 60 ±13 67 (55–78) Progression of AF (%) Predictors of progression Reference 2.16 Sustained AF ≥6 months: 11.5 Left atrial size, abnormal P-signal-averaged ECG Abe Y et al. Circulation 1997;96:2612-2616 4 8 at 1 year 18 at 4 years Age, AF at presentation Al-Khatib SM et al. American Heart Journal 2000;140:142-145 1 24 HATCH score Barrett TW et al. American Journal of Emergency Medicine 2013;8:792-797 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 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 CARAF, 2005 757 64 (median) 8 8.6 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 426 66 (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 1 15 (Permanent: 8 Other: 7) Age, heart failure, hypertension, stroke/TIA, COPD 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 Tours, 2010 2167 71 ± 13 2.6 Abbreviations: AF, atrial fibrillation; CARAF, Canadian Registry of Atrial Fibrillation; COPD, chronic obstructive pulmonary disease; ECG, electrocardiogram; TIA, transient ischemic attack. Registry Studies Study No. of patients Age (years) 58.3 ± 11.8 Followup (years) Progression of AF (%) Predictors of progression Reference 14 57 at 10 years 77 at 15 years Age, myocardial infarction, valvular heart disease, left atrial enlargement Kato T et al. Circ J 2004;68: 568-572. Tokyo, 2004 171 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 25.2 31 (30-year probability:29) Age, QRS abnormalities Jahangir A et al. Circulation 2007;115:3050-3056. RECORD-AF, 2011 5171 66 ± 11.9 1 31 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 15 Heart failure, hypertension, rate control De Vos CB et al. Am Heart J 2012;163:887-893. Florence, 1995 106 63 ± 11 6 Recurrent 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) Tokyo, 1981 94 60 >6 Sustained AF ≥6 months: 20.2–25.3 Rheumatic valvular disease; frequency of paroxysms Takahashi N et al. Jpn Heart J 1981;22:143-149. UK GPRD, 2005 418 70 ±14 2.7 11 at 1 year 17 at 2.7 years Valvular heart disease, moderate to high alcohol intake Ruigomez A et al. BMC Cardiovasc Disord 2005;5:20. 1 Age, heart failure, CTR ≥50%, Sustained AF ≥6 months: diabetes, LA ≥38 mm, LVEF ≤0.76, f 22 waves in V1 ≥2 mm Sakamoto H et al. Jpn Heart J 1995;36:191-199. 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 afterdepolarizations 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. • 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. Abbreviations: PKC, protein-kinase C; CaMKII, Ca2+-/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…) 1 • 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. 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 AFpromoted 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 wellestablished 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 antiremodelling therapies on myocardial fibrosis. • MicroRNAs are evolving as important regulators of pathology. Atrialselective 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 hypertensioninduced remodelling remains to be established. • Further studies are needed to identify effective approaches to preventing AF-progression and enable individualized therapy based on patientspecific 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 • 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 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 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: – • 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. – • Individualized use of novel antiarrhythmic drugs, early catheter ablation, and ‘upstream’ therapy to prevent the development of the AF substrate. 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 guidelinemandated 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 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 1 • 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. 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. J Am Coll Cardiol 2012;59:178-188 4 Meierhenrich R et al. Crit Care 2010;14:R108 2 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 pulsecheck 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.