ATRIAL FIBRILLATION Dr ABHAY BAJPAI Consultant Cardiologist & Electrophysiologist Epsom & St Helier University Hospitals NHS Trust St George’s Hospital NHS Foundation Trust

Electrical system

What characterises AF? AF is a rhythm disorder (arrhythmia) of the top chambers Rapid, disorganized electrical signals in the atria Conduction to the ventricles is limited by the AV node. AF leads to: Irregular ventricular rate (pulse)

ECG tracing Normal - Sinus rhythm Atrial Fibrillation

AF Burden in England 2.4% = 1.36 million people in England have AF Only 1.6% diagnosed – 474,000 undiagnosed!

AF Burden in England Prevalence increases with age 2.9% in people aged < 45 16.6% in people aged 45-65 80.5% in people aged > 65. Greater in men vs women, 2.8% vs 2.0%. Prevalence (%) The Rotterdam study Age (years) 55–59 65–69 60–64 70–74 75–79 80–84 85

AF Burden in England

Lifetime risk of developing AF At ≥40 years of age, the remaining lifetime risk for developing AF is: 26.0% for men 23.0% for women In the absence of previous chronic heart failure or heart attacks, the lifetime risk of AF at age ≥40 years is reduced similarly for both men and women: 16.3% for men 15.6% for women

Why do we develop AF? Cardiovascular conditions Metabolic conditions High Blood pressure Heart attacks / Angina (ischaemic heart disease) Heart failure Heart Valve disease Metabolic conditions Obesity Diabetes mellitus Overactive Thyroid - Hyperthyroidism Other Obstructive sleep apnoea syndrome – common in obese people Pneumonia / chest infections / other lung conditions Heart - Lung surgery High alcohol intake Familial Lone AF

Patients with AF (millions) AF Epidemic has begun! Year 2.08 2.44 2.26 5.1 2 4 6 8 10 12 14 16 1990 1995 2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050 Patients with AF (millions) 5.42 11.7 15.2 4.34 9.4 3.33 7.5 8.9 2.94 6.8 7.7 8.4 10.2 3.80 4.78 10.3 13.1 5.16 11.1 14.3 5.61 12.1 15.9 5.6 5.9 2.66 6.1 6.7 Olmsted County data, 2006 (assuming a continued increase in AF incidence) ATRIA study data, 2000 Olmsted County data, 20061 (assuming no further increase in AF incidence)

Why treat AF ? Independent risk factor for stroke Background Why treat AF ? Independent risk factor for stroke Approximately 5 x increased risk1 1 in 6 strokes occur in patients with AF2 AF-related strokes are typically more severe than strokes due to other aetiologies3,4 Independent risk factor for mortality Approximately twofold increased risk5 Independent risk factor for heart failure Heart failure further aggravates AF, worsening overall prognosis6 AF has serious consequences AF can result in multiple serious consequences, such as stroke, heart failure and death AF is an independent risk factor for stroke, increasing the risk by approximately fivefold;1 one in six strokes occur in patients with AF2 Furthermore, AF-related strokes are, in general, more severe than strokes due to other aetiologies3,4 and stroke risk persists even in patients with asymptomatic AF5 AF is also an independent risk factor for mortality – conferring an approximately twofold increased risk of death6 Additionally, AF is an independent risk factor for heart failure – and heart failure can further aggravate AF, worsening overall patient prognosis7 References Wolf PA et al. Stroke 1991;22:983–988 Fuster V et al. Circulation 2006;114:700–752; Lin HJ et al. Stroke 1996;27:1760–1764 Jørgensen HS et al. Stroke 1996;10:1765–1769 Page RL et al. Circulation 2003;107:1141–1145 Benjamin EJ et al. Circulation 1998;98:946–952 Wang T et al. Circulation 2003;107:2920–2925 1. Wolf PA et al. Stroke 1991;22:983–988; 2. Fuster V et al. Circulation 2006;114:700–752; 3. Lin HJ et al. Stroke 1996;27:1760–1764; 4. Jørgensen HS et al. Stroke 1996;27:1765–1769;5. . Benjamin EJ et al. Circulation 1998;98:946–952; 6. Wang T et al. Circulation 2003;107:2920–2925 11

AF significantly impairs quality of life Background AF significantly impairs quality of life Patients with AF experience significant impairments to their QoL1–3 * * * * SF-36 mean score AF significantly impairs quality of life Patients with AF have significantly lower QoL, as measured by the SF-36 scale, in terms of general health, physical health, mental health and social function, compared with subjects without AF Notably, patients with AF have been found to have numerically lower SF-36 scores than patients who had suffered a non-fatal MI Abbreviation SF-36, short form 36 References Dorian P et al. J Am Coll Cardiol 2000;36:1303–1309 Van den Berg MP et al. Neth J Med 2005;63:170–174 1. Dorian P et al. J Am Coll Cardiol 2000;36:1303–1309; 2. Van den Berg MP et al. Neth J Med 2005;63:170–174 * p<0.001 compared to AF patients 12

Symptoms of AF Typical symptoms of AF include: Background Symptoms of AF Typical symptoms of AF include: Palpitations (a sensation of rapid irregular heartbeat) Fatigue Shortness of breath Dizziness/light headedness ...... Or Stroke Chest pain - uncommon Blackout - uncommon AF may not cause any symptoms Approximately 1/3rd of patients Symptoms of AF The presence of AF in patients may be indicated by certain physical symptoms; these include palpitations, fatigue/weakness, chest pain, lightheadedness, syncope and dyspnoea.1 However, a substantial number of patients remain asymptomatic; this is a particularly serious situation because these patients may be at continuous risk of stroke2 The degree to which AF remains undetected was demonstrated in a study by Israel and colleagues.2 Their aim was to determine the incidence and time course of AF recurrences in patients with a history of paroxysmal or persistent (not permanent) AF, who had been fitted with an implantable monitoring device that specifically recorded AF episodes Patients were followed up for a mean period of 19 months (±11 months). During that period, patients were also monitored at regular intervals with standard serial ECG recordings Out of a total of 110 patients enrolled, 50 patients had device-documented AF episodes lasting longer than 48 hours. Of these, 19 (38%) were asymptomatic and presented in normal sinus rhythm at the respective follow-up visit (i.e. no AF detected with serial ECG) This prospective study clearly showed that in patients with recurrent AF episodes lasting longer than 48 hours, more than a third remained completely asymptomatic2 References Fuster V et al. Circulation 2006;114:700–752 Israel CW et al. J Am Coll Cardiol 2004;43:47–52 1. Fuster V et al. Circulation 2006;114:700–752; 2. Moran PS et al. The Cochrane Collaboration, April 2013 13

Classification of AF Paroxysmal < 7 days , commonly < 48hrs Persistent > 7days and < 1 year Long standing persistent > 1year Permanent

Background Progression of AF Progression of AF is thought to be driven by structural changes in the atria, including electrical, contractile changes, known as atrial remodelling1 First diagnosed episode of AF Paroxysmal (usually ≤48 hours) Persistent (>7 days or requires cardioversion) Progression of AF The progression of AF is hypothesized to be driven by structural changes in the atrium –including electrical and contractile changes – known as atrial remodelling AF is a progressive disease; it tends to progress from paroxysmal (self-terminating, usually within 48 hours) to persistent (non-self-terminating or requiring cardioversion), long-standing persistent (lasting longer than 1 year) and eventually to permanent (accepted) AF First-onset AF may be the first of recurrent attacks – or indeed, may already be permanent Reference Camm AJ et al. Eur Heart J 2010;31:2369–2429 Long-standing persistent (>1 year) Permanent (accepted) Different types of AF. The arrhythmia tends to progress from paroxysmal (self-terminating, usually <48 hours) to persistent (non-self-terminating or requiring cardioversion), long-standing persistent (lasting longer than 1 year) and eventually to permanent (accepted) AF. First-onset AF may be the first of recurrent attacks or already be deemed permanent1 1. Camm AJ et al. Eur Heart J 2010;31:2369–2429 15

Diagnosis and monitoring of AF via ECG Background Diagnosis and monitoring of AF via ECG An irregular pulse raises the clinical suspicion of AF AF typically progresses from short, rare episodes to longer and more frequent attacks AF Antiarrhythmic drugs Anticoagulation Rate control Cardioversion Paroxysmal Silent Persistent Long-standing persistent Permanent ‘Upstream’ therapy of concomitant conditions First documented Ablation Diagnosis and monitoring of AF via ECG An irregular pulse always raises the suspicion of AF, but an ECG recording is necessary to actually diagnose it1 AF is considered present if any detected arrhythmia:1 Has the ECG characteristics of AF and lasts sufficiently long for a 12-lead ECG to be recorded, or Lasts ≥30 seconds on a rhythm strip The risk of AF-related complications is not different between short AF episodes and sustained forms of the arrhythmia2 It is therefore important to detect paroxysmal AF to prevent AF-related complications (e.g. stroke) AF may manifest initially as an ischaemic stroke or TIA, and it is reasonable to assume that most patients experience asymptomatic, often self-terminating, arrhythmia episodes before AF is first diagnosed ECG is not ideal for detecting early AF because it relies on AF being present at the time of monitoring The rate of AF recurrence is 10% in the first year after the initial diagnosis, and ~5% per annum thereafter – co-morbidities and age significantly accelerate both the progression of AF and the development of complications Abbreviation TIA, transient ischaemic attack Reference Camm AJ et al. Eur Heart J 2010;31:2369–2429 Friberg L et al. Eur Heart J 2010;31:967–975 1. Camm AJ et al. Eur Heart J 2010;31:2369–2429 16

Valvular heart disease Cardiovascular conditions and risk factors are important predictors of AF Background The Framingham Heart Study Men (n=2,090) Women (n=2,641) Heart failure 4.5 5.9 Valvular heart disease 1.8 3.4 Hypertension 1.5 1.4 Cardiovascular conditions and risk factors are important predictors of AF Cardiovascular and other medical conditions, including diabetes mellitus and hypertension, have been shown to place individuals at increased risk for developing AF1 In 1994, based on a 38-year follow-up of a cohort of 4,731 participants aged between 55 and 94 years and without a history of AF in the Framingham study, Benjamin and co­-workers reported that heart failure, valvular heart disease, hypertension, diabetes mellitus, MI and male sex were all significant predictors for AF References Benjamin EJ et al. JAMA 1994;271:840–844 Diabetes mellitus 1.4 1.6 MI 1.4 1.2; not significant 1 2 3 4 5 6 7 1 2 3 4 5 6 7 8 9 Odds ratio Odds ratio 1. Benjamin EJ et al. JAMA 1994;271:840–844 17

Background AF and stroke Stroke is the most serious ongoing risk associated with AF1 In patients with AF, blood clots tend to form in the atria, particularly within the left atrial appendage, due to abnormal blood flow and pooling2 These clots may travel to the brain, causing an ischaemic stroke2 Around 20% of ischaemic strokes are caused by blood clots originating in the heart (cardioembolic); of these, AF is the most common cause3 AF and stroke Individuals with AF are at increased risk for a number of clinically significant sequelae, such as hypertension, coronary heart disease and stroke. The most common and potentially serious of these is stroke1 Owing to the relative stasis of blood in the atria, patients with AF are predisposed to developing blood clots in the atria.2 The left atrial appendage, a muscular pouch located in the wall of the left atrium, is thought to be a common source of blood clots in patients with AF3 If a clot, or part of a clot, breaks free, it forms an embolus that can leave the left atrium of the heart and travel to the brain where it can cause an ischaemic stroke2 Approximately 20% of ischaemic strokes are a result of cardiogenic emboli (i.e. embolized blood clots that originated in the heart) and are often referred to as cardioembolic strokes; AF is the most common cause of cardiogenic emboli3 References Wolf PA et al. Stroke 1991;22:983–988 Fuster V et al. Circulation 2006;114:700–752 Paciaroni M et al. Stroke 2007;38:423–430 1. Wolf PA et al. Stroke 1991;22:983–988; 2. Fuster V et al. Circulation 2006;114:700–752; 3. Paciaroni M et al. Stroke 2007;38:423–430 18

Patients with AF have an approximately fivefold increased risk of ischaemic stroke1 Background Framingham Heart Study (N=5,070) 60 Risk ratio=4.8 p<0.001 50 40 2-year age-adjusted incidence of stroke/1,000 30 Patients with AF have an approximately fivefold increased risk of ischaemic stroke AF is shown to substantially increase the risk of an ischaemic stroke1 The Framingham Heart Study prospectively followed men and women who were free of cardiovascular disease (including AF) at study enrolment for every 2 years for the development of cardiovascular disease2 A 34-year follow-up of this study, involving 5,070 participants, evaluated the impact of various cardiovascular conditions, including AF, on the incidence of stroke1,2 In a comparison of the 2-year age-adjusted incidence of stroke per 1,000 individuals with and without AF, those with AF were almost five times more likely to suffer an ischaemic stroke than those without AF (risk ratio=4.8, p<0.001, 2-year age-adjusted incidence of stroke: ~50/1,000 individuals with AF vs ~10/1,000 individuals without AF)1 Overall, it is estimated that ~15% of all ischaemic strokes are caused by AF2 References Wolf PA et al. Stroke 1991;22:983–988 Wolf PA et al. Arch Intem Med 1987;147:1561–1564 20 10 Individuals without AF Individuals with AF* *Patients were untreated with antithrombotic therapy when this study was performed in line with clinical practice at the time 1. Wolf PA et al. Stroke 1991;22:983–988 19

AF-related stroke is preventable Vitamin K antagonists and antiplatelet therapy for stroke prevention in AF AF-related stroke is preventable By preventing clot formation in the heart (thromboprophylaxis) Blood thinning therapy reduces the risk of stroke and thromboembolism but also increases the risk of bleeding AF-related stroke is preventable Ischaemic strokes in patients with AF can be prevented by thromboprophylaxis – i.e. inhibition of the formation of cardiogenic thrombi Thromboprophylaxis can be achieved by using drugs that interfere with the coagulation pathway (anticoagulants) or that inhibit platelet aggregation (antiplatelet drugs) Although anticoagulant and antiplatelet drugs are used for thromboprophylaxis in patients with AF, anticoagulation is more effective based on clinical trials data. ASA is recommended for thromboprophylaxis in patients at low risk of stroke1–3 Both anticoagulant and antiplatelet therapy carry an increased risk of bleeding, which must be balanced against the need for thromboprophylaxis for each patient Abbreviation ASA, acetylsalicylic acid References Fuster V et al. Circulation 2006;114:700–752 Singer DE et al. Chest 2008;133:546S–592S Camm J et al. Eur Heart J 2010;31:2369–2429 1. Fuster V et al. Circulation 2006;114:700–752; 2. Singer DE et al. Chest 2008;133:546S–592S; 3. Camm J et al. Eur Heart J 2010;31:2369–2429 20

Stroke risk in AF: the CHADS2 score Clinical data Stroke risk in AF: the CHADS2 score Congestive heart failure 1 point Hypertension 1 point Age >75 1 point Diabetes 1 point Stroke or TIA 2 points

CHADS2 score correlates with stroke rate Stroke rate per 100 patient years without antithrombotic therapy Reference Gage BF, et al. Validation of clinical classification schemes for predicting stroke. Results from the National Registry of Atrial Fibrillation. JAMA 2001;285:2864–2870. CHADS2 score Gage et al, JAMA 2001;285:2864–2870.

CHA2DS2-VASc score: definition Risk factor Points Congestive heart failure/LV dysfunction +1 Hypertension Age ≥75 years +2 Diabetes mellitus Stroke/TIA/TE Vascular disease (MI, aortic plaque, PAD)* Age 65–74 years Sex category (female) Cumulative score Range 0−9 CHA2DS2-VASc is a newly proposed scheme that takes into account some of the risk factors (female gender and vascular disease) not included in CHADS2 In addition, this scheme takes into account that in reality age does not suddenly become a risk factor at age 75 years (1 point is awarded for age 65–74 years, 2 points are awarded for age ≥75 years) Patients with a CHA2DS2-VASc score ≥2 (1 definitive risk factor [age≥75 or prior stroke/TIA] or 2 clinically relevant non-major risk factors) are considered to be at high risk of stroke and in need of anticoagulation Patients at intermediate risk, i.e. with a CHA2DS2-VASc score of 1 (1 clinically relevant non-major risk factor), may be managed with either ASA or OAC, although the latter is generally preferred In contrast patients with a CHA2DS2-VASc score of 0 (no risk factors) may not require any form of antithrombotic therapy, thus simplifying the selection of patients for anticoagulation Abbreviations ASA, acetylsalicylic acid (aspirin); LV, left ventricular; MI, myocardial infarction; OAC, oral anticoagulation; PAD, peripheral artery disease; TE, thromboembolism; TIA, transient ischaemic attack References Lip et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor based approach: The Euro Heart Survey on Atrial Fibrillation. Chest 2010;137:263–272. Lip et al. Improving stroke risk stratification in atrial fibrillation. Am J Med 2010;123:484–488. Score: 0 = low risk; 1 = intermediate risk; ≥2 = high risk Lip et al Chest 2010;137:263–272

Clinical data Blood thinning drugs The Rat Poison ! WARFARIN

Warfarin significantly more effective than clopidogrel + ASA combined Vitamin K antagonists and antiplatelet therapy for stroke prevention in AF ACTIVE-W results: patients with AF and ≥1 additional risk factor 10 Cumulative risk of stroke RR 1.44 ARR 1.67 p=0.0003 0.05 Clopidogrel/ASA RR=1.72 (1.24–2.37), ARR 0.99 p=0.001 8 Warfarin 0.04 RR 1.10 ARR 0.21 p=0.53 6 5.60 0.03 Annual incidence (%) Cumulative hazard rates Clopidogrel + ASA 4 3.93 0.02 2.42 2.21 Warfarin 2 Warfarin significantly more effective than clopidogrel + ASA combined ACTIVE-W results: patients with AF and ≥1 additional risk factor: In ACTIVE-W, patients (n=6,706) with AF and ≥1 additional risk factor for stroke were randomized to receive warfarin or clopidogrel plus ASA The additional risk factors for stroke were: age ≥75 years, previous stroke/TIA or systemic embolism, left ventricular ejection fraction <45%, peripheral arterial disease, or if aged 55–74 years, patients also had to have diabetes mellitus or previous coronary artery disease The primary endpoint was the first occurrence of stroke, non-CNS systemic embolus, myocardial infarction or vascular death Patients were allocated randomly to receive warfarin therapy (target INR 2.0–3.0) or clopidogrel (75 mg/day) plus ASA (75–100 mg/day) and were intended to be followed for approximately 2 years The trial was stopped early because of clear evidence of the superiority of warfarin therapy Patients on warfarin had 165 primary endpoint events (annual risk 3.93%) and those on clopidogrel plus ASA had 234 (annual risk 5.60%; RR=1.44; 95% CI 1.18–1.76; p=0.0003) and ARR of 1.67. Major bleeding rates were similar in both treatment groups It was concluded that warfarin therapy is superior to clopidogrel plus ASA for the prevention of vascular events in patients with AF at high risk of stroke Abbreviations CNS, central nervous system; INR, international normalized ratio; TIA, transient ischaemic attack, ARR, Absolute Risk Reduction Reference ACTIVE Writing Group of the ACTIVE Investigators. Lancet 2006;376:1903–1912 0.01 Primary endpoint* Major bleeding 0.05 1.0 1.5 Years Number at risk Clopidogrel + ASA 3,335 3,168 2,419 941 Warfarin 3,371 3,232 2,466 930 *Composite of stroke, non-CNS embolism, myocardial infarction and vascular death 1. ACTIVE Writing Group of the ACTIVE Investigators et al. Lancet 2006;367:1903–1912 25

Non-VKA Blood thinning drugs Clinical data Non-VKA Blood thinning drugs Dabigatran Rivaroxaban Apixaban Edoxaban These drugs are not inferior to Warfarin and appear to have lesser risks of major bleeds Less interaction with food or other drugs No blood testing (no INR testing) Rapid action, predictable action Loss of action if not taken drug for 12-24 hrs No antidote yet if bleeding

HAS-BLED Bleeding Risk Score Clinical data Anticoagulation carries a risk of bleeding CHA2DS2VASc score versus HAS-BLED Bleeding Risk Score Thrombus prevention Risk of bleeding

Unable to take blood thinners ? Clinical data Unable to take blood thinners ? -High bleeding risk -Drug allergy/intolerance Left Atrial Appendage Occluder Device

Rate and Rhythm Control Consider pharmacological and/or electrical rhythm control for people with Atrial Fibrillation whose symptoms continue after heart rate has been controlled or a rate-control strategy has not been successful Electrical Cardioversion (shock treatment) Rhythm maintaining drugs - Beta-blocker - Sotalol, Flecainide, Amiodarone etc Have potential side effects Rate controlling drugs - Beta blockers, Digoxin, Diltiazem, etc Note here the recommendation for using amiodarone before and for a year after electrical cardioversion. If Xarelto is used in this situation in addition, there is no need to worry about an interaction with amiodarone. As we mentioned earlier, caution must be exercised if dabigatran is used in combination with amiodarone due to an increased risk of bleeding. NICE AF Guideline June 2014

AF Ablation Invasive Frequently require General anaesthesia Works best for Paroxysmal AF patients (Pulmonary Vein Isolation) Poor results if AF > 1year or large Atrium (requires more extensive ablation) Multiple procedures common Invasive Frequently require General anaesthesia 1% risk of complications overall 1:800-1000 risk of fatality from procedure Radiofrequency energy – ‘Burning’ Cryothermal energy – ‘Freezing’ Note here the recommendation for using amiodarone before and for a year after electrical cardioversion. If Xarelto is used in this situation in addition, there is no need to worry about an interaction with amiodarone. As we mentioned earlier, caution must be exercised if dabigatran is used in combination with amiodarone due to an increased risk of bleeding.

AF Ablation No evidence currently of benefit in patients who are asymptomatic Blood thinners likely to continue longterm after ablation esp if high risk factors No evidence that improves prognosis / mortality from AF (except if AF related heart failure) Note here the recommendation for using amiodarone before and for a year after electrical cardioversion. If Xarelto is used in this situation in addition, there is no need to worry about an interaction with amiodarone. As we mentioned earlier, caution must be exercised if dabigatran is used in combination with amiodarone due to an increased risk of bleeding. NICE AF Guideline June 2014

Radiofrequency Ablation – ‘Burning’ St Jude Medical

Radiofrequency Ablation – ‘Gaps’ Courtesy Google!

Cryoballon Ablation – ‘Freezing’ Medtronic Inc Picture courtesy Gammie JS et al

Key points AF is the commonest rhythm problem There is considerable related morbidity and mortality Prevalence is increasing in epidemic proportions Significantly increases risk of stroke, esp in patients with score >1 Blood thinning agents significantly reduce stroke risk Higher incidence in patients with common health problems & increasing age Maintaining healthy lifestyle, controlling risk factors (eg Diabetes, BP) significantly reduces AF occurrence Persistent AF greater than 1 year is challenging to treat Rate control is equally good as rhythm control in asymptomatic patients Ablation procedures offer high success rates in paroxysmal AF.