Atrial Fibrillation and Stroke Integris Stroke Conference 2015

Sean M. Halleran, MD, FACC, FHRS

Atrial Fibrillation and Stroke

Integris Stroke Conference 2015

Clinical Cardiac Electrophysiology

• Disclosures

– Pfizer, Bristol Myers Squibb – speaker bureau

• Eliquis

– Janssen – speaker bureau

• Xarelto

– Medtronic – faculty

Atrial Fibrillation

• Most commonly occurring dysrhythmia

– currently affecting an estimated 2.2 million Americans

– current estimates suggest that the prevalence of AF will reach 4 million by 2030 and climb to 5.6 million by 2050

Atrial Fibrillation

• Lifetime risk for AF for men and women over age 40 = 25%

Atrial Fibrillation

• Burden of healthcare costs - astronomical proportions

– 1985-1999, number of AF-related hospitalizations increased 190%

– In 2001, AF was responsible for 416,000 hospital discharges

– $6041 paid to Medicare beneficiaries for each hospitalization

– post-discharge costs

• including medications • physician visits

• procedures (including echocardiograms and cardioversions), transportation

• and loss of work experienced by patients after diagnosis of AF

Atrial Fibrillation

Disease/Epidemiologic Associations

• Valvular heart disease • HCM • Congenital heart disease • Chronic lung dz • Obesity • Surgery – Cardiac – Non-cardiac • Alcohol • Hyperthyroidism • Obstructive sleep apnea

Atrial Fibrillation - Symptoms

or racing sensation in chest

• Shortness of breath – especially

intermittent or paroxysmal symptoms • Dizziness or lightheadedness

• Chest discomfort • ASYMPTOMATIC

– More common in elderly or inactive – 21% of patients with AF

Atrial Fibrillation

– First diagnosis or documented AF

• may ultimately be paroxysmal, persistent or permanent

– Paroxysmal - < 7 d (usually < 24 h), self terminating

– Persistent - > 7 d or

– Permanent - > 1 year, decision to no longer attempt maintence of SR

Atrial Fibrillation - Treatment

treatment of atrial fibrillation is prevention of STROKE

A day of atrial fibrillation is a bad day; a stroke is a bad life…

Atrial Fibrillation and Stroke

• 15-20% of all strokes are caused by AF

• Persons risk of stroke with AF is 5x greater • Mortality with AF related stroke is 2x greater

• Stroke risk does NOT depend on symptoms OR

frequency OR duration of atrial fibrilation

• Stroke risk is frequently NOT temporally related to AF events

• Estimated that 80% of strokes in patients with AF are preventable

Atrial Fibrillation and Stroke

• Increased Risk Factors for Stroke

– Hypertension – Diabetes

– Female gender – Age – 65-75

– Age > 75 – double risk factor

– Prior Stroke or mini-Stroke (TIA) – double risk factor – Heart Failure

– Vascular Disease (coronary, carotid, peripheral) – Hyperthyroidism

– Valvular Heart disease

• mitral stenosis (not MR), • heart valve replacments

– mechanical >> bioprosthetic – mitral >> aortic

Atrial Fibrillation - Treatment

complications (CVA)

– CHADS2 Score

CHADS2

• Score 1 = ASA or OAC • Score > 2 = OAC

CHA

DS

VASc Score

• Coronary, carotid, peripheral

– Age 65-75 1 – Female gender 1

• Age > 75 = OAC Stroke/TIA = OAC

Prevention of thromboembolic

complications (CVA)

• Typical agents – oral anticoagulants

– Warfarin – INR 2-3 typically – 2.5-3.5 with mitral stenosis

– Dabigitran (Pradaxa)

• Direct thrombin inhibitor

– Rivaroxaban(Xarelto)

• Oral factor Xa inhibitor

– Apixaban (Eliquis)

• Oral factor Xa inhibitor

– Edoxaban (Savaysa)

Prevention of thromboembolic

complications (CVA)

• European usage of ASA

– Clopidogrel ?

• Active A and Active W trials

• Take home message – aspirin and clopidogrel probably better than aspirin alone, worse than warfarin or novel oral anticoagulants

Prevention of Thromboembolic

Complications – AF - Dabigatran

• Dabigatran (Pradaxa) v. warfarin

– Direct thrombin inhibitor – BID dosing – RE-LY Trial, Connolly NEJM 2009

– 951 centers, 18,113 patients

• AF and at least 1 risk factor for CVA

– Warfarin to INR 2-3, Dabigatran 110 mg bid, Dabigatran 150 mg bid

– 2 year follow-up, annualized primary end-point

• Warfarin 1.69%

• Dabigatran 110 mg 1.53% (p<0.001 for NI)

Prevention of Thromboembolic

Complications – AF - Dabigatran

Prevention of Thromboembolic

Complications – AF- Rivaroxaban

• Rivaroxaban (Xarelto) v. warfarin • Factor Xa inhibititor – daily dosing • ROCKET AF Trial – AHA 2010

• 14,264 patients – CHADS2 > 2

• Rivaroxaban non-inferior to warfarin by ITT

• Superior while taking study drug (non-ITT) • Similar bleeding, less ICH, major bleeding

Primary Efficacy Outcome

Stroke and non-CNS Embolism

Event Rates are per 100 patient-years

Based on Protocol Compliant on Treatment Population

Warfarin

HR (95% CI): 0.79 (0.66, 0.96) P-value Non-Inferiority: <0.001

Days from Randomization

C u m u lat iv e ev en t r at e (% ) Rivaroxaban Rivaroxaban Warfarin Event Rate 1.71 2.16 ROCKET – AF Trial

Prevention of Thromboembolic

Complications – AF - Apixaban

• Apixaban (Eliquis) vs. warfarin • Factor Xa inhibitor – BID dosing • ARISTOTLE Trial – NEJM 2011 • 18,201 patients – CHADS2 > 1

• Superiority over warfarin for prevention of systemic embolization

• Superiority over warfarin for major bleeding

Granger CB, Alexander JH, McMurray JJV et al. Apixaban versus warfarin in patients with atrial fibrillation. N Eng J Med 2011

Prevention of Thromboembolic

Complications – AF - Edoxaban

• Factor Xa inhibititor – daily dosing

• ENGAGE AF- TIMI 48 – NEJM 2013 • 21,105 patients – CHADS2 > 2

• High dose vs. low dose edoxaban vs. warfarin

• Non-inferior to warfarin for stroke, systemic embolism

• Lower bleeding, less CV death • Higher stroke in pts CrCl > 95

Prevention of Thromboembolic

Complications – AF - Edoxaban

Atrial Fibrillation - Treatment

• Protection – Prevention of Stroke

• Symptoms – Reduce frequency and duration of episodes

– Rate control

AF – Rate control

• Beta-blockers - favored

• Calcium channel antagonists (non-dihydropyridine)

• Some AAD (sotalol, dronederone, amiodarone) • Digoxin ?

• Pacemaker

– Used with concomitant sinus node dysfunction

– Common conundrum – fast when in AF, slow when in SR

• Class I indication for permanent pacing to allow for medication of the fast

AF – Rhythm control

• Pharmacologic rhythm control

– Indicated for symptomatic relief of AF

– Non-indications

• Desire to stop anticoagulation • Reduce risk of stroke

– Choice based on

• Side effect profile

• Presence of structural heart disease • HF

• Hypertension

AF – Rhythm control

• Flecainide, propafenone, dronederone, sotalol

• Higher potency AAD

AFFIRM Trial

• In patients with CVA warfarin was stopped

– 57% of patients in the rhythm control arm – 33% in the rate control arm

AFFIRM Trial – Take Home

Message

• NOT that rhythm control is not worthwhile • Asymptomatic patients – prevention of

stroke and rate control are reasonable • Sinus rhythm is good; standard methods

of maintaining NSR (anti-arrhythmic drugs) may not be good

• DO NOT stop anti-coagulation in patients because you (or they) think they are in

The AF Rhythm Control

Conundrum

• Sinus rhythm appears to be associated with improved mortality

• Anti-arrhythmic medications that are designed to lead to SR have not been associated with improved mortality

• Is there something else that can lead to SR by using no or less medication?

Atrial Fibrillation Ablation

Atrial Fibrillation – Catheter

Ablation

LA/Pulmonary Vein – Muscle

Fibers

Premature Atrial Contraction from

Pulmonary Vein

Left Atrial Mapping and Catheter

Ablation

Visualization

:

Intracardiac Ultrasound

Transeptal Access to LA Tenting of the intra-atrial septum during transeptal catheterization

Catheter Ablation – AF

Electroanatomic Mapping

Atrial Fibrillation – Radiofrequency

Catheter Ablation

Cryothermal Balloon Pulmonary

Vein Isolation

Cryothermal vs. Radiofrequency

Ablation

Cryothermal lesion

Radiofrequency lesion

Catheter ablation of AF –

Pulmonary vein isolation

Pulmonary Vein Isolation

Pulmonary Vein Isolation

Pulmonary Vein Isolation

AF ablation outcomes

AF ablation outcomes

reduction unclear – trials ongoing

Cryptogenic Stroke

• Cryptogenic Stroke – 30-40% of ischemic strokes

• Pathophysiology heterogenous

– Cardioembolic – LAA (AF), LV thrombus – Atheroembolic

– Thrombophilia

– Inflammatory conditions – Atrial septal disorders

Cryptogenic Stroke

– ECG

– 24 hour ECG monitoring

– Carotid imaging (CTA or MRA) – Lipid panel

– Echocardiogram

ASSERT Trial

– 2580 patients with PPM or ICD, no hx AF

– At 3 mos, 10% incidence of sub-clinical atrial arrhythmias

– Associated with increased risk

• AF – HR 5.6

• Stroke or systemic embolism – HR 2.5

– In pts with CVA, subclinical AF present in 51%

Subclinical atrial fibrillation and the risk of stroke. Healey JS, et alN Engl J Med. 2012;366(2):120.

CRYSTAL - AF

– Implantable loop recorder vs. conventional monitoring for occult AF

– At 6 mos AF detection

• 8.9% in ILR group

• 1.4% in control group

• Median time to AF detection in ILR group @ 6 mos

– 41 days

• Median time to AF detection in ILR group @ 12 mos

ILR for Occult AF

• First patient in Oklahoma with ILR for cryptogenic CVA after CRYSTAL-AF

EMBRACE

Trial

– 30 day event monitor vs. 24 h holter – AF detection rate

• 16.1% in 30 day monitoring • 3.2% in 24 hour monitoring

Atrial fibrillation in patients with cryptogenic stroke. Gladstone D et alN Engl J Med. 2014;370(26):2467.

Bleeding Risk in AF patients

of Medicare Advantage patients

– Of 48,260 pts with AF, 34% (16,409) experienced incident of bleeding

– Of 16,409 pts with bleeding

• 43% had repeat bleeding

• 30% experienced bleeding while on OAC at time of

bleed

S. Deitelzweig, Bleeding as an Outcome Among Patients With Nonvalvular

Bleeding Risk in AF patients

CHADS2 score and HASBLED score

S. Deitelzweig, Bleeding as an Outcome Among Patients With Nonvalvular

Atrial Fibrillation in a Large Managed Care Population. Clinical Therapeutics 1536-1545.e1

CHADS2 Score Major Bleeding Event

Rate % per year

0 4.4

1 8.0

2 12.1

Bleeding Risk in AF patients –

HAS-BLED

AF Anticoagulation Conundrum

both high and competing risks for

thromboembolic complications and major bleeding?

Left Atrial Appendage

• 90% of left atrial thrombi located in LAA • Inflammation and fibrosis seen in atria of

Left Atrial Appendage

Treatment for AF and CVA

• Open surgical ligation or amputation of LAA

• Retrospective study 205 pts with MVR +/- LAA ligation

– Embolic events lower in pts with ligation – 3% vs. 17%

• Potential limitation of surgical ligation

– Incomplete ligation – 22%

• ACC/AHA recommendation for LAA amputation at time of MVR

Role of left atrial appendage obliteration in stroke reduction in patients with mitral valve prosthesis: a transesophageal echocardiographic study.

LAA -Treatment for AF and CVA

Percutaneous LAA occlusion

• Expandable device delivered via transseptal approach to the LAA

• Nitonol cage with PTFE covering

– PROTECT-AF – Lancet 2009

• Non-inferiority trial – 2:1 Watchman v. warfarin • CHADS2>1

• Primary efficacy – stroke, systemic embolism, death

• Primary safety - major bleeding, pericardial effusion, procedure related stroke, and device embolization

LAA -Treatment for AF and CVA

Percutaneous LAA occlusion

Watchman LAA Occluder

PROTECT-AF Trial Lancet 2009

LAA -Treatment for AF and CVA

Percutaneous LAA occlusion

• Watchman – PROTECT AF

– 18 mo f/u, similar event rates

• 3 events per 100 pt-years Watchman vs. 4.9 in warfarin

– At 2.3 years

• 3% event rates Watchman vs. 4.3%

– Safety endpoints

• 7.4 events per 100 pt-years Watchman vs. 4.4 in warfarin • Most early

• 50% pericardial effusion requiring drainage

– Watchman currently pending FDA approval; CE Mark approval in Europe

LAA -Treatment for AF and CVA

Percutaneous LAA occlusion

– Percutaneous device with FDA approval for soft tissue closure

– evaluated for safety and efficacy (not

approved) for occlusion of LAA in pts who

cannot take OAC and who are at high risk for stroke

LAA -Treatment for AF and CVA

Percutaneous LAA occlusion

LARIAT – Patient Selection

• NVAF, CHADS₂ ≥ 2, or a CHA₂DS₂-VASc ≥ 3. • Contraindication to OAC

– History of bleeding with high risk of recurrence – Recurrent syncope and falls

– High-risk occupations (e.g. athletes, divers, martial arts instructors)

– Aneurysms at risk for rupture (intracranial, aortic) – Fixed malignant hypertension

– Thrombocytopenia

– Dual antiplatelet therapy with increased HAS-BLED score

LARIAT - System

• Contraindications

– previous cardiac surgery – pericarditis,

– chest radiation

– Active LAA thrombus

• Cardiac CT to assess the anatomy of the LAA for suitability of the LARIAT system – anatomic contraindications

– LAA located behind the pulmonary artery – with superior orientation