Atrial fibrillation

Topics Mechanism of AF Management of new onset AF Role of TTE in AF Anticoagulant choice

Update Rhythm control vs rate control in AF

Update AF + HF Role of angiotensin inhibition

Mechanism of AF: Terminology Trigger – rapidly firing focus often arising in

pulmonary vein Substrate – mechanical/anatomical struc of the

atria where AF can occur Substrate remodelling Electrical remodelling Mechanisms of cardiac arrhythmias:

Triggered activity – additional depolarization's which occur during or immediately following a cardiac depol and may cause sustained cardiac arrhythmia

Reentry/reentrant mechanism – most common mechanism of cardiac arrhythmias and refers to presence of one or more electrical circuits in which electrical activation proceeds in a circular fashion to complete a elf sustain circuit.

AF BEGETS AF

Triggers Maintenance of AF

AF mechanism – most common triggers1. Myocardial tissue on pulmonary vein

1. Isolation show repetitive firing and even presence of episodic re-entrant activation in pulmonary veins.

2. Stretch – increase the propensity for rapid firing form PVs as a result of stretch sensitive ion channels1. Could explain association b/w AF and mitral

regurgitation

AF – not so common triggers3. Non PV sites of rapid firing:

Tissue near pulm vein, near SVC, coronary sinus

4. Atrial flutter Atrial flutter is a right atrial re-entry circuit, while

A fib is a left atrial issue Elimination of atrial flutter frequently does not

eliminate the predisposition of AF

Electrical remodellingFew minutes of paroxysmal AF

Decrease in atrial refractoriness

High rate of electrical activation

Initially, these changes are spatially uniform

Overtime, they become heterogeneous

Clinical implication: these transient changes are considered to be reason why patients revert to AF after cardioversion

Enhanced cellular Ca2+

Auto protective mechanisms which reduce Ca2+ entry

Electrical modelling and Substrate modelling combined mechanism

Maintenance of AF1. Electrical remodelling2. Atrial remodelling3. Role of ANS4. Role of fibrosis5. Re-enterant mechanism

AF- maintenance

Atrial remodelling Structural changes Fibrosis Electrical changes – refractory period

dispersion, conduction delay

Clinical implications of mechanistic model Refractory nature of AF

After initiation of AF – atrium relatively healthy – sinus rhythm can be spontaneously restored

As substrate remodels over time, AF no longer terminates spontaneously

RF of AF

Hypertension 60-80% Cardiovascular disease 25-30%

Cardiomyopathy Valvular disease CAD

NYHA II-IV 30% Diabetes 20% Age

Asso w/ atrial dilatation

New Onset AF

New Onset AF: Presentation Found incidentally – i.e nil symptoms May be symptomatic May have precipitating factors:

Surgery Infection Recent MI Thyrotoxicosis PE Myocarditis Pericarditis

New onset AF: terminology Paroxysmal AF – spont revert within 7 days Persistent AF – persist >7days with continuous

AF Long standing persistent AF – more than 12

months

New onset AF: Mx Categorise patients:

Symptomatic Severely symptomatic Organ failure

Cardiac – active ischemia, pulmonary oedema Renal - AKI

New onset AF: Stable - assessment

Hx: Look though old ECG – find out prvs hx of prior

supraventricular arrhythmia RF for AF Identify risks of stroke or bleeding

CHADS SCORE HAS BLED

O/E Vitals Resp: Pul oedema? Cardiac: fluid overload

HF changes management: HF can cause AFAF can cause AF

New onset AF: Stable - assessment

ECG – ischemia? Pre-excitation? Labs: FBC, EUC, CMP, TSH

Risk of AF is increased 3x EVEN IN SUBCLINIC HYPERTHYROIDISM: Serum TSH <0.5 mU/L Serum free T4 = normal

Imaging – CXR TTE

Role of TTE in AF Left atrial size: Mitral valve function:

Stenosis Regurg

Left ventricular function: pharmacotherapy choice Future stroke prognostication

BAATAF, SPINAF and SPAF – incdience of stroke 9.3%/ year in patients with moderate to severe left ventricular dysfunc.

HASBLED Hypertension History (Uncontrolled,

>160 mmHg systolic) Renal Disease Dialysis, transplant, Cr

>2.6 mg/dL or >200 µmol/L Liver Disease Cirrhosis or Bilirubin >2x

Normal or AST/ALT/AP >3x Normal Stroke History Prior Major Bleeding or Predisposition to

Bleeding Labile INR (Unstable/high INRs), Time in

Therapeutic Range < 60% Age > 65 Medication Usage Predisposing to

Bleeding (Antiplatelet agents, NSAIDs) Alcohol or Drug Usage History ≥ 8

drinks/week

Score >5– 9% annual risk of bleeding. High riskScore 4 – 8.9% annual risk of bleeding. High riskScore 3 – 5.8% annual risk of bleedingScore 2 – 4.1% annual risk of bleeding – moderate risk of major bleedingScore 1 – 3.4% annual risk of bleeding. Low risk

CHA2Ds2 VASc score Age

<65 = 0 67-74 = 1 >75 = 2

Sex Male = 0, Female = 1

Hypertension =1 Stroke/TIA/Thromboemolism =2 Vascular disease hx =1 DM =1

New onset AF-Stable - Mx Correct reversible causes

RULE OUT PRE-EXCITIATION AV NODAL BLOCKING drugs will lead to rapid accessory

pathway conduction, increasing risk of pre-excited AF leading to VF

1st line – metoprolol, non hydrodipine CCB 2nd line - digoxin 3rd line - amiodarone

HR targets Symptomatic – HR<85 Asymptomatic - HR<110

New onset AF-Stable - Mx 1st line – metoprolol, NHD CCB 2nd line – digoxin

Indication: Dilated heart failure, in pts with AF DUE TO HEART FAILURE Added to 1st line if BP sagging with 1st line and still in

RVR 3rd line – amiodarone

Indication: 1st and 2nd line fail Poor LVEF

Caution: Potential for pharmacological conversion and risk of

thromboembolism (TE)

1st line in stable AF pts Beta blocker vs CCB – usually depends on

consultants. Things to consider: Beta blocker useful with:

Ventricular response increases to inappropriately high rates during exercise

After MI Stable angina

CCB useful if: COPD Asthma

Start low 25 mg BD metoprolol – and titrate to BP and HR

Rhythm vs rate control in AF

Rhythm control vs rate control in AF AFFIRM and RACE trials

Embolic events occur with equal frequency regardless of rate control or rhythm control strategy

AFFIRM trial

Rate control and anticoagulation Statistically Significant trend

towards decrease in mortality

21.3% vs 23.8% Patients without hx of HF and

65 years or older had a SIGNIFICANT REDUCTION in mortality

Less likely to require hospitalisation 73 vs 80

Rhythm control and warfarin left up to discretion of investigator Deleterious effects or

antiarrhythmic likely contributing to increased mortality.

No Diff b/w two groups in incidence of cardiac death, arrythmia, or deaths due to ischemic or hemorrhagic stroke. No diff in functional status or QOL

RACE trial Rate control

Significant less likely to have a composite index of: (17% vs 22.6) Cardiovascular death Admission for HF TE event Severe bleeding Pacemaker

implantation Severe SE form

antiarrhythmic dugs

Rhythm control Higher incidence of

non fatal endpoints: HF TE PM Adverse drug effect

Rhythm control fails to reduce embolic risk because:

It never goes away: Even with successful cardioversion and antiarrhythmic drug

therapy – recurrence of AF is 35-60% with intermittent monitoring and 88% with continuous monitoring

Doesn’t take much – AF >more than 5 minutes increasing risk of TE events 6x

They have other risk factors- Pts with nonvalvular AF (eg. Hypothyroidism, cardiac surgery)

often have predisposing factors for TE when they are in SR – these include complex aortic plaque and left ventricular dysfunction.

SR doesn’t mean no AF Left atrium may show sinus mechanism, while atrial appendage

may display an AF contraction pattern

Rate control vs rhythm control Rate control

Preferred in patients with heart failure

Very elderly Under represented in clinical

trails AF permanent More sensitive to proarrhtymic

effects

Rhythm control When SR is maintained, exercise

capacity and quality of life is improved

Failure of rate control: Persistent symptoms – palp,

dyspnea, angina, near syncope despite adequate rate control

Inability to achieve adequate rate control

Young patients Who need to carry out activities

requiring optimal cardiac performance

New diagnosis – go for cardioversion if you have the following: Left atrium <4.5 to 5 cm Reversible underlying disorder

Hyperthyroidism, pericarditis, PE, post op AF

No HTN Normal eft ventricular systolic

func.

Impact of anticoagulation

Reduction of stroke Increase risk in bleeding

Multiple trials and subsequent meta-analyses show definite reduction of clinical stroke in patients with CHADsVASc>2

But CHADsVasc 1 and 0 not well studied

Annual risk of ICH in patients with AF who are not anticoagulated – 0.2%

Annual risk of ICH in patients with AF who are ant coagulated – 0.4%

Think twice for these patients: Thrombocytopenia or known

coagulopathy Recent surgery Prior severe bleeding while

on oral anticoag Suspected aortic dissec Malignant HTN

Anticoagulant choice In general, newer anticoag preferable to warfarin

Meta-analysis of RE-LY, ROCKET AF, ARISTOTLE and ENGAGE AF TIMI New agents had a lower rate of haemorrhagic stroke [RR

0.49] Aggregate Ich reduced RR0.480

Warfarin>new anticoag Patient already on warfarin, comfortable with INR and

within therapeutic range atleast 65% of time Unacceptable increase in cost Severe CKD Creat CL<30 (apxiban is the exception in US) If drug interactions:

Phenytoin HIV – protease inhibitor based antioretroviral therapy

Other anticoagulant options Aspirin monotherapy

CHADS2=0- i.e low risk 2007 meta analysis – not statistically significant risk

reduction For CHADS2>1

Consistently and substantially less effective in reducing TE risk in meta analysis of 6 trials.

Absolute rate increase of major bleeding was 0.9 events per 100 patient year more

Other anti-coagulant options

Aspirin + clopidogrel ACTIVE W [RCT] (compare clopidgrel + aspirin to

warfarin) Warfarin significantly lowered the annual rate of

primary end point which was a composite outcome of different TE

Decrease risk of major bleeding in warfarin group ACTIVE A (compare clopidogrel + aspirin to Asprin

alone) [for patient not candidate for warfarin] Reduction in TE in the DAPT group [2.4% vs 3.3%

annum] Increased incidence of bleeding [2.0% vs 1.3% annum]

Other anti-coagulant options Asprin + Low dose warfarin for INR 1.2-1.5

SPAF III trial – high risk of embolism

Specific patient groups Short duration PAF

Duration of AF doesn’t matter- anticoagulate according to CHADSVAC score

Renal patients Hyperthyroidism

Initially anticoag according to CHADSVASC – start treatment for hyperthyroidism – if it can be documented that nil AF for 3/12 then anticoagulation can be cased

Expert opinion

Management of AF in patients with heart failure

AF + HF AF + HF go together

Framingham Heart Study 2003 [n=1407 over 47 year interval] HF 1st – 5.4%/year incidence of AF AF 1st – 3.3%/year incidence of HF

Prevalence of AF increases from 4% to 40% as NYHA functional class increases from I to IV

AF + HF: mechanism Tachy/brady/abrupt change in rate decreases

cardiac output Persistent tachycardia leads to tachycardia

mediated cardiomyopathy Loss of atrial systole

diastolic heart failure where left ventricular filling occurs largely in late

diastole more dependent than normal hearts on atrial

contraction

AF + HF: acute management Cease/withold beta blockers until stabilisation Management fluid overload Rhythm control in young patients who can

tolerate burdens of rhythm control Rate control: Regardless of strategy used – must

anticoagulate

AF + HF: management

Manage heart failure aspect and stabilise

Rhythm control Rate control

Cather Ablation

Anticoagulate regardless of arm AV nodal

ablation

AF-CHF trial RCT- Long term rhythm control better than rate control

in pts with HF and paroxysmal AF? 1376 with LVEF <35%, HF, hx of PAF, 2 groups:

Rhythm: amiodarine, sotalol, dofetilide Rate control: with beta blockers

Outcome at 37 months No significant difference in primary outcome of death No outcome of event free survival Improvement in QOL and functional

capacity were similar in treatment arms

Author’s opinion re: AF and HF Attempt rhythm control initially for HF patients

with AF (anti-arrythmic drugs or catheter ablation) Allows determination if symptom rhythm

correlation exists If Rhythm control not possible, then rate

control via definite means AV node ablation with pacing support

“No high quality evidence exists that anti arrhythmic result in better outcome….[]…but data is older, retrospective and suspect”

AF + HF: ongoing management Rhythm control vs rate control in HF patients

AF-CHF Catheter ablation ?cardiovert Anti arrhythmic

Dofetilide – younger patients with persevered kidney fection

Amiodarone Sotalol – avoid in those with poor left ventricular

function – preferred in young healthy and those Rate control

Dofelitide Class 3 anti-arrhtymic drug DIAMON CHF Trial

1518 patients with symptomatic HF including 391 with AF at baseline

Dofetilide arm was more likely to be associated with reversion to SR at 1 month and 1 year

HOWEVER NO DIFFERENCE IN MORTALITY BETWEEN DOFETILIDE AND PLACEBO GORUP

AMIODARONE When used in low doses - <400mg/day

Lack of negative inotropic effect Low incidence of QT prolongation, but no

proarrhthymia CHF STAT trial – subset analysis

103 patients with AF – 51 randomly assigned to amiodarone 52 to placebo Amiodarone arm had lower mortality During AF – 16-20% reduction in mean ventricular rate

Issues encountered in amiodarone arm: 32% developed bradycardia – required discontuion of digoxin 19% required permanent pacemaker 14% other complications – hypothyroidism and neurotoxicity.

Cather ablation in patients with HF More optimistic re: outcomes in patients with HF and AF

ARC HF – 52 patients – RCT – catheter ablation or rate control Peak oxygen consumption significantly increase in ablation arm

compared with rate control QOL and BNP significant improved in ablation arm

PABA CHF trial – 81 patients with symptomatic drug resistant AF and an LVEF <40% RCT biventricular pacing – rate control or catheter ablation –

rhythm control At 6/12 catheter ablation group: better QOL, longer 6 min walk

distance, higher ejection fraction CAMTAF trial – 50 patients with persistent AF, symptomatic HF

and LVEF<50% Cather ablation group – 81% achieved SR, LVEF significantly higher

Catheter ablation in patients with HF

2014 Meta-analysis – 1838 AF patients with mean LVEF of 40%

Long term efficacy at end of follow up was 60%, fall of BNP 1187 to 657 pg/ml

Anselmino M, Matta M, D’Ascenzo F, et al. Catheter ablation of atrial fibrillation in patients with left ventricular systolic dysfunction: a systemic review and meta analysis. Circulation Arrhythmia Electrophysiology 2015; 7:1011

AF + HF: when to cardiovert? 1st episode of AF If after management of heart failure, patient

does not improve.

Rate control Rate control goal:

<110 <85 at rest <110 during moderate exercise

1st line – beta blocker (Carvedilol, extended metoprolol, bisprolol) Does not improve mortality in acute setting CCB has been show to increase mortaltiy Digoxin lesser effeicacy Amiodarone significant limitation

2nd line: digoxin added to betablocker IF decompenwsated – start with digoxin If not under contorl, then amiodarine

Angiotensin Inhibition: Mechanism Reduction in atrial stretch

?prevention of atrial fibrosis Prevention of electrical remodelling and direct

antiarrhythmic effects

Angiotensin Inhibition: Prevention of AF Few RCTs which show reduced incidence of AF

TRACE trial Left ventricular dysfunc and sinus rhythm after AMI, trandopril was

asso w/ significantly reduced incidence of AF at 2 and 4 year follow up 2.8 vs 5.3 rel to placebo

SOLVD trial Chronic left ventricular dysfunc in patients with IHD. Reduced

incidence of subsequent AF at a mean follow up of 2.9 years 2010 metanalysis 26 trials

ACE and ARB significantly reduces risk of development of AF More effective in patients with systolic heart failure Greater in prevent recurrent AF than compared to new AF Issues with paper:

Inclusion of post hoc analysis of randomist trialis performed for reasons other than prevention of AF (eg. HF, post MI, HTN)

Hetrogeniety Likely presence of public bias, ascertainment bias

In setting of hypertension: 2010 metanalysis found no significant reduction in risk of AF

Angiotensin Inhibition: Prevention of recurrent AF GISSI-AF RCT

Hx of symptomatic AF but in – valsartan or placebo

Did not prevent recurrent AF Downside of trial – only 8% had heart failure/left

ventricular dysfunc ACTIVE I study – RCT

Irbesartan or placebo Nil difference in indience of AF on follow up