FIBRILLAZIONE ATRIALE

Ictus criptogenetico: possiamo

ridurre questa diagnosi?

Maurizio Landolina MD, FESCDirettore

U.O.C. Cardiologia, Ospedale Maggiore di Crema

Speakers’ bureau appointment with:

•Boston Scientific

•LivaNova

•Medtronic

•St. Jude Medical

Advisory board relationship with Medtronic.

Disclosures

La mortalità a un anno dopo il primo ictus è del 22%.

Il rischio assoluto di recidiva di ictus cerebrale è del 10-15% nei dodici

mesi seguenti l’evento e, successivamente del 4-9% per ogni anno nei

primi cinque anni.

L’ictus cerebrale è la seconda causa di morte

WW (dopo le malattie cardiovascolari e prima delle

neoplasie) e la principale causa di disabilità.

Lozano R et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global

Burden of Disease Study 2010. Lancet. 2012;380:2095–2128; dati SPREAD 2012; Donnan et al. "Stroke". Lancet 371 (9624): 1612–23.

ICTUS

Identification

and

Diagnostic

Evaluation of

Patients with

Cryptogenic

Ischemic

Stroke or TIA

N Engl J Med 2016; 374: 2065-74

La fibrillazione atriale si traduce in un

rischio totale 5 volte maggiore di

sviluppare ictus

L’ictus ischemico associato alla FA, ha una prognosi

peggiore, in termini di mortalità e disabilità residua

rispetto agli ictus senza FA

Determinare la presenza di FA permette di instaurare una terapia anticoagulante, che ha

una efficacia preventiva di ictus maggiore rispetto alla terapia antiaggregante (raccomandata se l’FA non è documentata)

ICTUS CRIPTOGENICO & FIBRILLAZIONE ATRIALE

ATRIAL FIBRILLATION

Silent but deadly!

Furberg CD, Am J Cardiol 1994; 74: 236-41

The Clinical Presentation of AF

Crypto

Stroke

Ischemic

Stroke

Sudden

Death

Heart

Failure

Cognitive

Decline

Dementia

Asymptomatic Atrial Fibrillation

Symptomatic Atrial Fibrillation

Palpitations Tachy

ArrhythmiasHemodymanicDizzyness

Heart Failure

Syncope

Medical Attention

Botto GL. JCE. 2009;20:241-248

Improvement of device technology allows

greater quantification of AF burden

STUDI CON MONITORAGGIO ESTERNO IN PAZIENTI

POST-ICTUS CRIPTOGENICO

Study (Year) N AF Definition Monitoring Duration AF Yield

Tayal (2006) 56 Any duration MCOT 21 DaysOverall 23%AF < 30 sec 18%AF > 30 sec 5%

Gaillard (2010) 98 32 seconds TTM 30 days 9%

Bhatt (2011) 62 30 seconds MCOT 28 days24%AF > 5 min 9%

Flint (2012) 236 5 seconds MCOT 30 daysOverall 11%AF < 30 sec 4%AF > 30 sec 7%

Kamel (2013) 20 30 seconds MCOT 21 days 0%

Miller (2013) 156 30 seconds MCOT 30 daysOverall 17%AF < 30 sec 12%AF > 30 sec 4%

Gladstone (2014) 572 30 secondsEvent Monitor 30 days vs 24 Holter

16.1% in event monitor vs. 3.2% Holter

Glotzer TV, Ziegler PD. Heart Rhythm. 2015;12:234-241.

STUDI CON LOOP RECORDER IMPIANTABILE IN

PAZIENTI CON ICTUS CRIPTOGENICO

17

Study Study size

Mean Age (years)

Duration of monitoring(months)

Definition of AF Time to Diagnosis

(days)

AF detection rate (%)

Ritter1 60 NA 10 >30 seconds 64 17

Etgen2 22 65.8 12 >6 minutes 152 27

Cotter3 51 52 8 2 minutes 48 25

SURPRISE4 85 54 19 >2 minutes 109 16

Rojo-Martinez5 111 67 9 2 minutes 102 33

Ziegler6 1247 65.3 6 2 minutes 58 12

Poli7 74 66.4 12 > 2 minutes 105 33

Jorfida8 54 67.8 14.5 > 5 minutes 162 46

CRYSTAL AF9 (ICM arm) 221 61.6 6 12 36

>30 seconds 4184

252

91230

1Ritter et al, Stroke. 2013, 44:1449-52; 2Etgen et al, Stroke. 44:2007-2009; 3Cotter et al, Neurology. 2013, 80:1546-50; 4Christensen et al, Eur J Neurol. 2014, 21:884-

89; 5Rojo-Martinez Rev Neurol 2013; 57 (6): 251-257; 6Ziegler et al, Cerebrovasc Dis. 2015, 40:175-81. 7Poli Eur J Neurol. 2015 Oct 16 Epub ahead of print ;8 Jorfida J

Cardiovasc Med (Hagerstown). 2014 Nov 15. [Epub ahead of print] 9Sanna T et al, NEJM. 2014;370:2478-2486;

▪ 441 Pazienti con Stroke criptogenico/TIA

▪ Randomizzati a SoC monitoring o Reveal XT

▪ AF definita se ≥ 30 sec

▪ Identificata dall’investigatore

▪ Aggiudicata da un comitato indipendente

▪ Endpoint primario

▪ AF detection a 6 mesi

▪ Endpoint secondari

▪ AF detection a 12 mesi

▪ AF duration

▪ Correlazione con i sintomi

▪ Azioni mediche intraprese

Sanna T et al. N Engl J Med. 2014; 370: 2478-2486

CRYPTOGENIC STROKE AND UNDERLYING ATRIAL FIBRILLATION (CRYSTAL AF)

CRYSTAL AF: ENDPOINT PRIMARIO E SECONDARI

Detection of AF at 6 months

ICM finds 6x more patients with AF

Detection of AF at 12 months

ICM finds 7x more patients with AF

8.4%

1.4%

12.4%

2.0%

ICM Control

Median time to AF Detection 84 days 52.5 days

Patients found to have AF 29 4

% Asymptomatic Episodes 79% 50%

Tests required to detect AF Auto. AF detection

121 ECGs32 24-hr Holters 1 Event Recorder

ICM Control

Median time to AF Detection 41 days 32 days

Patients found to have AF 19 3

% Asymptomatic Episodes 74% 33%

Tests required to detect AF Auto. AF detection

88 ECGs20 24-hr Holters 1 Event Recorder

Sanna T et al. N Engl J Med. 2014; 370: 2478-2486

ICM Control

Median time to AF Detection 252 days 72 days

Patients found to have AF 42 5

% Asymptomatic Episodes 81% 40%

Tests required to detect AF Auto. AF detection

202 ECGs, 52 24-hr Holters1 Event Recorder

30.0%

3.0%

CRYSTAL AF: A 36 MESI

8.8x more than standard follow-up arm

Sanna T et al. N Engl J Med. 2014; 370: 2478-2486

21

PREDICTORS OF AF OFFER ONLY MODERATE

PREDICTIVE ABILITY

CRYSTAL AF sub-analysis: Thijs, Neurology (2016)

• Parameters tested:➢ Age, sex, race

➢ Body Mass Index,

➢ Type and severity of index

event

➢ CHADS2 score

➢ PR-interval

➢ Diabetes, hypertension

➢ Congestive heart failure

➢ Patent foramen ovale

➢ Premature atrial

contractions

Increasing age and a prolonged PR-interval were independently associated with

AF, but the predictive ability of these parameters was only moderate

Thijs et al. Predictors for Atrial Fibrillation Detection after Cryptogenic Stroke: Results from CRYSTAL AF. Neurology 86.3 (2016): 261-269

STROKE & AF: SYSTEMATIC REVIEW AND META-ANALYSISSposato – Lancet Neurol, April 2015

50 studi; 11.658 pazienti post stroke

Emergency room In Hospital 1° ambulatory

period

2° ambulatory

period

7.7% 5.1% 10.7% 16.9%

Sposato et al. Lancet Neurol 2015; 14: 377–87

26

Embolic Stroke of Undetermined Source and Detection of

Atrial Fibrillation on Follow-Up: How Much Causality Is There?

Among 275 ESUS pts, AF was detected during follow-up in 80 (29.1%), either during repeated ECG monitoring (18.2%) or during hospitalization for stroke recurrence (10.9%). More recurrent strokes or peripheral embolisms occurred in the AF group compared with the non-AF group (42.5% versus 13.3%, P = .001).

All patients Patients on antiplatelets

Ntaios G et al., J Stroke Cerebrovasc Dis 2016 (in press)

AF B

urd

en (

0 t

o 1

00%

, lo

g s

cale

)

0 6 3618 24 3012 42 48 54-54 -48 -42 -36 -30 -24 -18 -12 -6Months from TE

Temporal Relationship of Atrial

Fibrillation & Thromboembolism

Trial AF prior to

stroke (at

any time)

AF prior to

stroke (<30

days)

New AF

after stroke

TRENDS(Daoud EG, et al Heart

Rhythm 2011;8:1416-23)

20/40 (50%) 9/40 (22%) 6/40 (15%)

ASSERT(Brambatti M et al

Circulation 2014 Mar 14)

18/51 (35%) 4/51 (8%) 8/51 (16%)

IMPACT (all) Martin DT, ACC Session,

2014, March 29

20/69 (29%) n.a. 9/69 (13%)

Temporal Proximity of Silent AF Episodes

to Thromboembolic Event

Visione distorta: ictus da cause

differenti?

Is AF a Cause or a Marker of STROKE?

Stage I Stage II

Stage III Stage IV

Daccarett M, JACC 2011; 57: 831-8

Association of Left Atrial Fibrosis Detected by Delayed-Enhancement MRI and the Risk of

Stroke in AF Patients

387 pts,mean age 65+12 yrs, 36.8% female,9.3% with a history of previous stroke

Hypercoagulability and atrial fibrillation:

a two-way road?

Schematic diagram showing the potential association between hypercoagulability and atrial fibrillation (AF).

On the one hand, AF promotes a hypercoagulable state which is directly associated with the presence of

thrombo-embolic complications. On the other, hypercoagulability induces atrial fibrosis further enhancing AF,

mainly through the activation of the protease-activated receptor (PAR) signalling pathway. IL-6, interleukin-6;

MCP-1, monocyte chemoattractant protein-1; α SMA, α smooth muscle actin; TGFβ1, transforming growth

factor β1.

Eur Heart J. 2016;38(1):51-52

36 Reveal LINQ Insertable Cardiac Monitoring System | Confidential, for Internal Use Only

…

How Much AF Warrants

Anticoagulation?

Will Long-Term Monitoring for AF in

Cryptogenic Stroke Patients Impact

Hard Outcomes?

AF monitoring by pacemakers. The issue of

anticoagulant therapy

Capucci A et al., JACC 2005; 46: 1913-20

725 pts with brady-tachy syndrome, implanted with a MDT AT-

500 followed for 2 years

AF monitoring by pacemakers. The issue of

anticoagulant therapy

a. Lamas GA, NEJM 2002; 346: 1854-62 b. Glotzer TV, Circ Arrhyth Electrophysiol 2009; 2: 474-80

AF monitoring by pacemakers. The issue of

anticoagulant therapy

Subclinical atrial tachyarrhythmia: >6 minutes’ duration, >6 hours’ duration or >24

hours’ duration

ASSERT Trial, NEJM 2012; 366: 120-9

CHADS2 Score, AF Duration and Stroke Risk568 Pts with MDT AT500 IPG Continuously Monitored for 1 Year

No AF at FU (AT/AF < 5 min in 1 day)

5 min < AT/AF Episodes < 24 h

AT/AF Episodes > 24 h

CHADS2 score

0 1 2 3

1.7% 25%0% 0%

1.8% 0%1.3% 2.4%

0% 4.4% 33%4.4%

(3 out of 351 Pts) 0.8 % vs 5 % (11 out of 217 Pts) P = 0.035

Botto GL. J Cardiovasc Electrophys 2009; 20: 241-248

Sensitivity, Specificity and Predictive Ability for the CHA2DS2-VASc stroke risk

score. Relation to AF Burden

Boriani G, Stroke 2011; 42: 1768-70

Ongoing Studies on Pts with Potentially Asymptomatic AF

Study Inclusion criteria Randomization/

Design

Size

(N)

Endpoint Estimated

completion

date

ARTESiA

Apixaban for the Reduction of

Thrombo-Embolism in Patients

With Device-Detected Sub-

Clinical Atrial Fibrillation

Clinicaltrials.gov NCT01938248

Permanent PM, ICD or CRT

CHA2DS2-VASc score of ≥ 4.

Age ≥65

At least one episode of symptomatic AF ≥ 6-min

(Atrial rate >175/min if an atrial lead is present)

but no single episode >24 h in duration.

NO pts with clinical AF

Apixaban 5

(or 2,5) mg x 2

vs

Aspirin 81 mg x1

daily

4,000 1.Composite of

- ischemic stroke

- systemic

embolism

2.Major Bleeding

2019

NOAH AFNET 6

Non-vitamin K Antagonist Oral

Anticoagulants in Patients With

Atrial High Rate Episodes

Clinicaltrials.gov NCT02618577

Permanent PM or ICD.

Age ≥65 + additional CHA2DS2-VASc score point

of ≥ 2, i.e .

CHA2DS2-VASc ≥ 3

At least one episode of AHRE ≥6 min (Atrial rate

>180/min if an atrial lead is present),

but no single episode > 24 h in duration.

NO pts with overt AF

Edoxaban 60 (30 if

renal ins) mg x1

vs

Aspirin 100 mg x1

daily.

Double-blinded

double-dummy

3,400 Composite of time to

- first stroke

- systemic embolism

- CV death

2019

The (Danish) LOOP study

Clinicaltrials.gov

NCT02036450

Age > 70 years and at least one of the following

diseases:

- Diabetes

- Hypertension

- Heart failure

- Previous stroke

ILR

or

Standard

treatment of care

(ratio 1:3)

6,000 Composite of

- ischemic stroke

- systemic

embolism

????

46 Reveal LINQ Insertable Cardiac Monitoring System | Confidential, for Internal Use Only

Quando la posta in gioco è alta e la

causa dello stroke non è così

«CRISTALLINA»