Antonio Manari U.O. Cardiologia Interventistica  

Azienda Ospedaliera Santa Maria Nuova Reggio Emilia

La chiusura dell’auricola per la prevenzione dello stroke nel

paziente con FA

S. Margherita  17 febbraio 2012

Istituto di Ricovero e Cura a Carattere Scientifico

Who Gets Atrial Tachyarrhythmias?Atrial Fibrillation Demographics by Age

Feinberg WM, Blackshear JL, Laupacis A. Arch Intern Med. 1995;155:469-473

0%

5%

10%

15%

20%

25%

30%

35%

40%

50-59 60-69 70-79 80-89

Prevalence of AF

Strokes Attributable toAF

Prevalence of AF and Strokes attributable to AF by age.

Framingham Study, Wolf, 1991

Efficacy of Antithrombotic Treatment in Non-ValvularAtrial Fibrillation

META ANALYSIS• 26 Trials

• 28,044 Patients

• Mean Age 71 Years

• Mean Follow up 1.5 years

Comparison Trials Patients Reduction in Stroke

Warfarin Vs. Control 6 2,900 64%

Antiplatelet agents vs. control 8 4,876 22%

Warfarin vs. Antiplatelet 12 12,963 39%

Har RG, Ann Intern Med 2007; 146:857-86

warfarin better control better

AFASAK

SPAF

BAATAF

CAFA

SPINAF

EAFT

100% 50% 0 -50% -100%

Aggregate

Anticoagulation in atrial fibrillationStroke risk reductions

Stroke:RRR 62%

All-cause mortality: RRR 26%

Severe bleedings:1.2%/year

Warfarin is the gold standard in patients with atrialfibrillation.

Eur Heart J 2010

ESC Guidelines 2010 on the management of Atrial Fibrillation

“REAL WORLD” USE OF WARFARIN IN AF PATIENTS WITHOUT CONTRAINDICATIONS”

%

0 10 20 30 40 50 60Bath et al, 1993

Lip et al, 1994Stafford & Singer, 1996

Albers et al, 1997Whittle et al, 1997

Gurwitz et al, 1997Brass et al, 1997

Sudlow et al, 1998CQInv, 1998

Samsa et al, 2000McCormick et al, 2001

Harrold et al, 2002

2936

3220

4431

282324 34

4253

44,3

58,1 60,7 57,3

35,4

010203040506070

<55 55-64 65-74 75-84 85

Non-Valvular Atrial Fibrillation Warfarin use in AF Patients by Age

%

Ann Int Med 131(12), 1999

• Only 55% of AF patients with no contraindications have evidence of warfarin use in previous 3 months

• Other studies cite warfarin use in AF patients from 17-50%• Elderly patients with increased absolute risk least likely to be taking warfarin• Contraindications 30-40%

Age-related trends in AF

Age, years69-79 80-89 >89

100

80

60

40

20

0

Wolf PA, Arch Intern Med 1987; 147:1561-4White RH, Am J Med 1999; 106:165-71

Unmet need

Narrow anticoagulant therapeutic window

Stroke risk increases at INR < 2Bleeding risk increases at INR >3

Hylek EM et al, N Engl J Med 1996; 335: 540-546

11

0 20 40 60 80 100

Non-Valvular Atrial Fibrillation Adequacy of Anticoagulation in Clinic

%Bungard, Pharmacotherapy 20:1060, 2001

Low INR <1.6

TherapeuticINR 2-3

High INR >3.2

Efficacy 4-fold

ORAL ANTICOAGULATION AND RISK OF BLEEDING

ISCOAT Study 2,745 pts

Palareti et al, Arch Intern Med 2000; 160: 470-478

0

2

4

6

8

10

ELDERLY PTS YOUNG PTS

2.1 1.1

9.9

6.6

Major bleeds All bleedsN= 461

Age > 75 (79.9)N= 461

Age < 70 (56.5)

PT / Y

EAR

%

ns

RCT’s & WarfarinINR al momento dello Stroke

AFASAK SPAF I BAATAF SPINAFCAFA1.0

2.0

3.0

4.01.71.61.51.41.31.21.11.0

INRRatio

PTRatio

(ISI 2.4)

ACCP raccomandazioni: INR: 2.0–3.0

1.8

Target range per ogni studio

Risk adjusted percent time in therapeutic range as a quality indicator for out-patient oral anticoagulation: results of the Veterans Affairs Study to ImproveAnticoagulation (VARIA).

Rose AJ, Circ Cardiovasc Qual Outcomes 2011;4:22-9

In a recent analysis of anticoagulation management involving more than 120,000 patients in the Veterans Affairshealth care system, the mean proportion of time in the therapeutic range was 58%, with significant variationacross Sites.

Percentuale di tempo con INR in rangein RCTs in era contemporanea

0102030405060708090

100

Rivaroxaban Apixaban Dabigatran

5562,2 64

%

(2011) (2011) (2009)

15

19

23

27

Rivaroxaban Warfarin

23,722,2

Rocket-AF% sospensione del farmaco

1519232731

Apixaban Warfarin

25,327,5

ARISTOTLE%sospensione del farmaco

15

19

23

Dab 110 Dab 150 Warfarin

21 21

17

RE LY%sospensione del farmaco

Aderenza alla terapia nei RCTs in era contemporanea

Rocket-AF

• The median duration of treatment exposure was 590 days; the medianfollow-up period was 707 days

15

19

23

27

Rivaroxaban Warfarin

23,722,2

% sospensione del farmaco

0

1

2

3

4

5

6

Dab 110 Dab 150 Warfarin

0,82 0,89

2,432,292,6

3,25

4,435,1

4,37

< 65 65-74 >75

0

1

2

3

4

5

6

Dab 110 Dab 150 Warfarin

5,29 5,44 5,41

2,893,33

3,76

1,532,09 2,36

Cl Crea<50 Cl Crea50-70 Cl Crea >80

0

1

2

3

4

5

6

Dab 110 Dab 150 Warfarin

4,34,92

5,95

2,91 3,133,75

2,56

4,013,34

Peso<50 Peso50-99 Peso100

ARISTOTLEApixaban vs Warfarin

a high risk of bleeding (e.g., active peptic ulcer disease, a plateletcount of <100,000 per cubic millimeter or hemoglobin level of <10 g per deciliter, stroke within the previous 10 days, documentedhemorrhagic tendencies, or blood dyscrasias),

Prevenzione dello stroke emboliconella Fibrillazione Atriale

Mechanism of Stroke in Patients with AF

Devices per la chiusura 

percutanea

Left atrial appendage closure

Left atrial appendage closure

Left atrial appendage closure

Left atrial appendage closure

Left atrial appendage closure

Left atrial appendage closure

Left atrial appendage closure

Left atrial appendage closure

Left atrial appendage closure

Left atrial appendage closure

Left atrial appendage closure

April 23, 200941

PROTECT-AF TrialEnrollment Summary

Implant successful in 90.9%(408/449) of attempts

* One or more of the release criteria of acceptable device position, in-situ size (compression), stability, and LAA seal were not met for device release.

Included In Primary Analysis

Randomized PatientsN=707

WarfarinControl Group

N=244

WATCHMANDevice Group

N=463

No AttemptN=14

Device Implanted N=408

Unable to ImplantN=41

Device Release Criteria Not Met*

N=29

N=12

WarfarinStartedN=241

Warfarin NeverStarted

N=3

Implant Attempted

N=449

OtherN = 3

N=10

Window For Procedure Lapsed

Patient Died Before Procedure

N=1

Procedural Event

0,8

0,9

1

Primary Efficacy Results(CV deaths, stroke, systemic embolization)

707 pts with non-valvular AF (CHADS2 ≥1) E

vent

-free

pr

obab

ility

Days

Events Total Rate Events Total Rate Rel. Risk Non-Cohort (no.) pt-yr (95% CI) (no.) pt-yr (95% CI) (95% CI) inferiority Superiority

900 pt-yr 20 582.3 3.4 16 318.0 5.0 0.68 0.998 0.837(2.1, 5.2) (2.8, 7.6) (0.37, 1.41)

Device ControlPosterior

Probabilities

Randomization allocation (2 device : 1 control)

ITT Cohort:patients analyzed based on their randomly assigned group (regardless of treatment received)

244 147 52 12463 270 92 22

WATCHMAN

Control

0,7

0,8

0,9

1

0 365 730 1095

All Stroke

ITT cohort: patients analyzed based on their randomly assigned group (regardless of treatment received)E

vent

-free

pro

babi

lity

Days244 147 52 12463 270 92 22

900 patient-year analysis

Events Total Rate Events Total Rate RR Non- SuperiorityCohort eve pt-yr (95% CI) (no.) pt-yr (95% CI) (95% CI) inferiority

600 14 409.3 3.4 8 223.6 3.6 0.96 0.927 0.488pt-yr (1.9, 5.5) (1.5, 6.3) (0.43, 2.57)

900 15 582.9 2.6 11 318.1 3.5 0.74 0.998 0.731pt-yr (1.5, 4.1) (1.7, 5.7) (0.36, 1.76)

Device Control Posterior probabilities

Randomization allocation (2 device:1 control)

Control

Device

3001664-2

Hemorrhagic Stroke

ITT cohort: patients analyzed based on their randomly assigned group (regardless of treatment received)E

vent

-free

pro

babi

lity

Days244 147 53 12463 275 95 23

900 patient-year analysis

Events Total Rate Events Total Rate RR Non- SuperiorityCohort (no.) pt-yr (95% CI) (no.) pt-yr (95% CI) (95% CI) inferiority

600 1 416.7 0.2 4 224.7 1.8 0.13 0.998 0.986pt-yr (0.0, 0.9) (0.5, 3.9) (0.00, 0.80)

900 1 593.6 0.2 6 319.4 1.9 0.09 >0.999 0.998pt-yr (0.0, 0.6) (0.7, 3.7) (0.00, 0.45)

Device Control Posterior probabilities

Randomization allocation (2 device:1 control)

Control

Device

3001664-2

Events Total Rate Events Total Rate Rel. RiskCohort (no.) pt-yr (95% CI) (no.) pt-yr (95% CI) (95% CI)

900 pt-yr 48 554.2 8.7 13 312.0 4.2 2.08(6.4, 11.3) (2.2, 6.7) (1.18, 4.13)

0,8

0,9

1

Intent-to-TreatPrimary Safety Results

Eve

nt-fr

ee

prob

abili

ty

Days

Device Control

ITT Cohort:patients analyzed based on their randomly assigned group (regardless of treatment received)

244 143 51 11463 261 87 19

WATCHMAN

Control

Randomization allocation (2 device : 1 control)

LAA occlusion

Atrial fibrillation

High risk of stroke– Contraindication to OAC– High risk of bleeding with OAC– Difficult to maintain INR within the therapeutic range– Poor compliance– Difficulty to manage the patient because ol ogistic problems