Modern management of atrial fibrillation, from

blood pressure control to anticoagulation

Adel Khalifa S. Hamad, BMS, MD, FRCP(Canada)

Consultant Cardiologist & Interventional Cardiac Electrophysiologist

Bahrain Defence Force Hospital

Kingdom of Bahrain

December 6th, 2013

Pre

va

len

ce

, %

Age, Yr

Pre

va

len

ce

, %

Age, Yr

Prevalence of AF stratified by age

and gender

European age-related prevalence US age-related prevalence

(n=4053) (n=2590)

(n=7995) (n=10179)

Heeringa J et al. Eur Heart J 2006 Go AS et al, JAMA 2001

1. Dulli DA, et al. Neuroepidemiology 2003;22:118-123. 2. Lin HJ, et al. Stroke 1996;27:1760-1764.

AF-related strokes are associated with greater

disability and a higher mortality rate P

ati

en

ts w

ith

clin

ical

para

mete

r (%

) Disability at clinical presentation1

60

40

0

50

30

20

10

Severe limb weakness Bedridden

P<0.005 P<0.0005

Fata

l str

okes (

%)

30-day post-stroke mortality2

30

20

0

25

15

10

Strokes

with AF (N=103)

Strokes

without AF (N=398)

P<0.048

Strokes without AF (N=845) Strokes with AF (N=216)

Limitations of VKA therapy

Routine coagulation monitoring

Slow onset/ offset of action

Warfarin resistance

Numerous drug–drug interactions

Numerous food–drug interactions

Narrow therapeutic window (INR range 2.0–3.0)

Ansell J, et al. Chest 2008;133;160S-198S. Umer Ushman MH, et al. J Interv Card Electrophysiol 2008;22:129-137.

VKA therapy has several limitations

that make it difficult to use in practice

Frequent dose adjustments

Unpredictable response

INR control: Clinical trials VS. clinical

practice (TTR)

1. Kalra L, et al. BMJ 2000;320:1236-1239;

2. Samsa GP, et al. Arch Intern Med 2000;160:967-973.

Clinical trial1 Clinical practice2,3

<2.0 2.0–3.0 >3.0

Elig

ible

pati

en

ts r

ece

ivin

g W

arf

ari

n

(%)

38%

44%

18%

66%

9%

25%

INR

AK 14/41

Trials of new oral anticoagulants for

SPAF

Factor Xa inhibitors Direct thrombin

inhibitor

RE-LY

• Dabigatran

• ~18 000 pts

• PROBE design

• Mean CHADS2 2.1

• Stroke or systemic embolism

• Major bleeding

ROCKET-AF

• Rivaroxaban

• ~14 000 pts

• Double blind

• Mean CHADS2 3.5

• Stroke or systemic embolism

• Major and non-major clinically relevant bleeding

ARISTOTLE

• Apixaban

• ~18 000 pts

• Double blind

• Mean CHADS2 2.1

• Stroke or systemic embolism

• Major bleeding

AK 18/41

RE-LY® primary efficacy outcome: stroke or

systemic embolism

Dabigatran

110 mg BID

vs. warfarin

Dabigatran

150 mg BID

vs. warfarin

0.50 0.75 1.00 1.25 1.50

<0.001

<0.001

Superiority

P value

0.30

<0.001

Non-

inferiority

P value

Hazard ratio

Marg

in =

1.4

6

Connolly SJ et al. N Engl J Med 2009;361:1139–51; Connolly SJ et al. N Engl J Med 2010;363:1875–6

AK 20/41

ROCKET AF

primary efficacy endpoint ITT

Rivaroxaban

Warfarin

Cu

mu

lati

ve e

ven

t ra

te (

%)

0

1

2

3

4

5

6

Days since randomization

120 480 240 360 600 840 720 0

ITT population

HR=0.88 (0.75, 1.03) p<0.001 (non-inferiority)

p=0.12 (superiority)

Number of subjects at risk

Rivaroxaban 7,081 6,879 6,683 6,470 5,264 4,105 2,951 1,785

Warfarin 7,090 6,871 6,656 6,440 5,225 4,087 2,944 1,783

Stroke or systemic embolism

Patel MR et al. N Engl J Med 2011;365:883–891

AK 26/41

ARISTOTLE

Primary Efficacy Outcome

8726 8440 6051 3464 1754

8620 8301 5972 3405 1768

HR 0.79 (95% CI, 0.66, 0.95)

0 6 12 18 24 30

Months

4

3

2

1

0

Apixaban

Warfarin p (non-inferiority) <0.001

p (superiority) = 0.011

Perc

ent

with e

vent

Granger CB, et al. N Engl J Med. 2011;365:981-92.

21% RRR

Stroke or Systemic Embolism

AK 31/41

AK 1/41

LAA Occlusion procedures

Surgical Percutaneous

• PLAATO system

• WATCHMAN device

• Amplatzer cardiac plug

• LARIAT system

Events Total Rate Events Total Rate Rel. Risk Cohort (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

1.0

0 365 730 1,095

PROTECT AF: Intent-to-Treat

Primary Safety Results E

ve

nt-

fre

e

pro

ba

bili

ty

Days

Device Control

ITT Cohort:

patients analyzed

based on their

randomly assigned

group (regardless of

treatment received)

244 143 51 11

463 261 87 19

WATCHMAN

Control

Randomization allocation (2 device : 1 control)

0.8

0.9

1.0

0 365 730 1,095

Eve

nt-

fre

e

pro

ba

bili

ty

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 Control Posterior

Probabilities

Randomization allocation (2 device : 1 control)

ITT Cohort:

patients analyzed

based on their

randomly assigned

group (regardless of

treatment received)

244 147 52 12

463 270 92 22

WATCHMAN

Control

PROTECT AF: Intent-to-Treat

Primary Efficacy Results

AK 1/41

Mort

alit

y (

%)

Years

30

0 1 2 4

HR = 1.15 95% CI: 0.99–1.34

P = 0.08

3

Rhythm-control

Rate-control

0

25

20

15

10

5

5

AFFIRM: Mortality with rate and rhythm

control strategies

AFFIRM = Atrial Fibrillation Follow-up Investigation of Rhythm Management

Wyse DG et al. N Engl J Med 2002;347:1825–33

AFFIRM: Stroke incidence with rate and

rhythm control strategies

Wyse DG et al. N Engl J Med 2002

Inci

dence

(%

)

0

2

4

6

8

10

Ischaemic stroke

Intracerebral haemorrhage

Subdural/ subarachnoid haemorrhage

All CNS events

Rhythm-control

Rate-control

5.5

7.1

1.1 1.3 0.8

7.4

8.9

0.8

P = 0.79

P = 0.73

P = 0.68

P = 0.93

ATHENA study: Maintenance of sinus rhythm with

dronedarone delays hospitalization for CV causes or death

Hohnloser SH et al. N Engl J Med 2009

Hospitalization due to CV events or death from any cause

Cum

ula

tive inci

dence

, %

Years

60

n =

30

2327

2301

50

40

30

20

0 0 6 12 18 24

10

Placebo

Dronedarone

P<0.001

1858

1963

1625

1776

1072

1177

385

403

3

2

Technique of AF ablation

Ablation of triggering focus Circumferential PV isolation

MANTRA-PAF Medical Antiarrhythmic Treatment or Radiofrequency Ablation in

Paroxysmal Atrial Fibrillation

Cosedis Nielsen J et al, N Engl J Med 2012

MANTRA-PAF Medical Antiarrhythmic Treatment or Radiofrequency Ablation in

Paroxysmal Atrial Fibrillation

Quality of Life Scores

Cosedis Nielsen J et al, N Engl J Med 2012