Internal & Cardiovascular Medicine - Stroke Unit ... · University of Perugia, Italy NOAs for stroke prevention in Atrial Fibrillation: potential advantages in the elderly patients

Giancarlo Agnelli Internal & Cardiovascular Medicine - Stroke Unit

University of Perugia, Italy

NOAs for stroke prevention in Atrial Fibrillation:

potential advantages in the elderly patients

• Age as a risk factor for Afib (and related stroke)

• Age in the risk stratification scores

• Aspirin vs. VKA in the elderly patients

• Recent Afib trials with NOAs for stroke prevention

• Elderly patients in the NOAs trials: prevalence & outcome

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Prevalence of AF in US or Europe 4

Go et al., JAMA 2001 50-60% patients over 80% years

• Patients: 1676

Gender

• Males 868 (51.8%)

• Females 808 (48.2%)

Age*

Range: 20-97

Classe età N %

< 65 years 142/1675** 8.5

65-75 years 434/1675 25.9

76-79 years 307/1675 18.3

> 80 years 674/1765 40.2

> 90 years 118/1765 7.0

981

patients

(58.5%)

Age and VKA treatment for Afib

Perugia University Anticoagulation Clinic II






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Risk Factor

CHF / LV dysfunction 1

Hypertension 1

Age > 75 years 1

Diabetes mellitus 1

Stroke / TIA 2

Gage et al. JAMA 2001

CHADS2 Score

Derived from risk factors identified in datasets in non-VKA treated patients

Risk Factor Score

Congestive heart failure / LV dysfunction 1

Hypertension 1

Age ≥ 75 y 2

Diabetes mellitus 1

Stroke / TIA / systemic embolism 2

Vascular disease

(prior myocardial infarction, peripheral artery disease or aortic plaque)

1

Age 65 - 74 y 1

Sex category (i.e. female gender) 1

CHA2DS2 –VASc Score

To identify: truly low-risk patients by being more inclusive

CHADS2 CHA2DS2 -VASc

% in

Ris

k o

f T

hro

mb

oe

mb

oli

sm

Ca

teg

ory

High Risk (score ≥ 2)

Intermediate Risk (score 1)

Low Risk (score 0)

20,4

61,9

17,7

9,2

15,1

75,7

0%

20%

40%

60%

80%

100%

CHADS2 & CHA2DS2 VASc Score

H 1 point Hypertension

A 1 or 2 points Abnormal renal and liver function

S 1 Stroke

B 1 Bleeding

L 1 Labile INRs

E 1 Age (e.g. age > 65 years)

D 1 or 2 points Drugs or alcohol

Pisters et al., Chest 2010

3 points: 3.5%/years

HAS-BLED bleeding risk score






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• 973 people aged ≥ 75 in AF (mean age 81)

• Aspirin 75mg vs. Warfarin target INR 2.5

• Mean follow up 2.7 years

• Primary outcome measure:

– Fatal or disabling stroke (ischemic or haemorrhagic) or

other intra-cranial haemorrhage or systemic embolus

• Warfarin 1.8% v aspirin 3.8%

• RR 0.48 (0.28-0.80)

• NNT: 50 for 1 year

• p = 0.0027

Lancet Aug 2007

BAFTA

Stroke/systemic embolism

Connolly et al., N Engl J Med. 2011

Apixaban Aspirin

No. of

events

(%/yr)

No. of

events

(%/yr)

p

value

Patients (n) 2,808 2,791

Major

bleeding

44

(1.4%)

39

(1.2%)

0.57

Minor

bleeding 188 153 0.05

Cu

mu

lati

ve

ha

za

rd

Months

Hazard ratio with apixaban, 0.45

(95% CI, 0.32–0.62)

0 3 6 9 12 18

0.01

0.02

0.03

0.05

0.04

0.00

Aspirin

Apixaban

p < 0.001

Bleeding events

AVERROES: efficacy & safety






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• Rely

• Rocket-AF

• Aristotle

• Engage

• Averroe

NOACs: prevention of stroke in AFib

Connolly et al., N Engl J Med. 2009

Dabi.

110 mg

(%/y)

Dabi.

150 mg

(%/y)

Warf.

(%/y)

p,

dabi.

110 m

mg vs.

warf.

p,

dabi.

150 mg

vs warf.

Patients (n) 6,015 6,076 6,022

Severe

bleeds 2.71 3.11 3.36 0.003 0.31

life-

threatening

non-life

threatening

gastro-

intestinal

1.22

1.66

1.12

1.45

1.88

1.51

1.80

1.76

1.02

< 0.001

0.56

0.43

0.037

0.47

< 0.001

Stroke/systemic embolism Bleeding events

0.01

0.02

0.03

0.05

0.04

Cum

ula

tive

hazard

rate

Years 0 0.5 1.0 1.5 2.0 2.5

0.0

Warfarin

Dabigatran etexilate 110 mg b.i.d.

Dabigatran etexilate 150 mg b.i.d.

RELY (dabigatran)

* Based on protocol-compliant, on-treatment population.

Days from randomization

Cu

mu

lati

ve

ev

en

t ra

te (%

)

Rivaroxaban Warfarin

Event rate

(%/year) 1.71 2.16

Stroke and non-CNS embolism*

Rivaroxaban Warfarin p

value Rate

(%/year)

Rate

(%/year)

Major and

clinically relevant non-major

14.91 14.52 0.442

major 3.60 3.45 0.576

clinically

relevant non-major

11.80 11.37 0.345

Patel et al. N Engl J Med., 2011

0

1

2

3

4

5

6

0 480 600 720

Warfarin

Rivaroxaban

HR (95% CI): 0.79 (0.66–0.96)

Non-inferiority p < 0.001

120 240 360 840 960

Bleeding events

ROCKET- AF (rivaroxaban)

21% RRR 31% RRR

ISTH major bleeding Stroke or systemic embolism

Median TTR 66%

Apixaban 212 patients, 1.27% per year

Warfarin 265 patients, 1.60% per year

HR 0.79 (95% CI, 0.66–0.95); P=0.011

Apixaban 327 patients, 2.13% per year

Warfarin 462 patients, 3.09% per year

HR 0.69 (95% CI, 0.60–0.80); P<0.001

ARISTOTLE: (apixaban)

Kaplan-Meier of primary efficacy outcome ITT population

Warfarin

Edoxaban 60 mg (HR=0.87, 0.73–1.04)

Edoxaban 30 mg (HR=1.13, 0.96–1.34)

8

6

4

2

0

Str

oke o

r syste

mic

em

bolic

eve

nt

(%)

0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

No.at risk

Warfarin 7036 6798 6615 6406 6225 4593 2333 536

Edoxaban (60)7035 6816 6650 6480 6283 4659 2401 551

Edoxaban (30)7034 6815 6631 6461 6277 4608 2358 534

Years

Giugliano et al. N Engl J Med 2013; e-pub ahead of print

(TTR 68.4%)

Kaplan-Meier of principal safety outcome

Warfarin

Edoxaban 60 mg (HR=0.80, 0.71–0.91)

Edoxaban 30 mg (HR=0.47, 0.41–0.55)

12

10

8

6

4

2

0

Majo

r b

leed

ing

(%

)

0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

No.at risk

Warfarin 7012 6166 5630 5278 4941 3446 1687 370

Edoxaban (60)7012 6039 5594 5232 4910 3471 1706 345

Edoxaban (30)7002 6218 5791 5437 5110 3635 1793 386

Years

Median TTR=68.4%







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• Rely:

41% older than 75 years


• Rocket-AF



• Aristotle

• 31% older than 75 years

NOACs: prevention of stroke in AFib

• 3016 (17%) people aged ≥ 80 years

• 720 (4%) people aged ≥ 85 years

• 79 (0.45) aged ≥ 90 years

– Stroke & SSE ≥ 80 years

– Dabigatran 110 bid vs. warfarin: HR 0.68


– ICH≥ 80 years



Lancet Aug 2007

RELY

%/year

Age ≥ 75 years Age < 75 years

p-

value*

R

N=3082

W

N=3082 HR (95% CI)

R

N=3999

W

N=4088 HR (95% CI)

Stroke/SE1 2.29 2.85 0.80 (0.63-1.02) 2.00 2.10 0.95 (0.76-1.19) 0.31

Fatal/disabling

stroke1

1.14 1.50 0.76 (0.55-1.06) 0.90 1.09 0.83 (0.60-1.15) 0.72

Mortality2 2.08 2.49 0.84 (0.64-1.07) 1.71 2.01 0.85 (0.66-1.09) 0.93

Major

bleeding3

4.86 4.40 1.11 (0.92-1.34) 2.69 2.79 0.964 (0.78-

1.19)

0.34

ICH3 0.66 0.83 0.80 (0.499-

1.282)

0.37 0.68 0.54 (0.33-0.89) 0.27

CRNMB3 15.61 13.54 1.15 (1.03-1.23) 9.22 9.87 0.94 (0.83-1.05) 0.01

Halperin JL et al. presented at AHA 2012

R=rivaroxaban; W=warfarin; *p-value for interaction; ICH=intracerebral haemorrhage;

CRNMB=clinically relevant non-major bleeding 1ITT population, 2 safety population excluding a GCP violating site, 3safety population

ROCKET- AF

Subgroups: efficacy

Subgroup Edoxaban

Hazard Ratio

with High (95% CI)

Interaction

p-value

Hazard Ratio

with Low (95% CI)

Interaction

p-value

Patients 60 mg 30 mg Warfarin Edoxaban 60 mg vs warfarin Edoxaban 30 mg vs warfarin

All Patients 21105 1.57 2.04 1.80

Age Group

<75 years ≥75 years

12631 8474

1.35 1.91

1.71 2.55

1.48 2.31

0.59 0.87

Sex

Male Female

13065 8040

1.45 1.76

1.86 2.32

1.68 2.00

0.97 0.76

Region

North America Latin America

Western Europe

Eastern Europe Asia

4681 2661

3236

7144 3383

1.24 1.61

1.84

1.52 1.86

1.63 2.15

1.94

2.14 2.43

1.56 2.50

1.53

1.60 2.37

0.25 0.32

Race

White Non-White

17067 4037

1.53 1.74

1.95 2.43

1.68 2.34

0.28 0.49

0.5 0.75 1 1.5 2 2.5

Edoxaban better Warfarin better

0.5 0.75 1 1.5 2 2.75

Edoxaban better Warfarin better


Subgroups: safety

Subgroup Edoxaban Hazard Ratio with

High (95% CI) Interaction

p-value Hazard Ratio with

Low (95% CI) Interaction

p-value

Patients 60 mg 30 mg Warfarin Edoxaban 60 mg vs warfarin Edoxaban 30 mg vs warfarin

All Patients 21026 2.75 1.61 3.43

Age Group <75 years ≥75 years

12594 8432

2.02 4.01

1.23 2.26

2.62 4.83

0.57 0.95

Sex Male Female

13020 8006

2.90 2.48

1.66 1.54

3.47 3.35

0.34 0.78

Region North America Latin America Western Europe Eastern Europe Asia

4665 2651 3220 7121 3369

4.07 2.65 3.26 1.44 3.51

2.57 1.66 1.40 0.99 1.87

4.47 3.74 3.98 2.17 4.12

0.50 0.35

Race White Non-White

17008 4017

2.72 2.88

1.58 1.76

3.23 4.32

0.16 0.34

Edoxaban better Warfarin better Edoxaban better

0.6 0.8 1 1.2 1.4 0.2 0.3 0.4 0.6 0.8 1


0,30 0,23

0,50

0,33 0,39

0,26

0,74 0,74 0,70 0,80 0,85 0,85

0

1

2

RE-LY 150 mg

RE-LY 110 mg

ROCKET-AF ARISTOTLE ENGAGE 60 mg

ENGAGE 30 mg

NOAC Warfarin

Phase III AF trials: intracranial hemorrhage

P<0.001 P<0.001 P=0.02

P<0.001 P<0.001 P<0.001

1. Connolly et al. N Engl J Med 2009;361:1139–1151; 2. Patel et al. N Engl J Med 2011;365:883–891

3. Granger et al. N Engl J Med 2011;365:981–992; 4. Giugliano et al. N Engl J Med 2013; e-pub ahead of print

Patien

ts w

ith

IC

H (

%)

• Although safer than VKA, NOAs hold the risk of bleeding

• NOAs should be given for approved indications at validated

doses (assessing the potential benefit in the individual

patient)

• Patients should receive a complete information about the

NOAs treatment at the start-up visit

• An adherence to treatment plan as well as a follow-up plan

with regular visits should be set-up

• A hospital police to deal with bleeding complications and

emergency surgery should be set-up and spread-out

Responsible use of NOAs

Internal & Cardiovascular Medicine - Stroke Unit ... · University of Perugia, Italy NOAs for stroke prevention in Atrial Fibrillation: potential advantages in the elderly patients

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