NOAC trials for AF: A review - APHRS trials for AF.pdf · NOAC trials for AF: A review Chern-En Chiang, MD, PhD, FACC, FESC General Clinical Research Center Division of Cardiology

NOAC trials for AF:

A review

Chern-En Chiang, MD, PhD, FACC, FESCGeneral Clinical Research Center

Division of CardiologyTaipei Veterans General Hospital

National Yang-Ming UniversityTaipei, Taiwan

Presenter Disclosures

• Research Grant: nothing to disclose

• Honorarium: has spoken at symposia

sponsored by and served on scientific advisory

boards for Astrazeneca, Bayer, Boehringer

Ingelheim, Chugai, Daiichi-Sankyo, GSK, MSD,

Novartis, Pfizer, Roche, Sanofi-aventis, Servier,

Tanabe, Takeda, TTY

• Stockholding: None

• Role of aspirin in Asians

• Role of warfarin in Asians

• Role of NOACs in Asians

• Reversal agents

• Asian algorithm

Outlines

1. ASA is not effective in cohort

studies in Asia

Aspirin and warfarin in Chinese

Siu et al. Heart Rhythm. 2014 Aug;11(8):1401.

• 9,727 AF patients in HK, mean age 77 y, FU 3.2 years

CHADS2

CHA2DS2-VASc

Aspirin

-18.7%

-18.7%

Warfarin

-52.7%

--52.7%

2. ASA is not effective in RCT in Asia

Stroke 2006;37;447-451

JAST

Stroke 2006;37;447-451

3. ASA is worse than NOACs

AVERROES Trial

ASA(81-324 mg daily; up to 36 mo/end of study)

Apixaban(5 mg twice daily; 2.5 mg in selected patientsa; up to 36 mo/end of study)

E

Unsuitable for warfarin therapy

N= 5600Double-blindR

Connolly S, N Engl J Med 2011;364:806

Cu

mu

lative

Ris

k

0.0

0.0

10.0

30.0

5

0 3 6 9 12 18 21

ASA

Apixaban*

No. at RiskASA

Apix

2791 2720 2541 2124 1541 626 329

2809 2761 2567 2127 1523 617 353

Months

RR=0.4595% CI, 0.32-0.62

P<.001

AVERROES: Stroke or Systemic Embolic Event


*Apixaban is not FDA approved.

-55%

Fewer hemorrhagic stroke and ICH in Apixaban group

0.670.851 1

0

1

2

Hemorrhagic stroke ICH

Apixaban

HR


Chi-Wai HO, …Chung-Wah Siu, Stroke, 2015 Jan;46(1):23-30

Annual incidence of ICH

Real Life data from Hong Kong

110 mg




• Reversal agents

• Asian algorithm

Outlines

1. It is very difficult for Asians to

maintain optimal INR (2.0-3.0)

RE-LY AF registry

2. A lower INR, which is common in

Asia, could not protect your patients

from Stroke!

17.6

11.9

8.36

4.4 3.3 2.5 2 1.5 1.2 10

10

20

1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9

INRHylek EM, et al. N Engl J Med 1996;335:540

2.0

Low INR is not protective from strokeA

dju

ste

d O

dd

s r

ati

o

********

*

** P<0.05

3. In Asians, even a lower INR could

not protect you from bleeding!

35.419.8

37.1 29.1 28.6 18 28.4 22.2

54.566.2

50.3 55.2 6067

63.6 65

10.1 14 12.6 15.7 11.4 15 8 12.8

0%

50%

100%

INR>3.0

RE-LY ROCKET ARISTOTLE ENGAGE

Lip GYH, Wang KL, Chiang CE. Int J Cardiol 2015 Feb 1;180C:246

3.53 3.43

3.3

3.82

5.14

3.84

4.8

0

3

6


Non-…Asians

%

Major bleeding (Warfarin)More bleeding occurs even at lower INR range


0.71 0.63 0.67 0.74

1.1

2.46

1.88 1.92

0

1.5

3


Non-…Asians

%

Intra-cranial hemorrhage (Warfarin)More bleeding occurs even at lower INR range


4. In Asians, even a high TTR could

not protect you from hemorrhagic

stroke!

Time in Therapeutic Range for

Warfarin-treated Patients

INR 1.6─2.6 ≥70 years

% T

ime in t

hera

peutic r

ange (

media

n)

Yukihiro Koretsune, JCS2014

Hemorrhagic stroke

2.61

0.840.70.42

0.72

0.21

0

1

2

3

China Japan

Warfarin

Edoxaban 60

Edoxaban 30

%/y

5. Intra-cranial hemorrhage (ICH) is

more catastrophic in Asians!

Warfarin associated intracerebral

hemorrhage in Hong Kong Chinese

• The mean INR on presentation was 2.9 ± 1.0

• The mortality rate at 3-6 months for WICH

was 62.0%

Neurol Res. 2014 Feb;36(2):143




• Reversal agents

• Asian algorithm

Outlines

(NOACs)Non-vitamin K antagonist Oral Anti-Coagulants

(NOACs)

Lancet. 2014;383:955

• 4 trials

• N= 71,683 patientsGlobal

Wang, Lip, Lin, and Chiang, Stroke. 2015 Sep;46(9):2555-61

• 5 trials– Asians = 8,928 patients

– Non-Asians = 64,033 patients

Asians vsNon-Asians

Standard doses

• Dabigatran 150 mg

• Rivaroxaban 20 mg

• Apixaban 5 mg

• Edoxaban 60 mg

Lancet. 2014;383:955 Wang, Lip, Lin, and Chiang, Stroke. 2015 Sep;46(9):2555-61

Lancet. 2014;383:955

Stroke and systemic embolism

Global

-19%

P<0.0001

Stroke and systemic embolism

-35%

-15%

Interaction P=0.045

Asian

Non-Asian


Lancet. 2014;383:955

All-cause-mortality

Global

-10%

P=0.0003

All-cause mortality

-20%

-9%

Interaction P=0.219

Asian

Non-Asian


Lancet. 2014;383:955

Major bleeding

Global

-14%

P=0.06

Major bleeding

-43%

-11%

Interaction P=0.004

Asian

Non-Asian


Lancet. 2014;383:955

Hemorrhagic stroke

Global

-51%

P<0.0001

Hemorrhagic stroke

-68%

-44%

Interaction P=0.046

Asian

Non-Asian


Lancet. 2014;383:955

Gastrointestinal bleeding

Global

+25%

P=0.043

Gastrointestinal bleeding

-21%

+44%

Interaction P=0.041

Asian

Non-Asian


Low doses

• Dabigatran 110 mg

• Rivaroxaban 15 mg (J-ROCKET)

• Edoxaban 30 mg

Lancet. 2014;383:955 Wang, Lip, Lin, and Chiang, Stroke. 2015 Sep;46(9):2555-61

Global

Ruff, Lancet. 2014;383:955

-67%V

-69%V

Ischemic stroke

Global+28%P=0.046

Ruff, Lancet. 2014;383:955

Ischemic stroke

+6%

+29%

Interaction P=0.504

Asian

Non-Asian


Lancet. 2014;383:955

Myocardial infarction

Global

+25%

P=0.019


-8%

+28%

Interaction P=0.352

Asian

Non-Asian


NOACs in Asia

• Standard dose

Efficacy:

NOACsWarfarin

Safety:

NOACswarfarin

• Low dose

Efficacy:

NOACsWarfarin

Safety:

NOACswarfarinWang, Lip, Lin, and Chiang, Stroke. 2015 Sep;46(9):2555-61

0.0 0.5 1.0 1.5 2.0

1.14 (0.97-1.61)1.08 (0.73-1.61)

0.88 (0.75-1.05)0.71 (0.46-1.10)

0.81 (0.66-0.99)0.74 (0.50-1.10)

0.89 (0.75-1.05)0.78 (0.44-1.39)

0.93 (0.74-1.17)0.81 (0.54-1.21)

0.72 (0.56-0.92)0.45 (0.28-0.72)

Non-AsianAsian

Edoxaban 30mg o.d.Non-AsianAsian


Apixaban 5mg b.d.Non-AsianAsian

Rivaroxaban 20mg o.d.Non-AsianAsian

Dabigatran 110mg b.d.Non-AsianAsian

Dabigatran 150mg b.d.

Stroke and SEEin Asian vs non-Asian in 4 RCTs

V

Warfarin betterNOACs better


0.0 0.5 1.0 1.5 2.0

1.38 (1.15-1.64)1.77 (0.93-3.36)

1.01 (0.83-1.22)0.64 (0.28-1.46)

0.86 (0.68-1.10)1.17 (0.74-1.85)

0.94 (0.75-1.17)0.94

1.17 (0.89-1.53)1.01 (0.63-1.61)

0.82 (0.61-1.10)0.55 (0.32-0.95)

Non-AsianAsian







Ischemic strokein Asian vs non-Asian in 4 RCTs

V



0.0 0.5 1.0 1.5 2.0

0.32 (0.20-0.51)0.36 (0.15-0.86)

0.57 (0.39-0.84)0.40 (0.18-0.92)

0.62 (0.41-0.96)0.25 (0.10-0.62)

0.59 (0.37-0.93)0.40 (0.13-1.27)

0.37 (0.19-0.72)0.15 (0.03-0.66)

0.28 (0.13-0.58)0.22 (0.06-0.77)

Non-AsianAsian







Hemorrhagic strokein Asian vs non-Asian in 4 RCTs

V

V

V

V

V



Efficacy and safety endpoints of different NOACs in Asians

Stroke/SSE Ischemic stroke

Hemorrhagic stroke


All-cause death

Major bleeding Intra-cranial hemorrhage

GI bleeding Bleeding of any cause

Dabigatran 150 mg V V V V V V

Dabigatran 110 mg V V V V

RivaroxabanV NR

ApixabanV V V NR V

Edoxaban60 mg V V V V V

Edoxaban 30 mg V V V V


Efficacy and safety endpoints of different NOACs in non-Asians

Stroke/SSE Ischemic stroke

Hemorrhagic stroke


All-cause death

Major bleeding Intra-cranial hemorrhage

GI bleeding Bleeding of any cause

Dabigatran 150 mg V V V X

Dabigatran 110 mg V V V V

RivaroxabanV V X

ApixabanV V V V V V

Edoxaban60 mg V V V X V

Edoxaban 30 mg X V V V V V

Chiang, Wang, Lin, Europace. 2015 Oct;17 Suppl 2:ii31-ii39

Real-life data of dabigatran in Asia:

Taiwan experience

• Dabigatran (n=9940) and warfarin (n=9913)

non-valvular atrial fibrillation patients

• 88% taking dabigatran 110 mg

Stroke 2016 Feb;47(2):441

Stroke 2016 Feb;47(2):441

-38%

Stroke 2016 Feb;47(2):441

-56%

Stroke 2016 Feb;47(2):441

-42%

-55%

Low dose dabigatran (110 mg)Major

bleeding ICH

69%

Ischemic

strokeAll-cause

mortality

GlobalRE-LY

9% 20%

Asian meta-analysis

Wang

Hong Kong

Chan

79% 43% 43%

32% 71%

11%

3%

Taiwan NHIRD

Chan56% 38% 55% 42%

NS

NS

NS




• Reversal agents

• Asian algorithm

Outlines

Non-valvular AF

CHA2DS2-VASc score

1 (male)0 (male) or 1 (female)Ie. ‘low risk’

2

No antithrombotic

therapy

NOACsDabigatranApixaban

NOACsDabigatranEdoxabanApixaban

RivaroxabanLip GYH, Wang KL, Chiang CE. Int J Cardiol 2015 Feb 1;180C:246

Summary (I)

• Aspirin has no role in stroke prevention in AF in Asians

• Warfarin should only be spared for those in whom NOAC is contraindicated

• In our meta-analysis, standard-dose NOACs were more effective and safer in Asians than in non-Asians. The increased risk of GI bleeding was not found in Asians.

• Low-dose NOACs performed similarly in efficacy in both populations, but the safety was much better than warfarin in both populations. Increased risk of myocardial infarction was not found in Asians.

• All NOACs are preferable over warfarin

• NOACs is now revolutionizing SPAF in Asians

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Documents

NOAC trials for AF: A review - APHRS trials for AF.pdf · NOAC trials for AF: A review Chern-En Chiang, MD, PhD, FACC, FESC General Clinical Research Center Division of Cardiology