AF in Asian: which NOAC to choose for particular patient and at what dose?

DEJIA HUANG

West China Hospital of Sichuan University, Chengdu, China

Case report 64-year-old Chinese man with history of hypertension, COPD and

paroxysmal AF;

Persistent AF since 3 months ago;

No other underlying diseases.

BP: 136/82 mmHg. No chest pain;

No renal or liver dysfunction.

Medications: Perindopril 8mg daily, Verapamil 80mg tid

What is the risk of stroke and major bleeding for this Chinese man

CHA2DS2-VASc

Score

Stroke rate (%

per year)

0 0

1 1.3%

2 2.2%

3 3.2%

4 4.0%

5 6.7%

6 9.8%

7 9.6%

8 6.7%

9 15.2%

Risk of Stroke

HAS-BLED

Score

Bleeding rate (%

per year)

0 1.13%

1 1.02%

2 1.88%

3 3.74%

4 8.7%

≥5 12.5%

Risk of Bleeding

——Am Heart J 2006; 151:713——Eur Heart J 2010; 31:2369

What is the risk of stroke?According to a “real world” cohort of Chinese AF patients in Hong Kong (n=9727), the risk of stroke is 6.64% per year.

——Siu CW et al. Heart Rhythm 2014; 11:1401

What is the risk of stroke?According to Taiwan AF cohort (n=186,570), the risk of stroke is 2.11% per year.

——Chao TF, et al. Heart Rhythm 2016; 13:46

What is the risk of stroke?According to Taiwan BNHI database (n=7920),

the risk of stroke is 0.5% per year.

——Lin LY, et al. Atherosclerosis 2011; 217: 292

What is the risk of stroke?According to Swedish National Register data (n=140,420), the risk of stroke is 0.7% per year.

What is the really risk of stroke for this Chinese man?

1.3% per year (Euro Heart Survey 2006)

6.64% per year (Hong Kong Cohort 2014)

2.11% per year (Taiwan AF Cohort 2016)

0.50% per year (Taiwan BNHI database 2011)

0.70% per year (Swedish National Register data)

Which one do you choose?

How do you predict the stroke risk for this patient?

The tricky part is that the risk of stroke for this patient with CHA2DS2-VASc score of 1 may range from 0.5% to 6.64% yearly according to different cohorts.

Everyone who take an anticoagulant incurs an increased risk of bleeding. If he was at low risk of stroke, he may get no net clinical benefit from the drug.

What is the threshold of stroke risk for net benefit of anticoagulation (Warfarin Vs. NOACs): 1% or 2%?

Do you prescribe an anticoagulant for this patient?

Warfarin?

Risk of stroke: Hong Kong Cohort: 6.64%

Taiwan AF Cohort: 2.11%

Risk of bleeding: 1.88% (HAS-Bled)?

NOACs? If the risk of stroke for this patient is less than 2% per year: Euro Heart Survey 1.3%, Taiwan BNHI data 0.50%, and Swedish National Register data 0.70%.

NOAC Vs. Warfarin

INR2-3

Therapeutic window of dabigatran: not so broad

NOACs Vs. WarfarinAll cause mortalityRisk ratio (95%CI)

Major bleedingRisk ratio (95%CI)

RE-LY (150mg) 0.88 (0.77-1.00) 0.94 (0.82-1.07)

ROCKET-AF 0.92 (0.82-1.03) 1.03 (0.90-1.18)

ARISTOTLE 0.89 (0.80-0.99) 0.71 (0.61-0.81)

ENGAGE-AF (60mg) 0.92 (0.83-1.01) 0.80 (0.71-0.90)

Combined(n=58,498)

0.90 (0.85-0.95)P=0.003

0.86 (0.73-1.00)P=0.06

——Ruff CT, et al. Lancet 2014; 383:955

——Hori M et al. 2nd Asia Pacific Stroke Conference.

Rates of Major Bleeding in Asian Patients

in RE-LY Trial%

/

Ye

ar

Which of the NOACs will you prescribe to our patient and at what dose?

A) Dabigatran (150mg or 110mg Bid)

B) Rivaroxaban (20mg or 15mg Qd)

C) Apixaban (5mg or 2.5mg Bid)

D) Edoxaban (60mg or 30mg Qd)

Safety of NOACsDabigatran

Rivaroxaban ApixabanEdoxaban

110 150 60 30

Major bleeding

(% per year)2.71 3.11 3.6 2.13 2.75 1.61

Fatal bleeding

(% per year)1.22 1.45 0.2 — 0.21 0.13

Intracranial bleeding

(% per year)0.23 0.30 0.5 0.33 0.39 0.26

——Data from DE-LY, ROCKET-AF, ARISTOTLE and ENGAGE-AF trials

Major bleeding in ENGAGE-AF trial

3.43%

2.75%

1.61%

0.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%

3.5%

4.0%

Warfarin Edoxaban 60mg Edoxaban 30mg

P<0.01P<0.01

——Giugliano RP, et al. NEJM 2013; 369:2093

Reduced bleeding ≈ Reduced mortality: lower dose may be better

-100

-80

-60

-40

-20

0

Edoxaban 60mg—Warfarin

Edoxaban 30mg—Warfarin

Prior non-fatal bleeds

Bleeds contributed todeath

Fatal bleeds

-59

-88——Giugliano RP, et al. ESC 2014

Low Vs. High dose

More ischemic events but less bleeding;

Preventing excess drug exposure in vulnerable patients.

Dose reduction in NOAC trials RE-LY: 2-dose regimens: 110mg Vs. 150mg Bid;

ROCKET-AF: 20 15mg Qd for CrCl 30-49ml/min;

ARISTOTLE: 5 2.5mg Bid for any tow: age ≥ 80 years, body weight ≤ 60kg and serum creatinine ≥ 1.5mg/dL;

ENGAGE-AF: 60-30mg Qd or 30-15mg Qd for CrCl 30-50ml/min; body weight ≤ 60kg; use of Quinidine or Verapamil.

——Heidbuchel H, et al. EHRA guideline Europace. 2013; 15: 625

Dose reduction preserved efficacy: ENGAGE-AF trial

1.80%1.53%

2.68%

1.57%1.33%

2.32%

3.14%

0.0%

0.5%

1.0%

1.5%

2.0%

2.5%

3.0%

3.5%

WarfarinN=7036

WarfarinN=1787

WarfarinN=5249

All patients

EdoN=14059

Edo 60→30 and 30→15

N=3569

EdoN=10490

Edo 30→15N=1785

No Dose Reduction

Dose Reduction

P=0.97

SS

E (

% p

tsp

er

ye

ar)

SSE: Stroke or systematic embolism

Dose reduction with better safety: ENGAGE-AF trial

3.43%3.02%

4.85%

2.75% 2.66%3.05%

1.50%

0.0%

1.0%

2.0%

3.0%

4.0%

5.0%

6.0%M

ajo

r b

lee

din

g (

% p

tsp

er

ye

ar)

All patients No Dose Reduction

Dose Reduction

EdoN=14059

Edo 60→30 and 30→15

N=3569

EdoN=10490

Edo 30→15N=1785

WarfarinN=7036

WarfarinN=1787

WarfarinN=5249

P=0.02

Our patient: my choice 1) Apixaban 5mg or 2.5mg Bid;

2) Edoxaban 30mg Qd (Verapamil 53%);

3) Rivaroxaban 20mg or 15mg Qd;

4) Dabigatran 110 or 75mg Bid (Verapamil 12-180%)