dayi hu peking university

Dayi Hu

Peking University

PREVENTION OF STROKE IN PATIENTS WITH AF IN

CHINA

Atrial Fibrillation (AF)

The most common significant heart rhythm The most common significant heart rhythm disturbancedisturbance Incidence increases with age and the Incidence increases with age and the development of structural heart diseasedevelopment of structural heart diseaseCommon cause of stroke (10-15% of all strokes)Common cause of stroke (10-15% of all strokes)Associated with significant cardiovascular Associated with significant cardiovascular morbidity and mortality morbidity and mortality Tends to recur in at least half the patients being Tends to recur in at least half the patients being treated with antiarrhythmic drug therapytreated with antiarrhythmic drug therapy

Per

cent

of s

ubje

ct d

ied

in fo

llow

-up

years

Higher Mortality Rate In Patients With AF

Benjamin EJ, Circulation 1998; 946-952

10%

30%

50%

0 1 3 4 652 7 8 9 10

70%

Women, No AF

Men, AF

Women, AF

Men, No AF

men women

Odds Ratio for Death

1.2-1.8 1.5-2.2

The epidemiology of atrial fibrillation

Go: JAMA, 2001Go: JAMA, 2001

Prevalence Prevalence of AF(millioof AF(millio

n)n)

YearYear1990 1995 2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050

0.0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

ATRIA StudyATRIA Study

ATRIAL FIBRILLATION AND STROKE

Thrombembolic stroke

• High Incidence

• Multi-focal and severe

• Prone to hemorrhage

• High mortality

0

10

20

30

Wolf et al. Stroke 1991;22:983-988.

50–59 60–69 70–79 80–89

The Framingham Study: Attributable Risk of Stroke

%

AF prevalence Strokes attributable to AF

Age Range (years)

Ryder KM, et al. Am J Cardiol 1999; 84: 131R-138R.

Prevalence of AF in different countries

5.5%5.4%

≥ 50 yrs, USA (CHS), single ECG≥ 65 yrs, UK, single ECG≥ 60 yrs, Netherlands, single ECG & medical record ≥ 50 yrs, UK, single ECG ≥ 55 yrs, Netherlands, single ECG

≥ 35 yrs, USA, medical record≥ 50 yrs, UK, single ECG Review results≥ 60 yrs, Australia, triennial survey≥ 40 yrs, Japan, single ECG ≥ 60 yrs, Hong Kong, single ECG≥ 35 yrs, Denmark, single ECG25 - 64 yrs, west German, single ECG≥ 15 yrs, India, single ECG0.1%

5.1%3.7%

3.0%2.8%

2.4%1.5%

1.3%1.3%

0.60%0.28%

Estimate of prevalence of AF vary based on the characteristics of population studied and how AF is ascertained.

Atrial Fibrillation Demographics by Age

Adapted from Feinberg WM. Arch Intern Med. 1995;155:469-473.

U.S. population

Population withatrial fibrillation

Age, yr

<5 5-9

10-14

15-19

20-24

25-29

30-34

35-39

40-44

45-49

50-54

55-59

60-64

65-69

70-74

75-79

80-84

85-89

90-94

>95

U.S. populationx 1000

Population with AFx 1000

30,000

20,000

10,000

0

500

400

300

200

100

0

Prevalence of AF is increasing in USA N

umbe

r (×

10,0

00)

1984 19940

5.0

10.0

15.0

20.0

25.0

30.0

11.1

27.0

NEJM 1997 337:1360-1369

% o

f hos

pita

lizat

ion

7.65%7.90%

8.16%

1999 2000 20016.0%

6.5%

7.0%

7.5%

8.0%

9.0%

Qi W, et al. Chinese J Cardiol, 2003 ； 31 ： 913-916

Percent of Hospitalization in Patients with AF Is Increasing in China

Average

7.90%

The Epidemical Investigation of AF in China Fourteen Natural Populations, 13 Different Provinces

Incidence of AF Stratified by Age and Sex in Chinese Population

0

1

2

3

4

5

6

7

8

Age Group, yAge Group, y

Rat

e pe

r 100

Rat

e pe

r 100

30-3930-39 40-4940-49 50-5950-59 60-6960-69 OverallOverall

Men (n=13358)Men (n=13358)

Women (n=15521)Women (n=15521)

0.30.3 0.20.20.50.5 0.60.6

1.41.4 1.11.1

3.63.62.62.6

7.57.5 7.47.4

70-7970-79 ≥≥8080

0.90.9 0.70.7

Data collected from 13 natural populations from 14 different provinces across China

Hu D, et al. 2004 Chin J Intern Med; in press.

Prevalence of AF in China and other countries

5.5%5.4%

≥ 50 yrs, USA (CHS), single ECG≥ 65 yrs, UK, single ECG≥ 60 yrs, Netherlands, single ECG & medical record ≥ 50 yrs, UK, single ECG ≥ 55 yrs, Netherlands, single ECG

≥ 35 yrs, USA, medical record≥ 50 yrs, UK, single ECG Review results≥ 60 yrs, Australia, triennial survey≥ 40 yrs, Japan, single ECG ≥ 60 yrs, Hong Kong, single ECG≥ 35 yrs, main land, China, single ECG≥ 35 yrs, Denmark, single ECG25 - 64 yrs, west German, single ECG≥ 15 yrs, India, single ECG0.1%

5.1%3.7%

3.0%2.8%

2.4%1.5%

1.3%1.3%0.77%0.60%

0.28%

Patients with AF In China 8 million

Hospitalized Patients with AF in China: Causes and Associated Condition

Idiopathic AF

RVD

CHF

CAD

Advanced age

0 40% 50% 60%30%20%10%

58.1%

40.3%Hypertension

caidiomyopathy

34.8%

33.1%

23.9%

7.4%

5.4%

4.1%Diabetes

CAD: coronary artery disease; CHF: congestive heart failure; RVD: rheumatic valve disease

Chinese J Cardiol, 2003 ； 31 ： 913-916

Prevalence of Stroke in Chinese Patients with AF

%

12.95%

24.81%

17.5%

Hu D, 2004 Qi W, 20030

5%

10%

15%

20%

25%

Hu D, 2004Hu D, et al. 2004 Chin J Intern Med; in press. Random sample of population

Qi W, et al. 2003 Chin J Cardiol; 31: 913-916. Case-control study. Hospitalized patients

Hu D, et al. 2003 Chin J Intern Med; 42: 157-161. Case-control study. Hospitalized patients

Prevalence of Stroke in Patients with None Valve AF Stratified by Age

years0

5

10

15

20

25

Prev

alen

ce (

%)

30

>40 40 ～49

60 ～ 6950-59 70 ～79

>80

HU D, et al. Chin J Intern Med, 2003; 42: 157-161

Framingham Heart Study: Significant Multivariable Risk for developing AF

Prior MI

HTN

DM

VHD

CHF

AGE

0 4 5 6321 7 8 9

Male

Female2.1 (1.8-2.5)

2.2 (1.9-2.6) 4.5 (3.1-

6.6)

4.2 (4.2-8.4)1.8 (1.2-

2.5)

3.4 (2.5-4.5)1.4 (1.0-

2.0)1.5 (1.2-2.0)

1.4 (1.1-1.8)1.4 (1.0-

2.0)

1.6 (1.1-2.2)

Benjamin EJ, et al. JAMA, 1994; 271: 840-844

Risk Factors for Stroke in Chinese with Non Vascular AF: A Case-control Study

AGE >76 yrs

Hypertension

Diabetes

LA thrombi

SBP

1.76 (1.08-2.89)

1.52 (1.28-1.80)

1.39 (1.11-1.76)

1.71 (1.21-2.28)

1 2 3 4 5

2.77 (1.25-6.13)

HU D, et al. Chin J Intern Med, 2003; 42: 157-161

0

2

4

6

8

AFASAK58%7– 81

SPAF67%

27– 85

BAATAF86%

51– 96

CAFA42%

- 68– 80

SPINAF79%

52– 90

TOTAL68%

50–79Risk reduction

AF Investigators. Arch Intern Med 1994;154:1449-1457.Atwood et al. Herz 1993;18:27-38.

St ro

ke I n

cid e

n ce

(%)

95% CI

AF Investigators: Meta-analysis

Warfarin for Stroke Prevention

p < 0.03

p < 0.01

p < 0.02

p > 0.2p < 0.002

p < 0.001

Controls Warfarin

Antiplatetet and Anticoagulation showed Significant Lower Stroke in Chinese Hospitalized Patients with AF

Number of Strokes Prevented

Qi W, et al. Chinese J Cardiol, 2003 ； 31 ： 913-916

0 5% 10% 15% 20% 25%

No Therapy

Anticoagulation

Antiplatetet

5.5%

6.7%

24.2%

P<0.001

P<0.001

stroke rate

Prevalence of Antiplatetet and Anticoagulation in Chinese Hospitalized Patients with AF

None35%

Aspirin58%

Warfarin7%

Qi W, et al. Chinese J Cardiol, 2003 ； 31 ： 913-916

Prevalence of Antiplatelet and Anticoagulation in Patients with AF in Chinese Natural Population

None60%

Aspirin38%

Warfarin2%

Hu D, et al. 2004 Chin J Intern Med; in press

Is Warfarin Better than Aspirin?

If So

What is the Optimal INR?

For Chinese,

Is Warfarin Better than Aspirin?

If So

What is the Optimal INR?

For Chinese,

The Randomized Prospective Trial compared aspirin with adjusted –dose warfarin in NVAF Patients

18 hospitals from 7 provinces in China

• Age 40-80Age 40-80

ASPIRIN150-160mg

WARFARININR 2.0-3.0

Secondary endpoit: lacunar infarction, peripheral arteries embolism, TIA, silent stroke, acute myocardial infarction,serious bl

eeding

NVAF Patients

RandomizeRandomize(n =704 )(n =704 )

Primary endpoint: Death or IS

Study Design

Results—Study Patients

828 randomized704 included in ITT analysis

414 assigned to aspirin

369 in efficacy analysis

414 assigned to warfarin

335 in efficacy analysis

Results— Baseline Characteristics

Age, years(SD) 63.85(9.71 ) 62.60 (10.26) 0.55

Male gender 216(58.5) 204(60.9) 0.524

Age>=75 40(10.8) 42(12.5) 0.483

History of hypertension 163(44.2) 135(40.3) 0.229

History of dyslipidemia 55(15) 60(18) 0.280

Diabetes 52(14.1) 55(16.4) 0.391

CAD 137(37.4) 112(33.6) 0.295

Prior MI 42(11.4) 23(6.9) 0.041

Prior STROKE 80(21.7) 57(17) 0.118

Prior HF 122(33.1) 109(32.5) 0.882

DM 20(5.4) 23(6.9) 0.424

> = 1 risk factor 225 (61) 221(66.2)0.153

aspirin(n=369)

warfarin(n=335) P value*

*Analysis of variance *Analysis of variance PP value. value. ††Canadian Cardiovascular Society Class 4.Canadian Cardiovascular Society Class 4.

*Analysis of variance *Analysis of variance PP value. value.

Beta-blockers 186(50.4) 151(45.1) 0.157

ACEIs 185(50.1) 147(43.9) 0.097

CCBs 48(13) 58(17.3) 0.111

Diuretics 105(28.5) 79(23.6) 0.142

Digoxin 145(39.3) 115(34.3) 0.173

Statins 63(17.1) 49(14.6) 0.375

nitrates 89(24.1) 65(19.4) 0.131

Prior aspirin 159(43.1) 128(38.2) 0.188

Prior warfarin 27(7.3) 28(8.4) 0.607

AspirinN=369

WarfarinN=335 P value*

Results --Treatments Received and Concomitant Medications

Full Target Dosage 100% 68.3%

Mean (SD) Dose Received, mg 150-160 3.19±0.69

Treatments Received

Concomitant Medications (Percentage of Patients)

ResultsPrimary Endpoints

2.7%

6.0%p=0.03

WARFARIN ASPIRIN

RRR 56%

7

6

5

4

3

2

1

Death and Ischem

ic Stroke

（%

）

ResultsAll-Cause Death

Ischemic Stroke 2 1 Hemorrhage 0 2Neoplasia 2 1 AMI 1 0HF 1 0

SD 2 0 Total 8 4 P=NS

AspirinN=369

WarfarinN=335

ResultsIschemic stroke

1.8%

4.6%

p=0.04

WARFARIN ASPIRIN

62%Event rate (%

）

5

4

3

2

1

Results Total Embolic Events

5,4%

10.6%p=0.01

WARFARIN ASPIRIN

52%12

10

8

6

4

2

Event rate

（%

）

Results Secondary Endpoints

5.67 %

7.05 %

p=0.457

WARFARIN ASPIRIN

10

8

6

4

2

Event rate

（%

）

Secondary endpoit: lacunar infarction, peripheral arteries embolism, TIA, silent stroke, acute myocardial infarction,serious bleeding

Results Adverse Events-- Hemorrhage

0

5

10

15

aspirinWarfarin

Even

t Rat

e (%

)Ev

ent R

ate

(% )

MajorMajorBleedingBleeding

Major + MinorMajor + MinorBleedingBleeding

P<0.05P<0.05

6.86%6.86%2.44%2.44%

0.0%0.0%1.49%1.49%0.0%0.0% 0.89%0.89%

ICHICH

Results: combined end points联合

终点事件

联合

终点事件

(%)

(%)

月0 6 12 18 240

20

15

10

5

Aspirin （ 150-160mg ）Warfarin （ INR 2-3 ）

RRR

36 %

13.0%

8.4%

非瓣膜房颤 717 例，平均随访 19 个月。

Conclusions

• Compared to aspirin, adjusted-dosed warfarin (INR 2.0-3.0) can significantly reduce: -- primary endpoints by 44% 56% -- thromboembolism events by 52% -- combined endpoints by 36%39%• For Chinese NVAF patients, most of which (63.5% ) have at least one risk factor, warfarin is more effective than aspirin(150-160mg)• Warfarin is associated with increased risk of hemorrhage.

Is Warfarin Better than Aspirin?

If So

What is the Optimal INR?

For Chinese,

Distribution of 3482 INRs during follow-up

INR

0 1.0-1.4<1.0 1.5-1.9 2.0-2.4 2.5-2.9 3.0-3.4 3.5-3.9 >4.0

70

60

50

40

30

20

10

%

2378 （ 68.3% ）

• Follow-up period :median 19m （ 2 ～ 24m ）• Mean dose of warfarin: 3.19±0.69 mg （ 1.5-5mg ）

Thromboembolic event in WarfarinC

ombi

ned

Endp

oint

C

ombi

ned

Endp

oint

O

ccur

renc

e (%

)O

ccur

renc

e (%

)

0

2.0

1.5

1.0

0.5

2.5

3.0

INR0 1.0-1.4<1.0 1.5-1.9 2.0-2.4 2.5-2.9 >3.0

N=15 N=4

There were 19 cases of thromboembolic events, most of them occurred in INR <2.0.

Hemorrhage events in warfarin

10

8

6

4

2

%

INR0 1.0-1.9<1.0 2.0-2.9 3.0-3.9 4.0-4.9 5.0-5.9

Minor bleeding

Major bleeding INRs of 5 major bleeding :

4.75 , 4.98, 5.76, 5.24, 3.85

The optimal intensity of anticoagulation

<1.5 1,5-1.9 2.0-2.4 2.5-2.9 3.0-3.4 3.5-3.9 >4.0

INR

Embolic

Hemorrhage

4

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0

LOWEST EFFECTIVE ANTICOAGULATION INTENSITY FOR WARFARIN

INRINR

1.0 1.5 3.0 4.02.0

Rat

e fo

r em

bolic

Eve

ntR

ate

for e

mbo

lic E

vent

0.6

0.5

0.4

0.3

0.2

0.1

Rat

e fo

r em

bolic

Eve

ntR

ate

for e

mbo

lic E

vent4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

Conclusions

• INR >3.0 should be avoided to minimize the bleeding complications.• Under intense monitoring, adjusted-dose warfarin (INR 2.0-3.0) is effective and safe for the moderate to high risk atrial fibrillation patients.

Atrial fibrillation in China:

A Long Way to Go!

Difference in Trend between Paroxysmal AF and Persistent AF

0%1%2%3%4%5%6%7%8%

30～ 40～ 50～ 60～ 70～ 80～

persi stent AFparoxysmal AF

Hu D, et al. 2004 Chin J Intern Med; in press.

Similar trends and relatively lower prevalence of AF in China compared with USA, Australia and UK

0

2

4

6

8

10

12

14

30 40 50 60 70 80 90

ChinaFHS, USAAustraliaUK

FHS: the Framingham study. Wolf PA et al. Sroke 1991; 22: 983-988

Australia: Lake FR, et al. Aust NZ Med 1989; 19: 321-326

UK: Hill JD et al. J R Coll Gen Pract 1987; 37: 172-173

%

years

Risk of Stroke: Case-control Study

HU D, et al. Chin J Intern Med, 2003; 42: 157-161

%

Lone AF

PersistenceAF

Control of heart rate

Stroke Control

5.6

62.4

75.2

2.3

94.4

97.7 P<0.001

0

25

66.9

37.6

Paroxymal AF

Conversion

50

75

24.8

51.9

P=0.21

100

None valve AF

P=0.009

21.218.8

• Control the ventricular rate• Restore/maintain sinus rhythm• Prevent embolic complications

AF Treatment – Possible Objectives

No therapy24%

Control ofVenticular Rate

20% Cardioversion56%

Treatment of Chinese Hospitalized patients with paroxymal AF

Qi W, et al. Chinese J Cardiol, 2003 ； 31 ： 913-916

Amiodarone 31.0%

Cedilanid 29.6%

β-Blocker 18.3%

Propafenone 14.3%

None3%

Control ofVenticular Rate

83%

Cardioversion14%

Treatment of Chinese Hospitalized patients with persistent AF

Qi W, et al. Chinese J Cardiol, 2003 ； 31 ： 913-916

Amiodarone

Digoxin

β-Blocker

CCB