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Dayi Hu Peking University

PREVENTION OF STROKE IN PATIENTS WITH AF IN CHINA. Dayi Hu Peking University. Atrial Fibrillation (AF). The most common significant heart rhythm disturbance Incidence increases with age and the development of structural heart disease Common cause of stroke (10-15% of all strokes)

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Dayi Hu Peking University

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  1. PREVENTION OF STROKE IN PATIENTS WITH AF IN CHINA Dayi Hu Peking University

  2. Atrial Fibrillation (AF) • The most common significant heart rhythm disturbance • Incidence increases with age and the development of structural heart disease • Common cause of stroke (10-15% of all strokes) • Associated with significant cardiovascular morbidity and mortality • Tends to recur in at least half the patients being treated with antiarrhythmic drug therapy

  3. 70% men women 0 1 2 3 4 5 6 7 8 9 10 Higher Mortality Rate In Patients With AF Odds Ratio for Death 1.5-2.2 1.2-1.8 Men, AF Women, AF 50% Percent of subject died in follow-up 30% Men, No AF Women, No AF 10% years Benjamin EJ, Circulation 1998; 946-952

  4. The epidemiology of atrial fibrillation ATRIA Study Prevalence of AF(million) 1990 1995 2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050 Year Go: JAMA, 2001

  5. ATRIAL FIBRILLATION AND STROKE Thrombembolic stroke • High Incidence • Multi-focal and severe • Prone to hemorrhage • High mortality

  6. The Framingham Study: Attributable Risk of Stroke 30 AF prevalence Strokes attributable to AF 20 % 10 0 50–59 60–69 70–79 80–89 Age Range (years) Wolf et al. Stroke 1991;22:983-988.

  7. Prevalence of AF in different countries 5.5% ≥ 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 ECG 25 - 64 yrs, west German, single ECG ≥ 15 yrs, India, single ECG 5.4% 5.1% 3.7% 3.0% 2.8% 2.4% 1.5% 1.3% 1.3% 0.60% 0.28% 0.1% Estimate of prevalence of AF vary based on the characteristics of population studied and how AF is ascertained. Ryder KM, et al. Am J Cardiol 1999; 84: 131R-138R.

  8. Atrial Fibrillation Demographics by Age U.S. populationx 1000 Population with AFx 1000 Population withatrial fibrillation 30,000 20,000 10,000 0 500 400 300 200 100 0 U.S. population <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 Age, yr Adapted from Feinberg WM. Arch Intern Med. 1995;155:469-473.

  9. 25.0 20.0 15.0 10.0 5.0 0 Prevalence of AF is increasing in USA 27.0 30.0 11.1 Number (×10,000) 1984 1994 NEJM 1997 337:1360-1369

  10. Atrial Fibrillation in China?

  11. Percent of Hospitalization in Patients with AF Is Increasing in China 9.0% 8.16% 7.90% 7.90% 8.0% 7.65% 7.5% 7.0% % of hospitalization 6.5% 6.0% 1999 2000 2001 Average Qi W, et al. Chinese J Cardiol, 2003；31：913-916

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

  13. Incidence of AF Stratified by Age and Sex in Chinese Population 7.5 7.4 Men (n=13358) Women (n=15521) 3.6 Rate per 100 2.6 1.4 1.1 0.9 0.5 0.6 0.7 0.3 0.2 30-39 40-49 50-59 60-69 70-79 ≥80 Overall Age Group, y Data collected from 13 natural populations from 14 different provinces across China Hu D, et al. 2004 Chin J Intern Med; in press.

  14. ≥ 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 ECG 25 - 64 yrs, west German, single ECG ≥ 15 yrs, India, single ECG 5.1% 3.7% 3.0% 2.8% 2.4% 1.5% 1.3% 1.3% 0.77% 0.60% 0.28% 0.1% Prevalence of AF in China and other countries 5.5% 5.4% Patients with AF In China 8 million

  15. Hospitalized Patients with AF in China: Causes and Associated Condition 0 10% 20% 30% 40% 50% 60% 58.1% Advanced age 40.3% Hypertension CAD 34.8% 33.1% CHF 23.9% RVD 7.4% Idiopathic AF caidiomyopathy 5.4% 4.1% Diabetes CAD: coronary artery disease; CHF: congestive heart failure; RVD: rheumatic valve disease Chinese J Cardiol, 2003；31：913-916

  16. Prevalence of Stroke in Chinese Patients with AF 24.81% % 25% 17.5% 20% 12.95% 15% 10% 5% 0 Hu D, 2004 Qi W, 2003 Hu D, 2004 Hu 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

  17. Prevalence of Stroke in Patients with None Valve AF Stratified by Age 30 25 20 Prevalence (%) 15 10 5 0 years >40 40～49 50-59 60～69 70～79 >80 HU D, et al. Chin J Intern Med, 2003; 42: 157-161

  18. Framingham Heart Study: Significant Multivariable Risk for developing AF Male Female 2.1 (1.8-2.5) 2.2 (1.9-2.6) AGE 4.5 (3.1-6.6) 4.2 (4.2-8.4) CHF 1.8 (1.2-2.5) 3.4 (2.5-4.5) VHD 1.4 (1.0-2.0) Prior MI 1.5 (1.2-2.0) 1.4 (1.1-1.8) HTN DM 1.4 (1.0-2.0) 1.6 (1.1-2.2) 0 1 2 3 4 5 6 7 8 9 Benjamin EJ, et al. JAMA, 1994; 271: 840-844

  19. Risk Factors for Stroke in Chinese with Non Vascular AF: A Case-control Study AGE >76 yrs 1.76 (1.08-2.89) Hypertension 1.52 (1.28-1.80) Diabetes 1.39 (1.11-1.76) 1.71 (1.21-2.28) SBP 2.77 (1.25-6.13) LA thrombi 1 2 3 4 5 HU D, et al. Chin J Intern Med, 2003; 42: 157-161

  20. Controls Warfarin AF Investigators: Meta-analysisWarfarin for Stroke Prevention 8 p < 0.01 6 p < 0.02 p < 0.03 p < 0.001 p < 0.002 Stroke Incidence (%) p > 0.2 4 2 0 AFASAK 58%7–81 SPAF 67%27–85 BAATAF 86%51–96 CAFA 42%-68–80 SPINAF 79%52–90 TOTAL 68%50–79 Risk reduction 95% CI AF Investigators. Arch Intern Med 1994;154:1449-1457.Atwood et al. Herz 1993;18:27-38.

  21. P<0.001 stroke rate Antiplatetet and Anticoagulation showed Significant Lower Stroke in Chinese Hospitalized Patients with AF Anticoagulation 5.5% P<0.001 6.7% Antiplatetet No Therapy 24.2% 0 5% 10% 15% 20% 25% Number of Strokes Prevented Qi W, et al. Chinese J Cardiol, 2003；31：913-916

  22. Prevalence of Antiplatetet and Anticoagulation in Chinese Hospitalized Patients with AF Qi W, et al. Chinese J Cardiol, 2003；31：913-916

  23. Prevalence of Antiplatelet and Anticoagulation in Patients with AF in Chinese Natural Population Hu D, et al. 2004 Chin J Intern Med; in press

  24. For Chinese, Is Warfarin Better than Aspirin? If So What is the Optimal INR?

  25. For Chinese, Is Warfarin Better than Aspirin? If So What is the Optimal INR?

  26. The Randomized Prospective Trial compared aspirin with adjusted –dose warfarin in NVAF Patients 18 hospitals from 7 provinces in China

  27. Study Design • Age 40-80 NVAF Patients Randomize(n =704 ) ASPIRIN 150-160mg WARFARIN INR 2.0-3.0 Primary endpoint: Death or IS Secondary endpoit: lacunar infarction, peripheral arteries embolism, TIA, silent stroke, acute myocardial infarction,serious bleeding

  28. Results—Study Patients 828 randomized 704 included in ITT analysis 414 assigned to aspirin 414 assigned to warfarin 369 in efficacy analysis 335 in efficacy analysis

  29. Results— Baseline Characteristics aspirin(n=369) warfarin(n=335) P value* 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 *Analysis of variance P value. †Canadian Cardiovascular Society Class 4.

  30. Results --Treatments Received and Concomitant Medications P value* Aspirin N=369 Warfarin N=335 Treatments Received Full Target Dosage 100% 68.3% Mean (SD) Dose Received, mg 150-160 3.19±0.69 Concomitant Medications (Percentage of Patients) 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 *Analysis of variance P value.

  31. ResultsPrimary Endpoints 7 6 5 4 3 2 1 Death and Ischemic Stroke（%） 6.0% p=0.03 RRR 56% 2.7% WARFARIN ASPIRIN

  32. ResultsAll-Cause Death Aspirin N=369 Warfarin N=335 Ischemic Stroke 2 1 Hemorrhage 0 2 Neoplasia 2 1 AMI 1 0 HF 1 0 SD 2 0 Total 8 4 P=NS

  33. ResultsIschemic stroke 4.6% p=0.04 5 4 3 2 1 Event rate (%） 62% 1.8% WARFARIN ASPIRIN

  34. Results Total Embolic Events 10.6% p=0.01 12 10 8 6 4 2 Event rate（%） 52% 5,4% WARFARIN ASPIRIN

  35. Results Secondary Endpoints 10 8 6 4 2 p=0.457 7.05 % Event rate（%） 5.67 % WARFARIN ASPIRIN Secondary endpoit: lacunar infarction, peripheral arteries embolism, TIA, silent stroke, acute myocardial infarction,serious bleeding

  36. Results Adverse Events-- Hemorrhage P<0.05 Event Rate (% ) 6.86% 2.44% 1.49% 0.0% 0.89% 0.0% ICH MajorBleeding Major + MinorBleeding

  37. Results: combined end points 非瓣膜房颤717例，平均随访19个月。 20 Aspirin（150-160mg） Warfarin（INR 2-3） 13.0% 15 RRR 36 % 联合终点事件 (%) 10 8.4% 5 0 0 6 12 18 24 月

  38. 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.

  39. For Chinese, Is Warfarin Better than Aspirin? If So What is the Optimal INR?

  40. Distribution of 3482 INRs during follow-up 2378（68.3%） 70 60 50 40 30 20 10 • Follow-up period :median 19m（2～24m） • Mean dose of warfarin: 3.19±0.69 mg（1.5-5mg） % 0 <1.0 1.0-1.4 1.5-1.9 2.0-2.4 2.5-2.9 3.0-3.4 3.5-3.9 >4.0 INR

  41. 0 <1.0 1.0-1.4 1.5-1.9 2.0-2.4 2.5-2.9 >3.0 INR Thromboembolic event in Warfarin N=15 N=4 3.0 2.5 There were 19 cases of thromboembolic events, most of them occurred in INR <2.0. 2.0 Combined Endpoint Occurrence (%) 1.5 1.0 0.5 0

  42. Minor bleeding Major bleeding 10 8 6 4 2 % 0 <1.0 1.0-1.9 2.0-2.9 3.0-3.9 4.0-4.9 5.0-5.9 INR Hemorrhage events in warfarin INRs of 5 major bleeding : 4.75 , 4.98, 5.76, 5.24, 3.85

  43. The optimal intensity of anticoagulation 4 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Embolic Hemorrhage <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

  44. LOWEST EFFECTIVE ANTICOAGULATION INTENSITY FOR WARFARIN 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.6 0.5 0.4 0.3 0.2 0.1 Rate for embolic Event Rate for embolic Event 1.0 1.5 2.0 3.0 4.0 INR

  45. 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.

  46. Thanks！ Atrial fibrillation in China: A Long Way to Go!

  47. Difference in Trend between Paroxysmal AF and Persistent AF Hu D, et al. 2004 Chin J Intern Med; in press.

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

  49. Risk of Stroke: Case-control Study P<0.001 Stroke Control 100 97.7 P=0.009 94.4 75.2 P=0.21 75 % 62.4 66.9 51.9 50 37.6 24.8 21.2 18.8 25 5.6 2.3 0 Lone AF Persistence AF Paroxymal AF None valve AF Control of heart rate Conversion HU D, et al. Chin J Intern Med, 2003; 42: 157-161

  50. AF Treatment – Possible Objectives • Control the ventricular rate • Restore/maintain sinus rhythm • Prevent embolic complications

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