Cardiovascular DiseaseWHO June 2010, Geneva

Population Health Research Institute, 

McMaster University, Hamilton, Canada

NUI Galway, Galway, Ireland

DISCLOSURESPI‐INTERSTROKECo‐PI: PURE‐MRIPEER‐REVIEW Canadian Institutes of Health Research (CIHR) Heart and Stroke Foundation of Canada (HSFC)Canadian Stroke Network (CSN)Pfizer Cardiovascular Award

UNRESTRICTED INDUSTRY GRANTMerck, Sharp and DohmeBoehringer‐IngelheimAstra Zeneca

OVERVIEWGlobal burden of CHD and Stroke

PHRI Studies Traditional Risk factors for Acute Vascular Syndromes 

International Case‐control studiesINTERHEART and INTERSTROKE 

Deficit in knowledge of risk factors for chronic vascular syndrome (e.g. Covert stroke)

‘Causes of the causes’PURE prospective cohort study, and FAMILY study

Not include clinical trials (e.g. Polycap trial)

GLOBAL BURDEN OF CHD AND STROKE

Coronary Heart DiseaseLeading cause of mortality globally7.3 million deaths in 2001

Over 75% occurring in low/middle income countries

Stroke2nd leading cause of adult disability globally3rd leading cause of death worldwide (leading in cause of death in many regions)5.7 million deaths in 2005 (7.8 million 2030)

87% in low/moderate‐income countriesStrong et al Lancet Neurol 2007;6:182‐87; Sousa et al Lancet 2009

CHANGE IN THE RANK ORDER OF DISEASE BURDEN FOR 15 LEADING CAUSES, WORLD, 1990‐2020 (DALYS)

Lower resp infDiarrh disPerinatalUnipolar major dep.IHDCerebrovascularTBMeaslesTraffic accidentsCong anomaliesMalariaCOPDFallsIron-defic anaemiaProt-energy malnut

1 IHD2 Unipolar major dep.3 Traffic accidents4 Cerebrovascular5 COPD6 Lower resp inf7 TB8 War9 Diarrhoeal dis10 HIV11 Perinatal12 Violence13 Cong anomalies14 Self-inflicted injuries15 Trach., bronch. & lung CA

123456789101112131415

16 17 19 28 33 19 24 25 37 39

1990 2020

Prevention of Cardiovascular Disease  

• Critical component of ‘Successful Ageing’ of a Population

• Prevention requires identification of modifiable risk factors, quantify their importance, and develop interventions that are applicable in low, middle and high income countries

• Target both Acute and Chronic vascular disease 

– Acute Coronary Syndrome (MI) and stroke

– Congestive heart failure, chronic renal impairment, PVD, Subclinical (covert) stroke

INTERHEART

1. What are the most important risk factors for myocardial infarction, in middle and low-income countries

2. Is the impact of risk factors on MI similar or variable in different regions or ethnic groups?

3. What proportion of the risk of MI can be explained by known risk factors (population-attributable risk)?

Standardized International Case-control study in 52countries worldwide (15,152 cases 14,820 controls)

Cases and controls from 52 Countries Representing Every Inhabited Continent

RussiaSeychellesSingaporeS AfricaSpainSri LankaSultanate of OmanSwedenThailandUAEUKUSAZimbabwe

KuwaitMalaysiaMexicoMozambiqueNepalNew ZealandNetherlandsNigeriaPakistanPhilippinesPolandPortugalQatar

CroatiaCzech RepEgyptGermanyGreeceGuatemalaHungaryIndiaIranIsraelItalyJapanKenya

ArgentinaAustraliaBahrainBangladeshBeninBotswanaBrazilCameroonCanadaChileChina/Hong KongColombia

INTERHEARTPopulation Attributable Risk > 90% for nine easily measured risk factors

Risk factor Controls (%) Cases (%) OR (95% CI)* PAR (%)

Apo B/A1 ratio† 20.0 33.5 3.3 (2.8‐3.8) 49.2

Current smoking 26.8 45.2 2.9 (2.6‐3.2) 35.7

Psychosocial factors ‐ ‐ 2.7 (2.2‐3.2) 32.5

Abdominal obesity 33.3 46.3 1.6 (1.5‐1.8) 20.1

Hypertension 21.9 39.0 1.9 (1.7‐2.1) 17.9

Vegetables and fruit 42.6 32.8 0.7 (0.7‐0.8) 13.7

Exercise 19.3 14.3 0.9 (0.8‐0.97) 12.2

Diabetes 7.5 18.5 2.4 (2.1‐2.7) 9.9

Alcohol intake 24.5 24.0 0.9 (0.8‐1.9) 6.7

All risk factors ‐ ‐ 129.2 (90‐185) 90.4

Yusuf et al INTERHEART Lancet 2004;364:937‐52

Risk of AMI associated with current or former smoking, overall and by region

Region n Cont.% OR (99%CI)

Overall 26527 47.9 2.27 (2.11,2.44)

W Eur 1403 55.0 1.96 (1.47,2.62)

CE Eur 3624 54.2 1.92 (1.60, 2.30)

MEC 3301 45.4 2.64 (2.19,3.19)

Afr 1339 53.8 2.18 (1.60, 2.96)

S Asia 3706 41.0 2.43 (2.03,2.89)

China/HK 6062 42.7 2.30 (2.00,2.65)

SE Asia 2131 57.1 1.96 (1.54,2.49)

ANZ 1267 54.2 2.80 (2.03,3.86)

S Am 3068 48.9 2.35 (1.92,2.87)

N Am 626 64.6 1.82 (1.14,2.88)

0.5 1 2 4 8

Low Levels of Smoking and MI

0.75

1

2

4

8

Never 1-2 3-4 5-6 7-8 9-10 11-12 13-14 15-16 17-18 19-20 21+

OR

(95%

CI)

Adjusted for age sex and region

INTERSTROKE‐PHASE 1  

• International standardized case‐control study – Shared methodology with INTERHEART

• 22 countries (6,000 participants) Mar 07‐Mar 10– HIC: Australia, Canada, Croatia, Denmark, Germany, Iran, Poland– S America: Argentina, Brazil, Chile, Colombia, Ecuador, Peru– Asia: China, India, Philippines, Malaysia

– Africa: Mozambique, Nigeria, South Africa, Sudan, Uganda

• Case: First stroke admitted within 5 days of symptom onset– 1‐month follow‐up (m‐Rankin)

• Control: No history of stroke (Matched for age and gender)– Community and hospital‐based controls

Yusuf et al INTERHEART Lancet 2004O’Donnell et al Neuroepidemiology 2010

CHALLENGES TO STROKE EPIDEMIOLOGY STUDIES

• All large global epidemiological studies are challenging

• INTERHEART provided evidence of feasibility

SPECIFIC TO STROKE• Valid determination of Stroke Subtype

• (Ischemic, ICH and SAH) requires routine CT of brain

• Until recently, very limited availability in low‐income settings

• Questionnaire‐based research• Presents challenges, given many patients with stroke are unable to 

communicate

• Surrogate respondents (Robust Questionnaire: INTERHEART) O’Donnell and Yusuf Lancet Neurol 2009

INTERSTROKE POPULATION (CASES)

All HIC S America China/SEA India African 3,000 422 151 1146 958 323Age (Mean SD) 61.1 (12.7) 66.0 (13.3) 65.6 (13.4) 58.5 (11.6) 58.9 (12.0) 57.7 (15.3)

Age < 45 years (%) 339 (11.3) 30 (7.1) 12 (7.9) 123 (10.7) 107 (11.2) 67 (20.7)

Female (%) 1106 (36.9) 169 (40.0) 71 (47.0) 412 (36.0) 313 (32.7) 141( 43.7)

Intracerebral

Haemorrhage (%)

663 (22.1) 40 (9.5) 39 (25.8) 257 (22.4) 218 (22.8) 109 (33.8)

Ischaemic stroke (%) 2337 (77.9) 82 (90.5) 112 (74.2) 889 (77.6) 740 (77.2) 214 (66.3)

CT or MRI of brain (%) 99.9% 100% 100% 100% 99.7% 100%

Ischemic Stroke (78%) and ICH (22%)

ESC Barcelona 2010; O’Donnell  et al INTERSTROKE Lancet (In Press) 2010

10 RISK FACTORS FOR ALL STROKEPrevalence All Stroke

Control (%)

IS(%)

ICH(%)

OR (99%CI)

PAR (99%CI)

PHx Hypertension 31.8 54.7 60.3 2.64 (2.26-3.08) 34.5 (30.3-39.0)

PHx Hypertension/BP >160/90 37.0 66.3 83.1 3.89 (3.33-4.54) 51.8 (47.7-55.8)Smoking (Current) 24.5 37.2 31.3 2.09 (1.75-2.51) 19.0 (15.5-23.2)

WHR (T3 vs T1) 33.4 42.9 35.3 1.65 (1.36-1.99) 26.6 (18.8-36.1)Diet Risk Score ( T3 vs T1) 33.2 39.1 38.2 1.35 (1.11-1.64) 13.4 (6.9-24.3)Physical Active 12.1 8.3 6.8 0.69 (0.53-0.90) 28.7 (14.7-48.6)PHx Diabetes Mellitus 11.7 21.2 10.3 1.36 (1.10-1.68) 5.0 (2.6-9.5)Alcohol (1-30/month)

(>30/month/Binge)17.510.9

14.516.5

18.316.4

0.90 (0.72-1.11)1.51 (1.18-1.92)

3.7 (0.9-14.5)

Psychosocial Stress 14.7 20.0 19.0 1.30 (1.06-1.60) 4.6 (2.1-9.6)

Depression 14.2 21.1 15.5 1.35 (1.10-1.66) 5.2 (2.6-9.8)Cardiac 4.7 13.7 4.2 2.38 (1.77-3.20) 6.6 (4.8-9.1)ApoB/A1 (T3 vs T1) 33.3 50.9 38.1 1.89 (1.49-2.40) 24.9 (15.7-37.1)

ALL RISK FACTORS PAR 90.3% (85.3-93.7)

SUBGROUPSHypertension/BP>160/90

Smoking WHR (T3 v T1)Variable

OR (99%CI) OR (99%CI) OR (99%CI)Region

HIC (n=422) 2.89 (1.85-4.51) 2.88 (1.71-4.84) 3.18 (1.84-5.50)S America (n=151) 3.51 (1.72-7.18) 3.59 (1.28-10.1) 4.59 (1.65-12.8)China/SEA (n=1,146) 4.67 (3.65-5.98) 2.21 (1.64-2.99) 1.22 (0.88-1.68)India (n=958) 4.31 (3.26-5.70) 2.15 (1.58-2.93) 1.31 (0.91-1.88)Africa (n=323) 4.65 (2.90-7.45) 2.66 (1.29-5.48) 1.78 (1.00-3.14)

SexMale (n=1,894) 3.88 (3.22-4.68) 2.46 (2.02-3.01) 1.25 (0.99-1.59)Female (n=1,106) 4.89 (3.79-6.32) 1.56 (1.03-2.36) 2.70 (1.95-3.74)

Age≤ 45 years (n=415) 8.53 (5.39-13.49) 2.77 (1.72-4.47) 1.38 (0.83-2.28)> 45 years (n=2585) 3.89 (3.31-4.57) 2.17 (1.79-2.62) 1.71 (1.39-2.09)

m-Rankin (Stroke Severity)

m-R (0-2) 4.14 (3.48-4.92) 2.04 (1.68-2.48) 1.54 (1.25-1.91)m-R (3-6) 4.51 (3.62-5.62) 2.63 (2.05-3.38) 1.62 (1.24-2.13)

What are the “causes of the causes”?

CVD

Tobacco use

Physical Activity

Nutrition and diet

Social behavior

Smoking

Diabetes

Blood pressure

Cholesterol

Overweight/ obesity

Individualbiological RFs

Individual Behavioral RFs

Community

Clean indoor air regulationTobacco taxes/ priceRegulating age of youth smokingTobacco cessation support programsSocial/ cultural norms

Food policy Access to healthy choices – eg fruits/ vegExposure to unhealthy choices – eg fast food/ vendor machines/ large portion size

Social networksSocial capital

OthersAir pollution

Stress/ anxiety/ depression

Interactions of Environment/ Behaviour with Genes

Walkability of built environmentSafety from crime/ trafficPlaces for walkingAccess to facilitiesLand use mix

Access to health care, Poverty

PURE STUDY   

The Prospective Urban Rural Epidemiology (PURE)• Objective 

– To examine the relationship of societal influences on human lifestyle behaviours, cardiovascular risk factors, and incidence of chronic non‐communicable diseases

• About 100,000 individual from household (35‐70 yrs) in >600 communities in 17 low‐, middle‐, and high‐income countries.

• Data collection: – Individual (e.g. medical history, lifestyle behaviors, blood and urine 

collection (genetic analysis)– 4 environmental domains of interest‐the built environment, nutrition 

and associated food policy, psychosocial/socioeconomic factors, and tobacco environment. 

• A minimum follow‐up of 10 years is currently plannedTeo and Yusuf et al  Am Heart J 2009

PURE: OVERALL BY REGIONS

OBESITY BY ECONOMIC STATUS OF COUNTRY

Obesity = BMI >=30

Advertisement for Sugary Drinks and Mean BMI

Corr Coeff =0.71

Unpublished

Adjusted for: age, sex, level of education, tobacco use, physical activity (MET score), location (urban/rural), and country (Canada, Colombia, Brazil, India, and China)

USE OF EBM THERAPIES IN THOSE WITH CVD

HIC UMIC LMIC LIC Global

1470 3504 4995 1703 11,672ASA/ Other Antiplatelets

43.13 19.92 8.82 4.93 20.2

Beta blockers 29.80 24.09 2.07 6.58 17.1

ACE – I or ARB

37.82 27.85 10.03 3.64 17.9

Statin 45.03 15.44 4.22 2.23 12.4

CVD = heart attack, angina, other heart disease, Q wave and stroke

Unpublished

CREATE Registry: Mortality by SES

5.5

7.2

5.9

6.96.5 6.4

8.2

6.6

0

2

4

6

8

10

Crude Adjusted for treatments

RichUpp Middle ClassLow Middle ClassPoor

P = < 0.001

CREATE (N=20,000)

P = 0.97

Xavier D et al. Lancet 2008

30 D

ay M

orta

l ity

Prospective registry study in 89 centres from 10 regions and 50 cities in India of 20,937 patients.  Most patients were from lower middle 10737 (52.5%) and poor (19.6%) social classes.  

Subclinical (Covert) Stroke‐PURE‐MRI  

Cognitive loss, Depression, Parkinsonism, Gait, Frailty, Sleep Loss of ADL

PURE-Mind: (MRI of brain, cognitive and function) (1,100 in Canada)• Challenges: Measuring ADL across continuum, different settings, prospective

LADIS Study Arch Intern Med 2007Vermeer et al Lancet Neurol 2007

FAMILY Study (905 babies from 859 pregnancies)Blood Pressures at birth, 1, 2, 3 and 5 years

N 761 480 404 267 54 N 761 480 404 267 54

Unpublished

CONCLUSIONSCVD is a major global cause of mortality and dependence in high, middle and low‐income countries

Acute vascular Syndromes and (Chronic and Covert disease)

Considerable increase in knowledge about risk factors, and their modification, to prevent CVD

ACS and Acute Stroke have shared risk factors

Now need to understand the risk factors of risk factors, to guide population‐based interventions 

Successful Vascular Ageing across the life‐span 

ACKNOWLEDGMENTS

Prof Salim Yusuf, Director, PHRI, McMaster University

• Sonia Anand

• Jackie Bosch

• Sumathy Rangarajan

• Hertzel Gerstein

• Stephanie Ounpuu

• Janice Pogue

• Purnima Rao‐Melacini

• Jane De Jesus 

• Shofiqul Islam

• Michelle Zhang

• Guillaume Pare• Romania Iqbal• Koon Teo• Matthew McQueen• Mahshid Dehghan • Manisha Madhavan • Andrew Mente• Siu Lim Chin• Fahad Razak• MyLinh Duong• Zena Samaan• Andrew Mente• Daniel Corsi

• Changchung Xie

• Rizwan Afzal

• Katherine Morrison

• Stephanie Atkinson

• Kim Hall

• Sarah McDonald

and many others!

INTERSTROKE Investigators

THANK YOU