1. The widespread decline in cardiovascular mortality : A poorly understood triumph David Leon London School of Hygiene & Tropical Medicine Arctic University of Norway, UiT Course on Cardiovascular Epidemiology, Samara, Russia 4 April 2016

2. Trends in cardiovascular mortality rates in adults (30+ years) in high income countries, 1950-2010 2 M. Ezzati, Z. Obermeyer, I. Tzoulaki, B. M. Mayosi, P. Elliott, and D. A. Leon. Contributions of risk factors and medical care to cardiovascular mortality trends. Nat.Rev.Cardiol. 12 (9):508-530, 2015.

3. Men Women Source : Ezzati, M et al. Nat.Rev.Cardiol. 12 (9):508-530, 2015. 3

4. Men Women Source : Ezzati, M et al. Nat.Rev.Cardiol. 12 (9):508-530, 2015. 4

5. Approximately same pattern of decline seen at each age 5

6. Relative change in CVD death rates by decade, sex, and age group in 20 western high-income countries Source : Ezzati, M et al. Nat.Rev.Cardiol. 12 (9):508-530, 2015. 6

7. Being clear about what has declined 7

8. Demographic and epidemiological influences on disease burden Epidemiology focuses on disease / death rates But demographic factors also affect numbers of cases / deaths – Age structure of population – Size of population 8

9. Increasing or decreasing burden ? Global Burden of Disease study estimated between 1990 and 2013 globally : 41% increase in deaths from cardiovascular disease. This is a net effect of : 55% increase deaths due to population aging 25% increase deaths due to population growth 39% decrease deaths due to decline in age-specific death rates Source : Roth,GA et al N.Engl.J.Med. 372 (14):1333-1341, 2015 9

10. Percentage change in numbers of CVD deaths (1990-2013) by factor and region Source : Roth,GA et al N.Engl.J.Med. 372 (14):1333-1341, 2015 Eastern Europe Australasia North America Central Europe Western Europe Net % change 1990-2013 +21.1 +4.6 +1.5 -5.2 -12.8 Population growth Age-specific mortality ratesPopulation aging 10

11. Percentage change in numbers of CVD deaths (1990-2013) by factor and region Source : Roth,GA et al N.Engl.J.Med. 372 :1333-1341, 2015 Eastern Europe Australasia North America Central Europe Western Europe Net % change 1990-2013 +21.1 +4.6 +1.5 -5.2 -12.8 Population growth Age-specific mortality ratesPopulation aging Widespread decline in age-specific death rates 11

12. Key features to understand Continuous decline in women Decline in men started later, but in each country began roughly at same point Once underway, declines parallel (countries and sex) Same pattern of decline irrespective of age Declines continue up to the present 12

13. Components of cardiovascular disease Ischaemic Heart Disease + Stroke 13

14. 14 Stroke and heart disease mortality rates in the USA 1900 - 2010 Source : Lackland DT et al Stroke 45 (1):315-353, 2014

15. Age-standardised ischaemic heart disease (IHD) and stroke mortality by sex, England and Wales 1950–2000 Source : Brock A & Griffiths C Health Statistics Quarterly 18:5-17, 2003 15

16. Decline in cardiovascular mortality among women in Norway and UK, 1970-2011 UK Norway UK Norway Source : WHO HFA Age-standardised rates per 1000 Stroke (cerebrovascular disease)Ischaemic heart disease (IHD) 16

17. Decline in cardiovascular mortality among men in Norway and UK, 1970-2011 Stroke (cerebrovascular disease)Ischaemic heart disease (IHD) UK Norway UK Norway Source : WHO HFA Age-standardised rates per 1000 17

18. Key features Decline in stroke longer term and linear for both men and women Ischaemic heart disease dominant influence on total circulatory mortality particularly for men, showing onset of decline later than stroke But stroke constitutes larger fraction of total for women compared to men – sex differences in decline in total circulatory disease mortality reflects in part different balance between stroke and IHD Change over time in predominant stroke type 18

19. The Bethesda Conference 19

20. The Bethesda conference October 24-25 1978 20

21. The Bethesda conference October 24-25 1978 21

22. Potential explanations Bethesda conference framework 22

23. 1978 Bethesda conference Conclusions Coronary heart disease mortality decline since 1968 in USA was real – but found no clear evidence of decline occurring in other countries !!! Decline in risk factors and better medical care both contributed but did not fully explain decline Definitive explanation required further study as little data available on morbidity, effectiveness of treatments, temporal responsiveness comparability of cause of death 23

24. Puzzles identified Coronary heart disease decline in smoking fits with men (with little or no lag period) but not for women where decline in CVD mortality occurred at same time as smoking increased Increase in total fat consumption not consistent, but evidence of some decline in total cholesterol Improvements in treatment in hypertension occurring, but decline in mortality started earlier than these were available 24

25. What we now know in addition to the decline being widespread.... 25

26. Smoking Confirmed repeatedly as a key risk factor for IHD (and stroke) –Relative risks not substantial, but high prevalence of exposure, particularly among men, so high attributable fraction Smoking cannot explain when IHD decline in women in US and other countries began –Low initial prevalence –Smoking prevalence stable or increasing at same time as IHD declined In 1950s and 60s sex differences in smoking much larger than subsequently 26

27. Trends in smoking prevalence (aged 16+ years) Great Britain, by sex, 1948-2012 Source : Cancer Research UK 27

28. Trends in smoking prevalence Norway, by sex, 1927-2007 Source : Tidsskr Nor Legeforen 2009; 129: 1871-4 28

29. Blood pressure a strong candidate.... 29

30. Association of usual blood pressure with mortality from IHD and stroke IHDStroke Source : Lewington S et al. Lancet 360 (9349):1903-1913, 2002 1 million adults, 61 prospective studies 30

31. Trends in mean systolic blood pressure in the United States 31 Source : Lackland DT et al Stroke 45 (1):315-353, 2014

32. Estimated decline in mean SBP 1980 - 2008 Source : Danaei G et al Lancet 377 (9765):568-577, 2011 32 Men Women

33. Decline in blood pressure for 60+ years? Plausible long-term drivers could include : –reduced salt in diet (refrigeration) –reduction in seasonal cold stress Smoking may not be directly related to hypertension – hence decline would not be affected by smoking trends in a population Since 1980s increasingly effective anti- hypertensive medication BUT increase in obesity.... 33

34. Total cholesterol Explains some things only... 34

35. Source : Lewington S. Et al Lancet 370 :1829-1839, 2007 IHDStroke 900,000 adults 61 prospective studies Association of usual cholesterol level with mortality from IHD and stroke 35

36. Source : Lewington S. Et al Lancet 370 :1829-1839, 2007 IHDStroke 900,000 adults 61 prospective studies Association of usual cholesterol level with mortality from IHD and stroke Cholesterol a strong risk factor for IHD but not stroke 36

37. 37 Men Women Estimated decline in total cholesterol in high income regions North America, Australia and Western Europe 1980 - 2008 Source : Farzadfar, F et al Lancet 377:578-586, 2011

38. Clinical medicine : primary and secondary prevention 38

39. Source : Law MR et al Br.Med.J. 338:b1665, 2009 Relative risk estimates for IHD for a blood pressure reduction of 10 mm Hg systolic or 5 mm Hg diastolic in trials and in epidemiological cohort studies 39

40. Relative risk estimates for stroke for a blood pressure reduction of 10 mm Hg systolic or 5 mm Hg diastolic in trials and in epidemiological cohort studies Source : Law MR et al Br.Med.J. 338:b1665, 2009 40

41. Proportional effects on cause-specific mortality per mmol/L LDL cholesterol reduction from trials Source : Baigent C et al Lancet 366 (9493):1267-1278, 2005 41

42. Secondary prevention Heart 101 (17):1413-1421, 2015 Centres : Finland (several populations), Italy (Brianza and Varese), Germany (Augsburg), France (Haute-Garonne), Spain (Girona) and Estonia (Tallinn) 42

43. Annual percentage change in acute MI rates 1985-2010 in Europe* MenWomen 35-6465-7435-6465-74 Attack rate-3.7-4.5-3.3-4.9 Mortality rate-5.7-6.3-5.5-6.9 Total case-fatality-2.1-1.9-2.6-2.3 Pre-hospital case-fatality-1.8-1.1-2.2-1.7 In hospital case-fatality-3.2 -3.9-3.1 Source : Degano, IR et al Heart 101 (17):1413-1421, 2015 43 * Centres in Finland, Italy, Germany, France, Spain, Estonia

44. Towards explanations 44

45. The early phase (1950s and 60s) Cardiovascular disease mortality in women declined throughout while men started later in 1960s or 70s –Long term decline in blood pressure could exert strong downward pressure on stroke in both sexes –Haemorrhagic stroke predominant and only weakly related to smoking, but strongly to blood pressure –Sex differences in smoking habits greatest in this period, reflected in men’s mortality being more heavily weighted to IHD –For men, smoking attributable deaths larger than those attributable to blood pressure 45

46. The middle phase (1970s and 80s) In most high income countries smoking starts declining in men and women, adding to downward pressure of decline in blood pressure Cholesterol levels declining (?) Introduction of much more effective anti- hypertensives, and in 1980s start of clinical use of statins 46

47. Most recent phase (1990s >) Continued decline in smoking, blood pressure and cholesterol in high income countries Even more effective classes of anti- hypertensives Prevalence of use of statins and anti- hypertensives increases markedly Increased use of balloon angioplasty and stenting (primary and elective) and thrombolytics 47

48. Russia and other former communist countries are different 48

49. Men Women Source : Ezzati, M et al. Nat.Rev.Cardiol. 12 (9):508-530, 2015. 49

50. Men Women Decline in CEE countries only started in 1990s with exception of Hungary Former Soviet countries undergone massive fluctuations Over past 10 – 15 years nearly all countries declining Source : Ezzati, M et al. Nat.Rev.Cardiol. 12 (9):508-530, 2015. 50

51. Trends in death rates from cancers, cardiovascular diseases, and external causes in adults aged 25–64 years in Russia Source : Ezzati, M et al. Nat.Rev.Cardiol. 12 (9):508-530, 2015. 51

52. Why Central & Eastern Europe are different ? 52 Difficult question to answer definitively

53. Eastern Europe High prevalence of smoking among men Male smoking declined relatively recently In general low levels of smoking in women Hypertension rates higher than in West Slower and only recent adoption of improved models of primary and secondary prevention Alcohol implicated in massive fluctuations seen since 1985 53

54. Potential explanations Still a tricky problem to quantify 54

55. Much still to do Source : Townend N, et al Eur.Heart J., 2015 Cardiovascular deaths in Europe in latest year 55

56. Huge variation in mortality from cardiovascular disease across Europe today 56

57. 57 Source : WHO HFA database Age-standardised rates per 100,000 Male vs Female mortality rates from total cardiovascular mortality across European countries in 2010

58. 58 x6 -fold variation females X10-fold variation males Male vs Female mortality rates from total cardiovascular mortality across European countries in 2010 Source : WHO HFA database Age-standardised rates per 100,000

59. 59 Source : WHO HFA database Age-standardised rates per 100,000 Male vs Female mortality rates from total cardiovascular mortality across European countries in 2010

60. 60 Source : WHO HFA database Age-standardised rates per 100,000 Central Eastern Europe & Central Asia Male vs Female mortality rates from total cardiovascular mortality across European countries in 2010

61. 61 Source : WHO HFA database Age-standardised rates per 100,000 Male vs Female mortality rates from total cardiovascular mortality across European countries in 2010

62. 62 Source : WHO HFA database Age-standardised rates per 100,000 Western Europe (mainly !) Male vs Female mortality rates from total cardiovascular mortality across European countries in 2010

63. Cardiovascular disease remains number one cause of death in European region 63

64. Cardiovascular deaths as a percentage of total deaths in 2013 Ischaemic Heart Disease Stroke All cardiovascular disease Western Europe 181035 Central Europe 221950 Central Asia 301650 Eastern Europe (FSU) 361859 WHO European region 241446 Source : Global Burden of Disease study IHME website 64

65. Nevertheless the decline is a triumph 65

66. Thank you 66