Cleveland HeartLab 2014 5th Annual Symposium: Atherosclerosis Imaging: Implications of the Shift From Risk Estimation to Subclinical Disease Detection

1. AAtthheerroosscclleerroossiiss IImmaaggiinngg::
IImmpplliiccaattiioonnss ooff tthhee SShhiifftt FFrroomm
RRiisskk EEssttiimmaattiioonn ttoo
SSuubbcclliinniiccaall DDiisseeaassee
DDeetteeccttiioonn
Daniel Edmundowicz, MD, FACC
Professor of Medicine,
Chief of Cardiology
Medical Director, Temple Heart
and Vascular Institute
September 12, 2014

2. DDiisscclloossuurreess::
• Medical Advisory Board Member, GNC, Inc.

3. DDiisscclloossuurreess::
• I’m lipocentric: Unshakable conviction that
abnormal lipoprotein concentrations
– drive the formation of atherosclerotic plaque and
– both contribute to and magnify the inflammatory
transition that results in plaque rupture, erosion and
atherothrombosis.

4. OObbjjeeccttiivveess::
• Review the epidemiology and health
economics of our current approach to
Atherosclerotic Cardiovascular Diesease
(ASCVD).
• Recognize “ideal cardiovascular health”
when you see it and understand that it is
the “Holy Grail” of preventing ASCVD.

5. OObbjjeeccttiivveess::
• Identify weaknesses in our current
approach to ASCVD risk assessment.
• Review the utility of subclinical vascular
disease detection as it relates to improved
reclassification of individuals at risk.
• Recognize opportunities for further
refinement of prevention guidelines to
identify those individuals who will benefit
most from intervention.

6. Causes of Death by Gender
(United States: 2008)
A: Cardiovascular Disease D: Chronic Lower Respiratory Disease
B: Cancer E: Diabetes Mellitus
C: Accidents F: Alzheimer Disease
AHA Statistics. Circulation 2012;125:e2-e220

7. Deaths Attributable to Cardiovascular Disease
(United States: 2008)
AHA Statistics. Circulation 2012;125:e2-e220

8. The 20 Leading Diagnoses for Direct Health Expenditures
United States, 2008 (in billions of dollars)
AHA Statistics. Circulation 2012;125:e2-e220

9. The Unsustainable EEccoonnoommiiccss ooff OOuurr CCuurrrreenntt
AApppprrooaacchh

10. Intervening Too LLaattee iinn tthhee VVaassccuullaarr DDiisseeaassee
TTiimmeelliinnee::
Artistic Conceptual Design: John Rumberger, MD, PhD

11. IIddeeaall CCaarrddiioovvaassccuullaarr HHeeaalltthh

12. Lifetime Risk of Death from CVD
• 25,595 Back Men and White Men at age 55 Years of Age
• According to Aggregate Burden of Risk Factors and Adjusted for Competing Risks of Death
• CVD includes fatal coronary artery disease, non fatal myocardial infarction, fatal or non fatal stroke
Berry et al., N Engl J Med 366;4: 2012

13. Lifetime Risk of Death from CVD
• 17,222 Back Women and White Women at age 55 Years of Age
• According to Aggregate Burden of Risk Factors and Adjusted for Competing Risks of Death
• CVD includes fatal coronary artery disease, non fatal myocardial infarction, fatal or non fatal stroke
Berry et al., N Engl J Med 366;4: 2012

14. IImmpplliiccaattiioonnss::
• Lower RF burden in middle age results in:
– Longer life lived free of CVD (and other diseases)
– Compression of morbidity
– Greater health-related QOL
– Substantially decreased Medicare expenditures later
in life
• Challenge:
– This is NOT a substantial proportion of the
population!!

15. Baseline Risk Factors and Risk Profile
• Men and Women by Age Group
• Optimal Risk Factor Profile: Total Cholesterol < 180 mg/dl; Blood Pressure <120/80 mmHg; non smoker; not diabetic
Berry et al., N Engl J Med 366;4: 2012

17. County-level Estimates of Leisure-time Physical Inactivity among Adults aged ≥ 20 years:
United States 2008
www.cdc.gov/diabetes
Age-adjusted percent
Quartiles
0 - 23.2
23.3 - 26.2
26.3 - 29.1
> 29.2

18. www.cdc.gov/diabetes
Age-adjusted percent
0 - 19.4
19.5 - 23.8
23.9 - 27.0
27.1 - 30.7
> 30.8
County-level Estimates of Obesity among Adults aged ≥ 20 years:
United States 2008

19. County-level Estimates of Diagnosed Diabetes among Adults aged ≥ 20 years:
United States 2008
www.cdc.gov/diabetes
Age-adjusted percent
0 - 6.3
6.4 - 7.5
7.6 - 8.8
8.9 - 10.5
> 10.6

20. Inactivity
Obesity
Diabetes

22. KKeeyyeess AA,, JJAAMMAA 11995577;;116644::11991122--1199

23. Epidemiologic CChhaarraacctteerriissttiiccss ooff
AAtthheerroosscclleerroossiiss::
• A common-source epidemic resulting in a lipoprotein storage disorder
(plaque formation).
• The common source is primarily dietary saturated fatty acids and
cholesterol.
• Individuals with elevated lipoprotein levels early in life will have more
atherosclerosis and therefore a higher risk of CHD events than those
with similar lipoprotein levels occurring later in life. (incubation)
• The burden of atherosclerosis will be magnified by the presence of
concomitant factors that contribute to vulnerability (risk).

24. CCoommmmoonn SSoouurrccee EEppiiddeemmiiccss::

25. CCoommmmoonn SSoouurrccee EEppiiddeemmiiccss::

26. CCoommmmoonn SSoouurrccee EEppiiddeemmiiccss::

27. CCoommmmoonn SSoouurrccee EEppiiddeemmiiccss::

28. CCoommmmoonn SSoouurrccee EEppiiddeemmiiccss::

29. CCoommmmoonn SSoouurrccee EEppiiddeemmiiccss::

30. PPoolliioo::
• Extraordinarily common viral disease.
• Practically all kids were infected but only
a small number developed poliomyelitis.
• Still don’t know why some individuals
developed paralytic polio and some
developed lethal bulbar polio (host
susceptibility).

31. • Bigger, more
expensive iron lungs
• Genetic tests and
serum markers to
predict host
susceptibility
• Control of the
common source

32. For any common source epidemic, genetic and other
“host susceptibility” factors determine the response to
the common source:

34. KKeeyyeess AA,, JJAAMMAA 11995577;;116644::11991122--1199

36. BBeehhaavviioorr CChhaannggee??

37. Nutrition: AAmmeerriiccaa’’ss FFoooodd SSuuppppyy

38. KKeeyyeess AA,, JJAAMMAA 11995577;;116644::11991122--1199

39. Macronutrient Intake BByy GGeennddeerr IInn AAdduullttss AAggeedd
2200 aanndd OOvveerr::

40. Current Clinical AApppprrooaacchh ttoo PPrreevveennttiivvee
CCaarrddiioollooggyy::
• Intensity of treatment is matched to the
severity of the patient’s overall global
cardiovascular risk.
• Highest risk patients will benefit the
most from drug treatments
• Risk scores are calculated for the
estimation of the 10-year risk of
coronary heart disease.

41. WWeeaakknneesssseess ooff ppuubblliisshheedd rriisskk ssccoorreess::
• Historically dated populations
• Limited ethnic diversity
• Narrowly defined endpoints (CHD)
• Endpoints influenced by provider
preferences (surgery, PCI)
• Endpoints with poor reliability (subjective
angina, CHF)

42. Weaknesses inherent in iinnddiivviidduuaall aapppplliiccaattiioonn ooff
ggrroouupp rriisskk eessttiimmaattiioonn
• Individuals with the same risk estimate will
either have or not have the event of
interest.
• Only those destined to have the event will
have it prevented by the intervention

43. Weaknesses inherent in iinnddiivviidduuaall aapppplliiccaattiioonn ooff
ggrroouupp rriisskk eessttiimmaattiioonn
• Comparison of patient characteristics to
participants in RCT’s not really any better
• Only a fraction of participants in trials have
events and only a fraction of those events
are prevented by the intervention.

45. AApppprrooaacchh ttoo RRiisskk AAsssseessssmmeenntt
• Maintain the paradigm of matching
intensity of preventive efforts with
individuals absolute risk
• Acknowledge that none of the risk tools or
novel risk factors considered have been
evaluated in RCT’s

46. On the randomized, ccoonnttrroolllleedd cclliinniiccaall ttrriiaall::
BMJ 2003 327; 1459-61

47. EEffffeecctt ooff SSttaattiinn TThheerraappyy
Am J Cardiol 2006;98:1405–1408

48. EEffffeecctt ooff SSttaattiinn TThheerraappyy
Am J Cardiol 2006;98:1405–1408

49. KKeeyyeess AA,, JJAAMMAA 11995577;;116644::11991122--1199

50. Vascular Disease Timeline ((aa..kk..aa.. CChhrroonniicciittyy ooff
DDiisseeaassee))
Artistic Conceptual Design: John Rumberger, MD, PhD

52. “The best test for prediction of the risk of atherosclerosis
is the demonstration of atherosclerosis”
Ernest Schaeffer, MD, Editor-in-Chief of Atherosclerosis
“People who die of an MI are just as dead whether they
have no risk factors or every identifiable risk factor”
Harvey Hecht, MD, Director of Cardiovascular Computed
Tomography Lenox Hill Heart & Vascular Institute, New York

53. NNHHLLBBII CChhaarrggee ttoo tthhee WWoorrkkggrroouupp::

54. CCrriittiiccaall QQuueessttiioonn ##11::

55. Considerations wwhheenn eevvaalluuaattiinngg nneeww rriisskk
ffaaccttoorrss::

56. Assessing PPeerrffoorrmmaannccee ooff RRiisskk PPrreeddiiccttiioonn
MMooddeellss::
• Calibration:
– The ability of a model to predict the absolute
risk subsequently observed in the population
– May vary with time and place
– Depends upon the availability of local
mortality data and risk factor distribution in a
population at a given time

57. Assessing PPeerrffoorrmmaannccee ooff RRiisskk PPrreeddiiccttiioonn
MMooddeellss::
• Discrimination:
– The ability of a model to differentiate those
with the outcome versus those without the
outcome up to a certain point in time.
– Commonly expressed as the “C statistic”
ranging from 0.5 (random chance) to 1.0
(absolute discrimination) between cases and
controls
– Above 0.70 is acceptable

58. Assessing PPeerrffoorrmmaannccee ooff RRiisskk PPrreeddiiccttiioonn
MMooddeellss::
• Reclassification:
– Assesses the value of adding new information
in order to improve risk prediction
– ‘Net reclassification Improvement’ (NRI)
assumes that the addition of the new
information is acceptable if at least 10% of
individuals are appropriately reclassified.

59. CCrriittiiccaall QQuueessttiioonn ##11::

60. OOppttiioonnaall ssccrreeeenniinngg tteessttss::

61. Coronary Calcification Score

62. Multiple EEtthhnniicc SSttuuddyy ooff AAtthheerroosscclleerroossiiss
((MMEESSAA))
• NIH sponsored prospective cohort study examining
measures of subclinical atherosclerosis and
conversion to clinical events.
• 3,213 men and 3,601 women 45 to 84 years of age
• 38% white, 28% black, 22% Hispanic, and 12%
Chinese
• 6 U.S. communities

63. Coronary Calcium as a Predictor of Coronary Events
in Four Racial or Ethnic Groups: MESA
Prospective NIH study of 6722 men and women w/o CAD: median f/u 3.8 yrs
38.6% white, 27.6% black, 21.9% Hispanic, 11.9% Chinese
162 events; 89 death or MI
Detrano et al. NEJM 2008;358:1336-45.

64. Coronary AArrtteerryy CCaallcciiuumm DDeetteeccttiioonn
• FRS fails to identify many people destined
to have a CHD event.
• CAC has been shown to provide
incremental CHD risk prediction beyond
traditional risk factors
• Patients with advanced CAC burden (CAC
scores > 300) have the greatest risk.

65. NNeett RReeccllaassssiiffiiccaattiioonn IImmpprroovveemmeenntt::

66. Coronary Calcification aanndd PPllaaqquuee MMoorrpphhoollooggyy iinn
HHuummaannss::
Otsuka F et al. Arterioscler Thromb Vasc Biol. 2014;34:724-736

67. CCaallcciiffiieedd NNoodduullee::
Otsuka, F. et al. (2014) Clinical classification of plaque morphology in coronary disease
Nat. Rev. Cardiol. doi:10.1038/nrcardio.2014.62

68. PPllaaqquuee EErroossiioonn::
Otsuka, F. et al. (2014) Clinical classification of plaque morphology in coronary disease
Nat. Rev. Cardiol. doi:10.1038/nrcardio.2014.62

69. Immunoreactivity PPaatttteerrnn ooff BBoonnee MMaattrriixx
PPrrootteeiinnss::
Otsuka F et al. Arterioscler Thromb Vasc Biol. 2014;34:724-736

70. Nonmutually EExxcclluussiivvee TThheeoorriieess ffoorr VVaassccuullaarr
CCaallcciiffiiccaattiioonn::
Otsuka F et al. Arterioscler Thromb Vasc Biol. 2014;34:724-736

71. SSuummmmaarryy
• In the long run (becoming shorter) our current
approach to ASCVD is not sustainable.
• Ideal cardiovascular health exists (ASCVD is
preventable) in a small portion of the
population.
• Ultimately, as a society, we will need to
confront the common source of the epidemic.

72. SSuummmmaarryy
• New guidelines attempt to improve risk
assessment and are open to the
transition from risk factor identification
to earlier disease identification with a
clear call for more outcomes research
in the field demonstrating favorable risk
reclassification.

73. SSuummmmaarryy
• Detection of subclinical vascular disease
identifies individuals at increased risk for clinical
events who are most likely to benefit from
aggressive preventive intervention.
• These individuals will continue to be important
populations for further study of synergistic
environmental and biologic modifiers of disease
progression.
• Parachutes save lives without RCT’s