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Mahesh J. Patel, MD
Assistant Professor of Medicine
Cardiovascular Risk Assessment:
Guidelines & Novel Approaches
Clinical ASCVD
Diabetes mellitus
(age 40-75)
≥7.5% 10-y risk
(age 40-75)
LDL-C ≥ 190
High-intensity statin
High-intensity ...
No ASCVD, No Diabetes, & LDL 70-189
Overview
• The new ASCVD risk calculator
• The role of LDL in the context of the new
guidelines
• Novel assessment strateg...
Importance of Risk Assessment
Challenges in CV Risk Assessment
Greatest # of
sudden deaths
Highest CV
risk populations
Huikuri NEJM 2001
Challenges in CV Risk Assessment
Greatest # of
sudden deaths
Highest CV
risk populations
Huikuri NEJM 2001
• Age
• Gender
• Smoker
• Total cholesterol
• HDL-C
• Systolic BP
• HTN Rx
Framingham Risk Calculator
Calculates 10-year r...
82%
15%
3%
10-year Risk of CAD
< 10% 10-20% > 20%
• Framingham does not fully represent US population
• Does not assess ri...
• New risk tool was needed with greater emphasis on
• African Americans & other races
• Women
• Stroke as an outcome
• Geo...
WHITE
WOMEN
AA
WOMEN
WHITE
MEN
AA
MEN
N 11,240 2641 9098 1647
Ages
(years)
40-79 40-79 40-79 40-79
C-statistic 0.81 0.81 0...
External Validation of Risk Calculator
Ridker Lancet 2013
Figure Legend:
External Validation of Risk Calculator
Munter JAMA 2014
Reasons for
Geographic and Racial
Differences in St...
Risk
Factor
Units Value Optimal
Values
Sex M or F F
Age Years 55
Race AA or WH AA
TC mg/dL 210 170
HDL mg/dL 56 50
SBP mmH...
Patient Example – effect of race
Patient Example – effect of race
• Family History of premature ASCVD
• High LDL-C 160 – 190 mg/dL
• Highly sensitive C – Reactive Protein
• > 2.0 mg/L
• Co...
Coronary Artery Calcification
& All Cause Mortality
Budoff JACC 2007
CAC Registry of > 25,000 patients
Comparison of Novel Risk Markers for Improvement in
CV Risk Assessment in Intermediate-Risk Individuals
Yeboah J, et al. J...
Improving Risk Perception
Patient Example –
compare to optimal risk
Atherosclerosis: A Lifetime in the Making
- Pooled cohort of 18 studies
 250,000 patients
 Lifetime risk of CV death
Lifetime Risk of CV Death
Berry NEJM 2012
Subclinical atherosclerosis
Coronary artery calcification
LDL
ATP III
What about LDL ?
The Downsides of LDL Goals
• Potential underuse of statins in patients at high CV
risk but with low LDL-C
• Potential over...
27
Evolutionarily Normal LDL-C Levels
Martin Med Clinics NA 2012
28
Genetics of LDL
Cohen NEJM 2006
LDL receptor mutations PCSK9 mutations
High LDL
29
Genetics of LDL
Cohen NEJM 2006
LDL receptor mutations PCSK9 mutations
High LDL Low LDL
30
Reduction in LDL-C & CHD Risks
Opie Lancet 2006
Reducing LDL-C by approx 40 mg/dL
reduces CHD risks by 20%
31
Reduction in LDL-C & Atherosclerosis
Progression
O’Keefe JACC 2004
Regression line
indicates that there is
NO atheroscl...
LDL in the New Guidelines
• 1) LDL-C > 190 mg/dL
– one of 4 statin benefit groups
• 2) LDL-C > 160 mg/dL
– can consider st...
HIGH MODERATE LOW
≥ 50%
reduction in LDL
30 – 50%
reduction in LDL
< 30%
reduction in LDL
Atorvastatin 40-80 mg
Rosuvastat...
• Expected response
• High intensity: ≥ 50% LDL reduction
• Moderate intensity: 30-50% LDL reduction
• Inadequate response...
Estimates of LDL-C
• Friedewald equation estimates LDL-C when TG < 400 mg/dL
• LDL-C = TC – HDL – TG/5
Martin JACC 2013
LDL cholesterol measurements
- 1.3 million US adults in total
- 191,000 with est LDL-C < 70 mg/dL
LDL-C m...
LDL particle measurements
Cromwell J Clin Lipidology 2007
3066 adults w/o CVD
LDL-P measurements
by NMR spectroscopy
Follow-up (years)
0 1 2 3 4 5
CumulativeIncidence
0.02
0.04
0.06
LDL-P < LDL-C
Concordant
LDL-P > LDL-C
0
0.02
0.04
0.06
0...
• 38 y/o white man p/w atypical chest pain.
• PMH – smoking & central obesity (BMI 34 kg/m2)
• BP 122/80. PE otherwise unr...
• 10-year risk ASCVD: 8.5%
• 10-year risk with optimal RF: 0.6%
• Lifetime ASCVD risks: 50%
• Lifetime risk with optimal R...
Patient KM
Coronary CTA: 50% soft plaque in the
proximal LAD
• Recommendations arose solely from high
quality evidence.
• Definitive recommendations were not
provided in areas lacking...
• Rather than LDL-C and nonHDL-C goals, the initiation
and intensity of statin therapy is the primary goal of
treatment in...
• Risk calculator should help initiate
conversation on ASCVD risk assessment but
should not be used as a strict criterion ...
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Prevention 2014: Cardiovascular Risk Assessment: Guidelines and Novel Approaches

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Mahesh J. Patel, MD

1st Annual Duke Preventive Cardiology Symposium
Saturday, April 26, 2014
The overall goal of this activity is to review the latest advancements in the management of lipids in clinical practice, including the new American Heart Association and American College of Cardiology guidelines on lipids announced in November 2013. Topics include learning about evaluation and treatment options in lipids and lipoprotein disorders, as well as focusing on new prevention guidelines, physical activity, nutrition, drug therapies, advanced lipoprotein testing, special patient populations, and new technologies for lifestyle management.

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Prevention 2014: Cardiovascular Risk Assessment: Guidelines and Novel Approaches

  1. 1. Mahesh J. Patel, MD Assistant Professor of Medicine Cardiovascular Risk Assessment: Guidelines & Novel Approaches
  2. 2. Clinical ASCVD Diabetes mellitus (age 40-75) ≥7.5% 10-y risk (age 40-75) LDL-C ≥ 190 High-intensity statin High-intensity statin High-intensity statin Moderate-intensity statin Moderate-to-high intensity statin Benefit Group Statin Dose Moderate-intensity statin
  3. 3. No ASCVD, No Diabetes, & LDL 70-189
  4. 4. Overview • The new ASCVD risk calculator • The role of LDL in the context of the new guidelines • Novel assessment strategies
  5. 5. Importance of Risk Assessment
  6. 6. Challenges in CV Risk Assessment Greatest # of sudden deaths Highest CV risk populations Huikuri NEJM 2001
  7. 7. Challenges in CV Risk Assessment Greatest # of sudden deaths Highest CV risk populations Huikuri NEJM 2001
  8. 8. • Age • Gender • Smoker • Total cholesterol • HDL-C • Systolic BP • HTN Rx Framingham Risk Calculator Calculates 10-year risk for CHD death or nonfatal MI High risk: > 20% Intermediate risk: 10-20% Low risk: < 10%
  9. 9. 82% 15% 3% 10-year Risk of CAD < 10% 10-20% > 20% • Framingham does not fully represent US population • Does not assess risk for related CVD outcomes such as stroke • Does not account for lifetime risk of CAD Limitations of the FRS Ford JACC 2004
  10. 10. • New risk tool was needed with greater emphasis on • African Americans & other races • Women • Stroke as an outcome • Geographic and SES diversity • Pooled Cohort Equation • Atherosclerosis Risk in Communities (ARIC) • Cardiovascular Health Study (CHS) • Coronary Artery Risk Development in Young Adults (CARDIA) • Framingham Original and Offspring studies • ASCVD events • CHD death • Non-fatal MI • Stroke (fatal or non-fatal) • Internal and external validation New ASCVD Risk Calculator
  11. 11. WHITE WOMEN AA WOMEN WHITE MEN AA MEN N 11,240 2641 9098 1647 Ages (years) 40-79 40-79 40-79 40-79 C-statistic 0.81 0.81 0.75 0.71 ASCVD Risk Model Characteristics
  12. 12. External Validation of Risk Calculator Ridker Lancet 2013
  13. 13. Figure Legend: External Validation of Risk Calculator Munter JAMA 2014 Reasons for Geographic and Racial Differences in Stroke (REGARDS) study
  14. 14. Risk Factor Units Value Optimal Values Sex M or F F Age Years 55 Race AA or WH AA TC mg/dL 210 170 HDL mg/dL 56 50 SBP mmHg 145 110 HTN Rx Y or N Y N Diabetes Y or N N N Smoker Y or N N N Patient Example – effect of race
  15. 15. Patient Example – effect of race
  16. 16. Patient Example – effect of race
  17. 17. • Family History of premature ASCVD • High LDL-C 160 – 190 mg/dL • Highly sensitive C – Reactive Protein • > 2.0 mg/L • Coronary artery calcium • Score > 300 Agatston units • Score > 75th percentile for age, sex, &race • Ankle – brachial index • < 0.9 Additional ASCVD Risk Assessment Strategies
  18. 18. Coronary Artery Calcification & All Cause Mortality Budoff JACC 2007 CAC Registry of > 25,000 patients
  19. 19. Comparison of Novel Risk Markers for Improvement in CV Risk Assessment in Intermediate-Risk Individuals Yeboah J, et al. JAMA 2012;308:788-795 0.623 C-statistic 0.784 0.652 0.675 0.640 0.650 Yeboah JAMA 2012 1330 intermediate CV risk individuals from MESA cohort
  20. 20. Improving Risk Perception
  21. 21. Patient Example – compare to optimal risk
  22. 22. Atherosclerosis: A Lifetime in the Making
  23. 23. - Pooled cohort of 18 studies  250,000 patients  Lifetime risk of CV death Lifetime Risk of CV Death Berry NEJM 2012
  24. 24. Subclinical atherosclerosis Coronary artery calcification
  25. 25. LDL ATP III What about LDL ?
  26. 26. The Downsides of LDL Goals • Potential underuse of statins in patients at high CV risk but with low LDL-C • Potential overuse of non-statin agents & combination therapies (strategies which have a less robust evidence base compared to statin monotherapy) • No RCT directly supporting this approach
  27. 27. 27 Evolutionarily Normal LDL-C Levels Martin Med Clinics NA 2012
  28. 28. 28 Genetics of LDL Cohen NEJM 2006 LDL receptor mutations PCSK9 mutations High LDL
  29. 29. 29 Genetics of LDL Cohen NEJM 2006 LDL receptor mutations PCSK9 mutations High LDL Low LDL
  30. 30. 30 Reduction in LDL-C & CHD Risks Opie Lancet 2006 Reducing LDL-C by approx 40 mg/dL reduces CHD risks by 20%
  31. 31. 31 Reduction in LDL-C & Atherosclerosis Progression O’Keefe JACC 2004 Regression line indicates that there is NO atherosclerosis progression at LDL-C < 67 mg/dL
  32. 32. LDL in the New Guidelines • 1) LDL-C > 190 mg/dL – one of 4 statin benefit groups • 2) LDL-C > 160 mg/dL – can consider statin therapy • 3) Measure LDL-C to monitor therapeutic adherence & response
  33. 33. HIGH MODERATE LOW ≥ 50% reduction in LDL 30 – 50% reduction in LDL < 30% reduction in LDL Atorvastatin 40-80 mg Rosuvastatin 20-40mg Atorvastatin 10-20 mg Rosuvastatin 5-10 mg Simvastatin 20-40 mg Pravastatin 40-80 mg Lovastatin 40 mg Fluvastatin XL 80 mg Pitavastatin 2-4 mg Simvastatin 10 mg Pravastatin 10-20 mg Lovastatin 20 mg Fluvastatin 20-40 mg Pitavastatin 1 mg Statin intensity & LDL Reduction
  34. 34. • Expected response • High intensity: ≥ 50% LDL reduction • Moderate intensity: 30-50% LDL reduction • Inadequate response • Focus on medication & lifestyle compliance • Fine tune statin dosing to maximize response/tolerability • Do NOT routinely add 2nd drug • Consider 2nd drug in high risk patients Monitoring Statin Response & Adherence
  35. 35. Estimates of LDL-C • Friedewald equation estimates LDL-C when TG < 400 mg/dL • LDL-C = TC – HDL – TG/5
  36. 36. Martin JACC 2013 LDL cholesterol measurements - 1.3 million US adults in total - 191,000 with est LDL-C < 70 mg/dL LDL-C measurements by vertical spin density gradient ultracentrifugation
  37. 37. LDL particle measurements Cromwell J Clin Lipidology 2007 3066 adults w/o CVD LDL-P measurements by NMR spectroscopy
  38. 38. Follow-up (years) 0 1 2 3 4 5 CumulativeIncidence 0.02 0.04 0.06 LDL-P < LDL-C Concordant LDL-P > LDL-C 0 0.02 0.04 0.06 0.08 0 1 2 3 4 5 60 1 2 3 4 5 0.02 Follow-up (years) CumulativeIncidence 0.04 0.06 LDL-P > LDL-C LDL-P < LDL-C Concordant LDL-P > LDL-C LDL-P < LDL-C Concordant 16% 33% 54% MetSyn LDL-C underestimates LDL-attributable risk LDL-C overestimates LDL-attributable risk LDL-C 104 117 130 mg/dL LDL-P 1372 1249 1117 nmol/L Otvos J Clin Lipidology 2011 LDL-P & LDL-C Discordance and CV Events Discordance defined as > 12 percentile units MESA 6814 patients w/o CVD at entry
  39. 39. • 38 y/o white man p/w atypical chest pain. • PMH – smoking & central obesity (BMI 34 kg/m2) • BP 122/80. PE otherwise unremarkable. • TC 170, TG 104, HDL-C 21, LDL-C 128 • 3 normal stress tests over 2 years Patient KM
  40. 40. • 10-year risk ASCVD: 8.5% • 10-year risk with optimal RF: 0.6% • Lifetime ASCVD risks: 50% • Lifetime risk with optimal RF: 5% • Statin was recommended but he declined Patient KM
  41. 41. Patient KM Coronary CTA: 50% soft plaque in the proximal LAD
  42. 42. • Recommendations arose solely from high quality evidence. • Definitive recommendations were not provided in areas lacking high quality evidence. • Lifestyle modification is the foundation of ASCVD risk reduction. Conclusions
  43. 43. • Rather than LDL-C and nonHDL-C goals, the initiation and intensity of statin therapy is the primary goal of treatment in 4 major risk groups : • ASCVD • LDL > 190 mg/dL • DM • 10 year risk > 7.5% • 10-year ASCVD risk ≥ 7.5% • New Pooled Cohort Equation for ASCVD risk prediction has flaws but is an improvement from FRS Conclusions
  44. 44. • Risk calculator should help initiate conversation on ASCVD risk assessment but should not be used as a strict criterion for or against statin therapy. • Clinical judgment and patient preference should be highly integrated into all treatment decision strategies. Conclusions

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