SOONER RATHER THAN LATER:

The Early Detection of CAD by CT coronary calcification study

Gary Oppenheim, MD, FACC Swedish Heart and Vascular

7/12/19

Disclosures

• Speaker for Regeneron • Speaker for Sanofi • Speaker for Boehringer Ingelheim • Speaker for Amgen • Speaker for Boston Scientific • Speaker for Lilly

How many of these patients are in your practice?

A striking example of “residual risk” in a patient whose LDL was “under control” and whose stress tests were normal

What is Residual Risk?

Clinical event or disease progression on therapy The substantial risk that remains after you thought the patient was “under control” ( e.g. LDL goal < 70)

Residual Cardiovascular Risk in Major Statin Trials

40 CHD events occur in patients treated with statins

30 28.0 Placebo Statin

19.4 20 15.9

13.2 12.3 11.8 10.9 10.2 10 8.7 7.9 6.8 5.5

0 4S1 LIPID2 CARE3 HPS4 WOSCOPS5 AFCAPS/

TexCAPS6 N 4444 9014 4159 20 536 6595 6605

Δ LDL -35% -25% -28% -29% -26% -25% Secondary High Risk Primary

14S Group. Lancet. 1994;344:1383-1389. 4HPS Collaborative Group. Lancet. 2002;360:7-22. 2LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 5Shepherd J, et al. N Engl J Med. 1995;333:1301-1307.

3Sacks FM, et al. N Engl J Med. 1996;335:1001-1009. 6 Downs JR, et al. JAMA. 1998;279:1615-1622.

Residual CVD Risk in Patients Treated With Intensive Statin Therapy

40 Statistically significant, but clinically inadequate CVD reduction1

Standard statin therapy 30 26.3 Intensive high-dose statin therapy 22.4

20 13.7 12.0 10.9

8.7 10

0 PROVE IT-TIMI 222 IDEAL3 TNT4

N 4162 8888 10 001

LDL-C,* 95 62 104 81 101 77 mg/dL 1Superko HR. Br J Cardiol. 2006;13:131-136.

2Cannon CP, et al. N Engl J Med. 2004;350:1495-1504. 3Pedersen TR, et al. JAMA. 2005;294:2437-2445. *Mean or median LDL-C after treatment

4LaRosa JC, et al. N Engl J Med. 2005;352:1425-1435.

Coronary Artery Disease (CAD): The Diagnosis Often Comes Too Late

(Adapted from Levy et al.)

Levy D et al in Textbook of Cardiovascular Medicine, 1998.

Accurate Identification of Risk • “Clinicians need assistance in the identification

of patients who are at very high risk of developing acute coronary events. In a large proportion of previously asymptomatic individuals, sudden coronary death or acute myocardial infarction occurs as the first manifestation of coronary atherosclerosis. Therefore, treating such events is analogous to locking the barn door after the horse has been stolen. … it is now increasingly clear that patients experiencing these events may have subclinical disease.. …. Clearly, the prevention of such events is now a very important goal”. Eugene Braunwald 2005

Jim Fixx - marathon runner, exercise advocate, author - dead at 53 of a heart attack

Sir Winston Churchill - broke every tenet of “healthy life style” - dead at age 91

Individual Coronary Risk Assessment: Who REALLY is at RISK in Your Practice?

Assessment of Cardiovascular Risk Contribution of Multiple Risk Factors

Framingham multivariate risk factor prediction

model

10-year probability of coronary event

Age

HDL-C Total or LDL-C SBP

Diabetes

Smoker

Wilson PW, et al: Circ 97:1837-47, 1998

12

CAD Risk Factors Smoking Hypertension Hypercholesterolemia Diabetes

New risk factors

Genomic predisposition

Endothelial dysfunction: The risk of the risk factors

Vascular lesion and remodeling Thrombosis Inflammation Vaso-

constriction Plaque rupture/

erosion CP949994-1

Effects of Increasing TC Levels on the Risk for CHD in the Presence of Other Risk Factors

05

10152025303540

185 210 235 260 285 310 335

Low HDL

Smoking

Hyperglycemia

Hypertension

No Other Risk Factors

Schaefer EJ, adapted from the Framingham Heart Study

Serum Cholesterol (mg/dL)

What about the Standard Lipid Profile? Patients with CAD have similar cholesterol

levels to those without disease

120.0

015

0.00

180.0

021

0.00

240.0

027

0.00

300.0

033

0.00

360.0

040

0.00

Major CV Event

No CV Events

Serum Total Cholesterol (mg/dl)

70%

LDL levels with and without CAD

77% of subjects

with CAD had LDL < 130

72% of subjects

without CAD had LDL < 130

Sachdeva A et al. Am Heart J 2009; 157:111-117.

HDL among subjects with and without CAD

45% of subjects

with CAD had HDL > 40

48 % of subjects without CAD had HDL > 40

Sachdeva A et al. Am Heart J 2009; 157:111-117.

Lifetime risk (to age 95) for CVD and mortality at age 50 Lloyd-Jones DM et al. Circulation 2006

Risk factor level Men: Lifetime CVD risk (%)

Women: Lifetime CVD risk (%)

Men: Median survival (y)

Women: Median survival (y)

Optimal risk factors*

5.2 8.2 >39 >39

>1 not-optimal risk factor

36.4 26.9 36 39

>1 elevated risk factor

45.5 39.1 35 39

1 major risk factor 50.4 38.8 30 35 >2 major risk factors

68.9 50.2 28 31

*Optimal risk factor levels=total cholesterol <180 mg/dL (4.65 mmol/L), blood pressure <120/80 mm Hg, nonsmoker, and nondiabetic

1 major risk factor

0 major risk factors

2 major risk factors

3 major risk factors

4 major risk factors

62.4% have 0 to 1 major risk factor(s)

N=87,869

4 Major modifiable risk factors: hypertension, smoking, hypercholesterolemia, diabetes

Prevalence of major risk factors in CHD

Khot, et al. JAMA. 2003

19.4%8.9%

27.8%

43.0%

0.9%

How Good Is NCEP III At Predicting MI? JACC 2003:41 1475-9

222 patients with 1st MI, no prior CAD men <55 y/o (75%), women <65 (25%)

Risk >20%/ 10 yrs.

Risk 10-20%/ 10 yrs.

Risk <10%/ 10 yrs.

NCEP Goal LDL<100

NCEP Goal LDL<160

NCEP Goal LDL<130

Qualify for Rx Not-Qualify for Rx

6% 6%

Total

12% 8% 10%

Total

18%

61%

9%

Total

70%

Framingham risk and MI in young women

Ñ Young women<65 years

presenting with MI

Ñ None had a calculated risk 95%

of >20%. 5%

Ñ 82% of women not eligible for

pharmacotherapy as by Low risk Intermediate risk NCEP ATP III guidelines.

Akosah et al JACC 2003

How about a Stress Test? • “The majority of people destined to die

suddenly will not have a positive stress test. Such persons probably will not have ischemia before the fatal event; the likely reason that they will die suddenly is that only a mild, non-flow-limiting lesion will have been present before the sudden development of an occlusive thrombus.”

Epstein et al. NEJM 1989

Normal vessel

Minimal CAD

Progression

Artery can compensate for up to 40% plaque volume

(lumen size remains constant)

Artery at maximum expansion:

lumen narrows

Severe CAD

Moderate CAD

Glagov S et al, N Engl J Med, 1987.

Glagov Hypothesis: Coronary Remodeling

IVUS and a “Normal” Coronary Angiogram

Nissen – AJC 2001

Calcium is Very Sensitive for obstruction

l INVASIVE ANGIOGRAPHY nBudoff et al (1851 patients) - 95% nHaberl et al (1764 patients) - 99% nRumberger et al (213 patients) – 97% nKnez et al (2111 patients) – 99% n Becker 2007 (1347 patients) – 99%

Negative predictive value declines to 84% in younger cohorts (<40 years old)

ASNC/ACC Appropriateness 2006

ASNC/ACC Appropriateness - Functional Testing Inappropriate

Functional Testing Appropriate

68%

18%

14%

200 Pre-MI Stenosis

>70% 50-70% < 50%

# patients

E Falk, PK Shah, V Fuster. Circulation 1995;92:657

Event Reality Most Heart Attacks are Caused by Non-Obstructing Plaque

86% of MIs are from plaque <70% obstructing 68% of MIs are from plaque <50% obstructing

Stenosis severity by angiography of ASVD preceding MI

STABLE PLAQUE UNSTABLE PLAQUE

Modified from Libby P. Circulation. 1995;91:2844-50

Atherosclerotic Plaque

RISK?

“The best test for the prediction of the risk of atherosclerosis is the

demonstration of atherosclerosis”

Ernest Schaeffer Editor-in-Chief of Atherosclerosis

rundy. Circulation 2008;117:569-573

“Imaging has at least 3 virtues”

It individualizes risk assessment beyond use of age, which is a less reliable surrogate for

atherosclerosis burden

It provides an integrated assessment of the

lifetime exposure to risk factors

It identifies individuals who are susceptible to developing atherosclerosis beyond

established risk factors

2.72 2

12.47

3.55

6.15

12.29

0

2

4

6

8

10

12

14

DM Smoke HTN <10 10-100

101-400 401-1000

>1000

EBT Coronary Calcium Score

All Cause Mortality [NDR] n = 10,377 asymptomatic men and women f/u = 5.0+3.5 yrs.

Shaw, Raggi et al Radiology 2003

EBT found to be independent and incremental to risk factors

All Cause Mortality in Patients Without Known CAD

Prediction of Cardiac Events in Asymptomatic Patients by EBT

The St. Francis Heart Study, JACC 2005

SFHS 3

0.12

0.7

2

2.4

3.3

0

0.5

1

1.5

2

2.5

3

3.5

0 > 0 > 100 > 200 > 600

Baseline EBT Calcium Score

Ann

ual E

vent

Rat

e (%

)

Calcium Score >100 vs <100

Rel

ativ

e R

isk

9.5

Any Event

10.7

Cor. Event

9.9

MI/ SCD

CAC vs HISTOLOGY

• High correlation of score (r=0.96) and area (r=0.95) with histomorphometry (p<0.0001)

• “.. the amount of coronary calcium increases as the extent of atherosclerosis increases”

Mautner GC et al: Radiology 1994;192:619-623

Calcium Score Total Plaque Burden

Total Coronary Artery Plaque Burden and EBCT Coronary Calcium Score:

defining the tip of the atherosclerotic iceberg Mild Plaque Severe Moderate

Event Rates Based upon Scores

0.1

2.1

4.14.8

02

46

Annual Event Rate

Zero 1 99 100-400 >400EBT Calcium Score

Raggi, Circulation 2000

Event Rates Based upon Scores

0.8

21

4148

020

4060

10 Year Event Rate

Zero 1 99 100-400 >400EBT Calcium Score

Raggi, AHJ 2001

Looking upside down: what is value of absence of CAC?

Study Type Population (n)

CAC=0 (%)

FU (Years)

Number of events (%)

Meta-Analysis * 71,595 29,312 (41%)

4.3 154 (0.47%) CVD events

Retrospective** 44,052 19,898 (45%)

5.6 104 (0.52%) Deaths

Prospective*** 6,809 3,414 (50%)

4.1 17 (0.52%) CHD events

*Sarwar A, Shaw LJ, Shapiro MD, Blankstein R, Hoffman U, Brady TJ, Cury R, Budoff MJ, Blumenthal RS, Nasir K. JACC Imaging 2009 ** Blaha M, Budoff MJ, Shaw LJ, Khosa F, Rumberger JA, Berman D, Callister T, Raggi P, Blumenthal RS, Nasir K. JACC Imaging 2009 *** Budoff M, McClelland R, Nasir K, Greenland P, Kronmal RA, Kondos G, Shea S, Lima JAC, Blumenthal RS. Am Heart J 2009

SHIFT IN THINKING

FROM:

%STENOSIS=Sx’s TO:

PLAQUE BURDEN=RISK

Time to Follow-up (Years)

0 (n=11,044) 1-10 (n=3,567) 11-100 (n=5,032)

101-299 (n=2,616)

300-399 (n=561)

400-699 (n=955)

700-999 (n=514)

1,000+ (n=964)

Cum

ulat

ive

Surv

ival

0.0 2.0 4.0 6.0 8.0 10.0 12.0

0.70

0.75

0.80

0.85

0.90

0.95

1.00

All Cause Mortality and CAC Scores:

Long Term Prognosis in 25, 253 patients

Budoff, et al. JACC 2007; 49: 1860-70

10.4

SIGNIFICANCE OF “MILD-MODERATE” CAD EVENT FREE SURVIVAL BASED ON DEGREE STENOSIS IN MULTIVESSEL CAD

40

50

60

70

80

90

100

0 2 4 6 8 10 YEARS

NONE 1-29% 30-50%

C.A.S.S. REGISTRY

© 2014 Virginia Mason Medical Center

Coronary Artery Calcium Score

53

Malik S, Budoff M, Katz R, Blementhal RJ, Alain Bertoni, Blumenthal RS, Nasirk K, Szklo M, Barr G, Wong ND ( Diabetes Care 2012)

Are all Diabetics Equivalent?

CAC and FRS in uncomplicated type 2 diabetes

510 asymptomatic type 2

diabetic subjects

Mean F/U=2.3 yrs

No event observed with

CAC=0

Anand DV et al, Eur Heart J. 2006; 27(6):713-21.

47%

25%

28%

Number needed to treat: CAC 0 549 CAC 1-100 94 CAC > 100 24

75% of all events occurred in 25% with CAC>100

EISNER STUDY: Does CAC Testing Has Such a Dramatic Downstream Impact?

4 YEAR FOLLOW-UP No-CAC Testing

(n = 623) CAC Testing (n = 1,311)

P value

Downstream Tests Stress Test 33.9% 34.6% 0.74 Cardiac CT 7.1% 7.7% 0.62 Cardiac Catherization 2.9% 3.3% 0.71 Coronary Revascularization 1.8% 2.3% 0.46 Downstream Costs Median Procedure costs* $721 $904 0.56 Median Medication costs $2,937 $3,149 0.09

*Include $150 for CAC testing. Rozanski et al, J Am Coll Cardiol. 2011;57:1622-1632

NEW GUIDELINES

Measurement of CAC is reasonable for cardiovascular risk assessment in asymptomatic adults at intermediate risk (10% to 20% 10-year risk.

Measurement of CAC may be reasonable for cardiovascular risk assessment persons at low to intermediate risk (6% to 10% 10-year risk).

In asymptomatic adults with diabetes, 40 years

of age and older, measurement of CAC is reasonable for cardiovascular risk assessment.

Recommendations for Calcium Scoring Methods

I IIa IIb III

I IIa IIb III

I IIa IIb III

CAC & 2018 ACC/AHA guidelines

l In adults 40 to 75 years of age without diabetes mellitus and with LDL-C levels ≥70 mg/dL (≥1.8 mmol/L), at a 10-year ASCVD risk of ≥7.5%, start a moderate-intensity statin if a discussion of treatment options favors statin therapy. Risk-enhancing factors favor statin therapy (see below).If risk status is uncertain, consider using coronary artery calcium (CAC) to improve specificity (see below).If statins are indicated, reduce LDL-C levels by ≥30%, and if 10-year risk is ≥20%, reduce LDL-C levels by ≥50%.

CAC & ACC/AHA 2018 guidelines

l In adults 40 to 75 years of age without diabetes mellitus and 10-year risk of 7.5% to 19.9% (intermediate risk), risk-enhancing factors favor initiation of statin therapy (see No. 7).Risk-enhancing factors include and, if measured in selected individuals• apolipoprotein B ≥130 mg/dL• high-sensitivity C-reactive protein ≥2.0 mg/L• ankle-brachial index <0.9 and l• lipoprotein (a) ≥50 mg/dL or 125 nmol/L, especially at higher values of lipoprotein (a). Risk-enhancing factors may favor statin therapy in patients at 10-year risk of 5-7.5% (borderline risk)

CAC & 2018 ACC/AHA guidelines

l In adults 40 to 75 years of age without diabetes mellitus and with LDL-C levels ≥70 mg/dL-189 mg/dL (≥1.8-4.9 mmol/L), at a 10-year ASCVD risk of ≥7.5% to 19.9%, if a decision about statin therapy is uncertain, consider measuring CAC.• If CAC is zero, treatment with statin therapy may be withheld or delayed, except in cigarette smokers, those with diabetes mellitus, and those with a strong family history of premature ASCVD. • A CAC score of 1 to 99 favors statin therapy, especially in those ≥55 years of age. • For any patient, if the CAC score is ≥100 Agatston units or ≥75th percentile, statin therapy is indicated unless otherwise deferred by the outcome of clinician–patient risk discussion.

<10% 10-20 >20 % 10-year risk

ATPIII Score Risk Assessment

CAC Score high

Intermediate

Zero

Reclassification of ATP III Risk Categories Using CAC

Scheme according to Wilson PWF et al

JACC 41:1889 – 1906, 2003 with HNR data

63% To Low Risk

14% To High Risk

l Computed tomography for coronary calcium should be considered for cardiovascular

risk assessment in asymptomatic adults at moderate risk. IIa

Prospective Predictive Value of CAC for Future Cardiac Events in Asymptomatic Individuals

Becker et al. AHJ 2008;155:154-60

1726 asymptomatic pts (1018 men, 708 women, age 57.7 ± 13.3 yrs; 40.3 ± 7.3 months

In the group without risk factors, 39% (134 of 345) were >75th %

0.81

0.63 0.65

Warranty of a CAC Score

0.80

0.85

0.90

0.95

1.00

0 5 10 15Followup (years)

FH CHD (-) FH CHD (+)

Kaplan-Meier survival estimates

99.3% 99.6%

6,944 (42%) CAC=0

48 deaths

Ketlogetswe AHA 2010

Rotterdam – Annals 2012

Visualizing coronary calcium is associated with improvements in adherence to statin therapy.

30

40

50

60

70

80

90

100

CAC=0 CAC 1-99 CAC 100-399 CAC>400

P<0.0001

Kalia N, Miller LG, Nasir K, Atherosclerosis. 2005 Jul 25; [Epub ahead of print]

Negative Predictive Power of EBT • 1764 persons underwent EBT and

angiogram • Sensitivity (score >0) 99% in men, 100%

in women • Negative test in 0.7% of men had >50%

stenosis (negative predictive power = 99%) Haberl et al. JACC Feb 2001

Does CAC scanning improve outcomes?

Parameters No SCAN CACS>400 P Change in LDL-C

-11 mg/dL -29 mg/dL <0.001

Change in SBP -5 mm Hg -9 mm Hg <0.001 Exercise 36% 47% 0.03 New Lipid Rx 19% 65% <0.001 New BP Rx 18% 46% <0.001 New ASA Rx 7% 21% <0.001 Lipid Adherence 80% 88% 0.04

Rozanski. Berman. EISNER. JACC 2011;57:1622. CACS 0 = 631. CACS>400 = 109.

EISNER Study – Costs Compared to No Scan Group

P<0.005 for both measures Rozanski JACC 2011

EISNER Study

l CACS may effectively triage care – evaluation, intensification of therapy – without increasing cost

l Compared with the no-scan group, the scan group showed a net favorable change in systolic blood pressure (p 0.02), low-density lipoprotein cholesterol (p 0.04), and waist circumference (p 0.01), and tendency to weight loss among overweight subjects (p 0.07), and improvement of FRS compared to no scan group

• MI in 41 pts during 3.2 + 0.7 years

• LDL levels similar in MI and non-MI pts

• Relative risk of MI in presence of CAC progression was 17.2-fold higher (P<0.0001)

Progression of Coronary Artery Calcium and Risk of First MI

495 Asymptomatic Patients Started on Statin Therapy

Raggi P et al. Arterioscler Thromb Vasc Biol. 2004;24:1272-77.

In progressors

Follow-up (years)

Surv

ival

Pro

babi

lity

0.50

0.75

1.00

CAC > 100 to 400

0 5 10 15 20

CAC > 400

CAC = 0

CAC > 1 to 100

Follow-up (years)

Surv

ival

Pro

babi

lity

0.50

0.75

1.00

CAC > 100 to 400

0 5 10 15 20

CAC > 400

CAC = 0CAC > 1 to 100

In non-progressors

Budoff JACC Imag 2010 4,609 consecutive asymptomatic individuals

ST FRANCIS RANDOMIZED TRIAL Randomized Double Blind Placebo Controlled Trial of Atorvastatin in the Prevention of Cardiovascular Events Among Individuals With Elevated CAC Score

Arad Y et al. J Am Coll Cardiol 2005: 46: 166-172.

Atorvastatin 20 mg (N=490)

MI

Stroke

CVD Death

CABG/PTCA

No Prior CVD Men, Women 50-70 years

CAC >80%

of age-gender

Placebo (N=515)

•Mean duration of treatment was 4.3 years. •Treatment with atorvastatin reduced clinical endpoints by 30% (6.9% vs. 9.9%), and MI/ Death by 44% (NNT 30) •Event rates were more significantly reduced in participants with baseline calcium score >400 (8.7% vs. 15.0%, p=0.046 [42% reduction]). (NNT 16)

OUTDATED and UNPROVEN FALLACIES

l Radiation – every study published since 2014 demonstrates median doses of radiation of CAC to be <1 mSev (similar to breast mammogram screening or abdominal CT screening for aneurysms)

l Anxiety over abnormal results – not only never demonstrated, but Taylor and O’Malley actually demonstrated this to be false, in their randomized trial (JAMA 2003) there was no increase in anxiety or

UNPROVEN FALLACIES – Part 2

l Overtesting – “High Agatston score did not result in increased revascularization, and knowledge of the presence of coronary calcium did not increase revascularizations” n Budoff JCCT 2013 – MESA (CAC reported) vs

RECALL (CAC not reported) population based studies

Carotid Intima-media Thickness

•Normal and diseased arterial histology

A Picture is Worth a Thousand Words..

2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk

• The addition of CIMT measures to FRS was associated with small improvement to risk prediction, but this improvement is unlikely to be of clinical importance (NR = 3.6%)1

• CIMT is not recommended for routine measurement in clinical practice for risk assessment for a first ASCVD event (Class III recommendation) 1. JAMA 2012: 796-803

MESA – CIMT vs. CCA

Carotid Intima-Media Thickness Is Only Weakly Correlated With the Extent and Severity of

Coronary Artery Disease

Mark R. Adams, MBBS, FRACP; Akihiro Nakagomi, MD; Anthony Keech, MBBS, MEpidemiol, FRACP; Jacqui Robinson, RN; Robyn McCredie, BSc;

Brian P. Bailey, MBBS, FRACP; S. Ben Freedman, MBBS, PhD, FRACP; David S. Celermajer, MBBS, PhD, FRACP

Circulation 1995;92:2127-34

Echolucent (soft) Carotid Plaque Predict Coronary Event Risk

• 215 stable CAD pts.; followed monthly X 30 months or until an event

• 112 had echolucent (soft) plaques 29 coronary events

• 103 without soft plaques 4 coronary events

• Presence of soft carotid plaques associated with higher risk of coronary events – p<0.001

• 11 strokes - 10 in group with soft plaque

Osamu Honda,MD et.al.; Journal of ACC, vol. 43, No. 7, 2004: 1177-1184

114 “The crack can be fixed --

it’s your cholesterol level that worries me.”

y access to immediate PCI for STEMI, it would save lives.

How much would we have to lower LDL in every adult to save an equal number of lives ?

Answer : 1.4 mg/dl !

OR for risk of CHD with each unit lower LDL (meta-analyses of Mendelian randomization studies and of statin trials)

Effect of Lower LDL Beginning Early in Life on Risk of CHD

Ference et al JACC Nov 2012

Earlier Later

LDL Exposure over time : Equivalent to ‘Pack-Years’ ?

1 PPD X 40 Yrs 2 PPD X 20 Yrs

LDL 300 X 20 Yrs

} 40 pack-Years

} 6000 LDL-Years

Steinberg & Grundy J Am Coll Cardiol Nov 2012

LDL 200 X 30 Yrs LDL 120 X 50 Yrs

Primary Prevention: Crucial Opportunity to Reduce the

Burden of CHD

Law MR et al. BMJ 1994;308:367-372.

Age 70

Reduction in risk in men with 10% reduction in cholesterol (10 cohort studies)

Age 50

Age 40

120

0

1

2

3

100 160 220 8565

4525

LDL-C, mg/dL

HDL-C, mg/dL

Ris

k of

CH

D

Patient 1 LDL-C 100 mg/dL HDL-C 65 mg/dL Risk level 0.4 Patient 2 LDL-C 100 mg/dL HDL-C 45 mg/dL Risk level 0.6 Patient 3 LDL-C 100 mg/dL HDL-C 25 mg/dL Risk level 1.2 Patient 4 LDL-C 220 mg/dL HDL-C 45 mg/dL Risk level 1.2

*Men 50 to 70 years of age Castelli WP. Can J Cardiol. 1988;4(suppl A):5A-10A.

3

2

1

4 Equivalent Risk

0

5

10

15

20

25

0 20 40 60 80 100

Outcome Data Lack of Similar Benefit

VA-HIT AIM-HIGH

HERS

ILLUMINATE

HHS

BIP FIELD ACCORD

HDL-C (mg/dL)

% w

ith C

V Ev

ent

No Relationship of HDL raising and decreased events

statin trials ?

Statin Relation of HDL

to CV risk TNT Atorvastatin 10 mg Positive TNT Atorvastatin 80 mg Null

PROVE-IT Atorvastatin 80 mg Null PROVE-IT Pravastatin 40 mg Null

AFCAPS/Tex CAPS Lovastatin 20/40 mg Null LIPID Pravastatin 40 mg Null CARE Pravastatin 40 mg Null

4S Simvasatin 20/40 Null JUPITER Rosuvastatin 20 mg Null

Saely Lancet 376; 9754, (2010) pp 1738

In statin trials, HDL has minimal effect on CV Events

raise it ?

Niacin None

Fibrates None

CETP Inh None – Raises

It depends on how you raise the HDL

Intervention Effect on MI Exercise Lowers Alcohol (F1/d;M2/d) Lowers D/C Smoking Lowers Weight Loss Lowers Low Saturated Fat Diet

Lowers

©2012 MFMER | 3170367-

125

Major Statin Trials : Similar LDL Reduction & Benefit

50 210 LDL-C (mg/dL)

70 190 170 150 130 110 90 0

5

10

15

20

25

% w

ith C

AD e

vent

Relationship of LDL lowering and decreased events

©2012 MFMER | 3170367-

126

Major Statin Trials : Similar LDL Reduction & Benefit

50 210 LDL-C (mg/dL)

70 190 170 150 130 110 90 0

5

10

15

20

25

% w

ith C

AD e

vent

Secondary

Mixed

Primary

Relationship of LDL lowering and decreased events

©2012 MFMER | 3170367-

127

50 210 LDL-C (mg/dL)

70 190 170 150 130 110 90 0

5

10

15

20

25

% w

ith C

AD e

vent

WOSCOPS

AFCAPS

CARE

4S

LIPID

HPS

PROSPER

Secondary

Mixed

Primary

ASCOT-LLA

PROVE IT

TNT

JUPITER

Relationship of LDL lowering and decreased events

Major Statin Trials : Similar LDL Reduction & Benefit

Walking the dog

Courtesy Jim Sowers

©2004 PPS®

Hypertension Obesity Hyper- insulinemia Diabetes Hypertri-

glyceridemia Small,

dense LDL Low HDL Hypercoagu-lability

Atherosclerosis

Insulin Resistance

Interrelation Between Atherosclerosis and Insulin Resistance

“Houston—We Have a Problem!! Prevalence in US

Prevalence

(%)

0

5

10

15

20

25

30

35

40

45

20-29 30-39 40-49 50-59 60-69 >70

Men Women

Age (years) 8814; NHANES III; 1988-1994; ATP III criteria

Ford E et al. JAMA. 2002(287): 356

Cardiovascular Mortality Associated With Metabolic Syndrome (MS)

NHANES III data; ATP III criteria

0

2

4

6

8

10

12

No MS MS

Incidence of CV

Mortality

Isomaa, et al Diabetes Care 2001; 24:683.

14

2.2%

12.0% P<0.001

70

80

90

100

Diet and Heart Disease Lyon Diet Heart Study: Cumulative Survival without Cardiac Death and Nonfatal MI post MI

de Lorgeril M et al. Circulation 1999;99:779-785. ã1999 Lippincott Williams & Wilkins. www.lww.com

1

% W

ithou

t Ev

ent

Canola oil margarine, low cholesterol, low saturated fat, high in fruits and vegetables, high fiber

Experimental Diet

Control AHA Diet

P = 0.0001

Year 2 3 4 5

Heart Disease and Exercise • FACT:

– 30 minutes of modest exercise decreases heart disease deaths by 50%

• GOAL: – Individual prescription and assessment – 30-60 minutes of aerobic activity daily – Resistance training 2-3x week – MEDICALLY SUPERVISED program for high

risk patients • The more you do …the greater the

benefit

Diabetes Prevention Program (DPP): Results

29%

22%

14%

PLACEBO

Developed Diabetes

Risk Reduction

METFORMIN

INTENSIVE LIFESTYLE

INTERVENTION

31%

58%

DPP Research Group. NEJM. 2002;346:393-403.

CV Mortality Risk Doubles with Each 20/10 mm Hg BP Increment*

*Individuals aged 40-70 years, starting at BP 115/75 mm Hg. CV, cardiovascular; SBP, systolic blood pressure; DBP, diastolic blood pressure Lewington S, et al. Lancet. 2002; 60:1903-1913. JNC 7. JAMA. 2003;289:2560-2572.

CV mortality

risk

SBP/DBP (mm Hg)

0

1

2

3

4

5

6

7

8

115/75 135/85 155/95 175/105

Achieving low BP and very low LDL slows progression of atherosclerosis

• Progression of atherosclerosis as measured by IVUS (atheroma volume)

• Patients with CAD in 7 trials: REVERSAL, CAMELOT, ACTIVATE, ASTEROID, ILLUSTRATE, PERISCOPE, STRADIVARIUS

• LDL < 70 and BP <120 best group • Chhatriwalla AK, Nicholls SJ, Wang TH, et al. Low levels of low-density

lipoprotein cholesterol and blood pressure and progression of coronary atherosclerosis. J Am Coll Cardiol 2009; 53: 1110-1115.

Sleep Apnea—and CV Risk

Sleep disorders are relevant to: – Arrhythmias – CAD and its progression – Sympathetic stimulation – Hypertension – Cardiomyopathy (CMO) – Heart failure (CHF) – Stroke – Diabetes and Metabolic Syndrome

Subclinical Atherosclerosis

Widowmakerthemovie.com

“A new scientific truth is not usually presented in a way that convinces its opponents, rather, the opponents gradually die off and a rising generation becomes familiar with the truth from the start.” --Max Planck

Questions?

•gary.oppenheim@swedish.org Cell 206-795-5558