Arshed A. Quyyumi MD Professor of Medicine

Arshed A. Quyyumi MDArshed A. Quyyumi MDProfessor of MedicineProfessor of MedicineDivision of CardiologyDivision of Cardiology

Emory University School of MedicineEmory University School of MedicineAtlanta, Georgia, USAAtlanta, Georgia, USA

Atlanta

Current management of stable Current management of stable coronary artery diseasecoronary artery disease

Stable CAD: Multiple treatment options

Reduce symptoms

Treat underlying

diseasePCI

Lifestyle intervention

CABG

Medicaltherapy

Beta blockersCalcium antagonistsNitratesRanolazine

LifestyleInterevntionAspirinLipid loweringACE inhibitorsARBsRx Insulin resistance

Severe obstruction (angina, no rupture) vs mild obstruction (no angina, likely to rupture)

RevascularizationAnti-anginal Rx

Exertional angina• (+) ETT

Severe fibrotic plaque• Severe obstruction• No lipid• Fibrosis, Ca2+

Pharmacologic stabilizationEarly identification of high-risk?

Plaque rupture• Acute MI• Unstable angina• Sudden death

Vulnerable plaque• Minor obstruction• Eccentric plaque• Lipid pool• Thin cap

Courtesy of PH Stone, MD.

Components of Secondary Prevention

Cigarette smoking cessationCigarette smoking cessationBlood pressure controlBlood pressure controlLipid management to goalLipid management to goalPhysical activityPhysical activityWeight management to goalWeight management to goalDiabetes management to goalDiabetes management to goalAntiplatelet agents / anticoagulantsAntiplatelet agents / anticoagulantsRenin angiotensin aldosterone Renin angiotensin aldosterone system blockerssystem blockersBeta blockersBeta blockers

AHA/ACC Guidelines for Secondary Prevention for Patients with Coronary and Other

Atherosclerotic Vascular Disease: 2006 Update

Landmark Statin Trials Landmark Statin Trials

MIRACLHPSPROSPERALLHAT-LLTASCOTCARDSALLIANCEPROVE ITA to Z

Focus on other high-risk groups:Focus on other high-risk groups:– ACS, elderly, diabetes, hypertensionACS, elderly, diabetes, hypertension

TNTIDEALSPARCL

Focus on the value of intensive statin treatment in:Focus on the value of intensive statin treatment in:– Higher-risk patients with CHDHigher-risk patients with CHD– Patients with prior stroke or TIA without established Patients with prior stroke or TIA without established

CHDCHD

4SWOSCOPSCAREAFCAPS/TexCAPSLIPID

Early trials proved relative risk reduction in Early trials proved relative risk reduction in morbidity and mortality vs placebomorbidity and mortality vs placebo

Comparisons beyond placeboComparisons beyond placebo– Versus usual care (ALLIANCE, ALLHAT-LLT)Versus usual care (ALLIANCE, ALLHAT-LLT)– Active comparator (PROVE IT, A to Z)Active comparator (PROVE IT, A to Z)

STATINS

Goal of therapy

Mechanisms of action of statins– Regression of atherosclerosis?– Non-lipid lowering effects

JAMA, March 3, 2004—Vol 291, No. 9 1071

Effect of Intensive Compared With Moderate Lipid-Lowering Therapy on Progression of Coronary

Atherosclerosis

Effect of 13 weeks of statin therapy on carotid plaque composition

MMP-2

TIMP-1

control pravastatin Circulation 2001;102:928

VBWG

Liao JK. Am J Cardiol. 2005;96(suppl 1):24F-33F.MMPs = matrix metalloproteinases

Platelet activation

Coagulation

Endothelial progenitor cells

Effects on collagen

MMPs

AT1 receptor VSMC proliferation

Endothelin

Macrophages Inflammation Immunomodulation

Endothelial function

Reactive oxygen species

NO bioactivity

Pleiotropic effects of statins

Statins

Should “low” cholesterol be Should “low” cholesterol be lowered in the high risk patient?lowered in the high risk patient?

What is the goal for statin What is the goal for statin therapy?therapy?

Elevated Cholesterol Levels AssociatedElevated Cholesterol Levels AssociatedWith High Risk of CHDWith High Risk of CHD

Multiple Risk Factor Intervention Trial(MRFIT) (N=361,662)

Framingham Study(N=5209)

Adapted from Martin MJ, et al. Lancet. 1986;2:933-936, with permissionReproduced from Castelli WP. Am J Med. 1984;76:4-12, with permission

Total Cholesterol (mg/dL)

6-Y

ear

CH

D I

nci

de

nce

p

er 1

000

Men

204 205–234 235–264 265–294 295

0

25

50

75

100

125

150

Ag

e-A

dju

sted

6-Y

ear

CH

D

Mo

rtal

ity

per

100

0 M

en

Total Cholesterol (mg/dL)

0

2

4

6

8

10

12

14

16

18

160 200 260 300140 180 220 240 280 320

Each 1% reduction in total cholesterol resulted in a 2% decrease in CHD risk

Each 1% increase in total cholesterol associated with a 2% increase in CHD risk

LaRosa JC et al. N Engl J Med. 2005;352.

0

30

5

10

15

20

25

Statin

Placebo

HPS

CARE

LIPID

HPS

CARE

LIPID

4S

4S

LDL cholesterol (mg/dL)0 2101901701501301109070

TNT (80 mg atorvastatin)

TNT (10 mg atorvastatin)

Event(%)

Relationship between LDL Levels and Event Rates in Secondary Prevention Trials of Patients with Stable CHD

HMG-CoA Reductase Inhibitor: Secondary HMG-CoA Reductase Inhibitor: Secondary PreventionPrevention

Statin benefit independent of baseline lipids: Meta-analysis of 14 trials

Groups

13.5 0.760.790.80

0.76

Total-C (mg/dL)

>201-251>251

LDL-C (mg/dL)

13.915.2

13.414.215.8

18.214.311.4

13.4

18.818.016.8

14.218.222.7

17.616.7

19.717.416.6

HDL-C (mg/dL)≤35

>35-43

0.79

0.780.790.79

0.790.780.80

>43

≤124>124-177

>177

Events (%)

Treatment(45,054)

Control(45,002)

Treatment better

Controlbetter

1.51.00.5

≤201

0.8120.4

13.815.3

>135-174>174

≤135

0.79

TG (mg/dL)

Overall 17.814.1

CTT Collaborators. Lancet. 2005;366:1267-78.CHD death, MI, stroke, coronary revascularizationCholesterol Treatment Trialists’ Collaboration

Relative risk



Observational study of self-reported physical activity in 772 men with established coronary heart disease

Light or moderate exercise is associated with lower risk

Wannamethee SG et al. Circulation 2000;102:1358-1363

Exercise Evidence: Mortality RiskExercise Evidence: Mortality Risk

Adiposity predicts mortality

Adams KF et al. New Engl J Med. 2006;355:763-78.

Relative risk of death

All men (n = 313,047; 42,173 deaths)All women (n = 214,218; 19,144 deaths)

2.0

1.5

1.0

00 20 25 30 35 40 45

Current BMI (kg/m2)

3.0

2.5

National Institutes of Health-AARP Diet and Health Study527,265 men and women age 50-71 years

Weight Management RecommendationsWeight Management Recommendations

III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII

Goal: BMI 18.5 to 24.9 kg/m2Waist Circumference: Men: < 40 inches (< 35.4’ or 90cm SA) Women: < 35 inches (< 31.5” or 90cm SA)


Assess BMI and/or waist circumference on each visit encourage weight maintenancephysical activity, caloric intake, behavioral programs

If waist circumference high: lifestyle changes and consider treatment strategies for metabolic syndrome.

Goal: reduce body weight by 10 percent

*BMI is calculated as the weight in kilograms divided by the body surface area in meters2. Overweight state is defined by BMI=25-30 kg/m2. Obesity is defined by a BMI >30 kg/m2.


Parikh P et al. J Am Coll Cardiol. 2005;45:1379-87.Trichopoulou A et al. BMJ. 2005;330:991-7.Knoops KTB et al. JAMA. 2004;292:1433-9.

2005European Prospective Investigation into Cancer and Nutrition–elderly cohort (N = 74,607)†

*Blood levels of n-3 fatty acids inversely related to death†Greater adherence associated with lower mortality

2002Nurses’ Health Study(N = 84,688)

2004The Healthy Aging: A Longitudinal Study in Europe (N = 2339)

2002Physician’s Health Study(N = 20,551)*

2003Cardiovascular Health Study(N = 5,201)*

2003European Prospective Investigation into Cancer and Nutrition–Greek cohort (N = 22,043)†

Diet reduces mortality in primary prevention trials

1) Abundance of plant food – whole grain breads, pastas, cereals,– Fruits and Vegetables– Beans– Nuts/Seeds

2) Minimally Processed Fresh Foods3) Desserts composed mainly of fresh fruits with rare sweets containing refined sugars or honey 4) Olive Oil as principal source of fat5) Daily Dairy product (cheese or yogurt) in low to moderate amounts6) Fish and Poultry in low to moderate amounts7) Up to four eggs weekly8) Rare Red Meat 9) Wine in low to moderate amounts with meals

Nine Main Components of the Mediterranean diet:



Aspirin Evidence: Dose and EfficacyAspirin Evidence: Dose and Efficacy

0.5 1.0 1.5 2.0

500-1500 mg 34 19

160-325 mg 19 26

75-150 mg 12 32

<75 mg 3 13

Any aspirin 65 23

Antiplatelet Better Antiplatelet Worse

Aspirin Dose No. of Trials (%)Odds Ratio for

Vascular Events

0

P<.0001

Indirect Comparisons of Aspirin Doses on Vascular Events in High-Risk Patients

Antithrombotic Trialists Collaboration. BMJ. 2002;324:71-86

Renin-Angiotensin-Aldosterone Renin-Angiotensin-Aldosterone System Blockers RecommendationsSystem Blockers Recommendations

CV and renal continuum: RAAS as a mediator of pathophysiology

Adapted from Dzau V et al. Circulation. 2006;114:2850-70.

Risk factors

Vasoconstriction/Na/H2Oretention (High BP)

Oxidative & mechanical stressinflammation

Early tissue dysfunction

Atherothrombosis& progressive CVD

Tissue injury (MI, stroke,renal insufficiency, PAD)

Pathological remodeling

Target organ damage

End-organ failure(CHF, ESRD)

Death

RAAS

ESRD = end-stage renal disease.

EUROPA, HOPE, PEACE, QUIET: Effect of ACEIs on CV endpoints

Fox KM et al; EUROPA study. Lancet. 2003;362:782-8.Yusuf S et al; HOPE study. N Engl J Med. 2000;342:145-53.

Braunwald E et al; PEACE trial. N Engl J Med. 2004;351:2058-68.Pitt B et al; QUIET study. Am J Cardiol. 2001;87:1058-63.

*Primary endpoint†Secondary endpoint

EUROPACV death/MI/cardiac arrest*

PEACECV death/MI/CABG/PCI*

HOPECV death/MI/stroke*

15

5

10

0

20

0

Placebo

Ramipril 10 mg

2 41

22% RRRHR 0.78 (0.70–0.86)P < 0.001

3

5

10

0

15Placebo

Perindopril 8 mg

20% RRRHR 0.80 (0.71–0.91)P = 0.0003

5

0

8

0

Placebo

Quinapril 20 mg

1

13% RRRHR 0.87 (0.59–1.29)

1

2 3

QUIETCV death/MI/cardiac arrest†

Time (years)

Trandolapril4 mg

Placebo30

20

10

1 2 3 4 50

6

4% RRRHR 0.96 (0.88–1.06)P = 0.43

Patients(%)

1 3 40 52

3

VALIANT: ACEI and ARB show similar effects in post-MI patients with LV dysfunction

0.4

0.3

0.2

0.1

0.00 6 12 18 24 30 36

0.4

0.3

0.2

0.1

0.0

6 12 18 24 30 36Months Months

Probabilityof event

Death from any cause Combined CV endpoint*

0

Captopriln = 4909

Valsartan/captopriln = 4885

Valsartann = 4909

*CV death, reinfarction, or hospitalization for HF.Pfeffer MA et al. N Engl J Med. 2003;349:1893-

906.

ONTARGET: Time to primary outcomeN = 25,620 with vascular disease or high-risk diabetes

ONTARGET Investigators. N Engl J Med. 2008;358:1547-59.

Telmisartan

0.20

0.15

0.10

0.05

0.000 1 2 3 4 5

Ramipril Telmisartan plus ramipril

Cumulative hazard ratio

Follow-up (years)

AHA/ACC guidelines for secondary CVD prevention—2006 Update: ACEI and ARB

– Use indefinitely in all patients with LVEF ≤40% and in those with HTN, T2DM, or chronic kidney disease unless contraindicated • LOE I (A)

– Consider in all other (high- risk) patients • LOE I (B)

– Use in ACEI-intolerant patients with HF and in post-MI patients with LVEF ≤40% • LOE I (A)

– Consider in other ACEI-intolerant patients • LOE I (B)

Smith SC Jr et al. J Am Coll Cardiol. 2006;47:2130-9.LOE = level of evidence

ACEI ARB

What is the definitive role of PCI in chronic angina and stable CAD?

• PCI improves angina and short-term exercise capacity

• However, compared to optimal medical therapy, does PCI– Prolong survival?– Reduce risk of subsequent MI?– Reduce hospitalization for unstable angina?– Decrease need for subsequent CABG?– Improve quality of life?

Courtesy of WE Boden, MD.

COURAGE: Defining optimal care

Reduce symptoms

Treat underlying

disease

Revascularization?

Intensive lifestyle

intervention

Intensive medicaltherapy

Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation

COURAGE: Study design

Boden WE et al. Am Heart J. 2006;151:1173-9. Boden WE et al. N Engl J Med. 2007;356:1503-16.

Optimal medical therapy* + PCI (n = 1149)

Optimal medical therapy*(n = 1138)

AHA/ACC Class I/II indications for PCI, suitable coronary artery anatomy + ≥70% stenosis in ≥1 proximal epicardial vessel + objective evidence of ischemia

(or ≥80% stenosis + CCS class III angina without provocation testing)

Primary outcomes: All-cause mortality, nonfatal MI

Follow-up: Median 4.6 years

Randomized

*Intensive pharmacologic therapy + lifestyle interventionCCS = Canadian Cardiovascular Society

Secondary outcomes: Death, MI, stroke; ACS hospitalization

COURAGE: Baseline angiographic data

PCI + medical therapy(n = 1149)

Medical therapy(n = 1138)

Vessels with disease (%) 1 2 3

313930

303931

Disease in graft vessel* (%) 62 69

Proximal LAD disease (%) 31 37†

Ejection fraction (%) 60.8 60.9

Boden WE et al. N Engl J Med. 2007;356:1503-16.

*Patients who underwent previous CABG†P = 0.01

COURAGE: Treatment effect on primary outcome

HR 1.05(0.87-1.27)P = 0.62*


All-cause death, MI

*Unadjusted, log-rank

No. at riskMedical therapy 1138 1017 959 834 638 408 192 30PCI 1149 1013 952 833 637 417 200 35

Medical therapy PCI + medical therapy

Survival free of primaryoutcome

0 2 4 70

0.5

0.6

0.7

0.8

1.0

0.9

Years6531

COURAGE: Treatment effect on angina

0

10

20

30

40

50

60

70

80

Baseline 1 3 5

PCI + medical therapy Medical therapy


P < 0.001P = 0.02 NS

Angina-free(%)

NS

Years

COURAGE: Summary and implications

• PCI added to optimal medical therapy did not reduce risk of death, MI, or other major CV events compared with optimal medical therapy alone

• Findings reinforce existing clinical practice guidelines– Optimal medical therapy and aggressive management of

multiple treatment targets without initial PCI can be implemented safely in the majority of patients with chronic stable angina, even those with objective evidence of ischemia and significant multivessel CAD


Pfisterer and Gersh Lancet 2010

BARI 2D: Study design

BARI 2D: Enrollment, randomization, and treatments

BARI 2D: Death, MI, stroke for medical therapy vs type of revascularization

BARI 2D: All-cause death by type of insulin therapy

BARI 2D: Conclusions

BARI 2D: Implications

Stable CAD: Multiple treatment options

Reduce symptoms

Treat underlying

diseasePCI

Lifestyle intervention

CABG

Medicaltherapy

Aspirin

Beta blockersCalcium antagonistsRanolazine

Lipid loweringACE inhibitorsARBs

Thank you

Arshed A. Quyyumi MD Professor of Medicine

Documents

weeks of statin therapy

higherrisk patients

goaldiabetes management

secondary preventionvbwgdraft

high risk patient

rupture vs mild obstruction

lipid fibrosis

relative risk reduction