Arshed A. Quyyumi MD

1
Current management of stable coronary artery
disease
Atlanta
Arshed A. Quyyumi MD Professor of
Medicine Division of CardiologyEmory University
School of Medicine Atlanta, Georgia, USA

2
Stable CAD Multiple treatment options
Beta blockers Calcium
antagonists Nitrates Ranolazine Lifestyle Interev
ntion Aspirin Lipid lowering ACE
inhibitors ARBs Rx Insulin resistance
Lifestyle intervention
Medicaltherapy
Reduce symptomsTreat underlying disease
CABG
PCI
3
Severe obstruction (angina, no rupture) vs mild
obstruction (no angina, likely to rupture)

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

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

• Plaque rupture
• Acute MI
• Unstable angina
• Sudden death

• Exertional angina
• () ETT

Revascularization Anti-anginal Rx
Pharmacologic stabilization Early identification
of high-risk?
Courtesy of PH Stone, MD.
4
Components of Secondary Prevention
Cigarette smoking cessation Blood pressure control Lipid management to goal Physical activity Weight management to goal Diabetes management to goal
Antiplatelet agents / anticoagulants
Renin angiotensin aldosterone system blockers
Beta blockers
AHA/ACC Guidelines for Secondary Prevention for
Patients with Coronary and Other Atherosclerotic
Vascular Disease 2006 Update
5
Landmark Statin Trials
4S WOSCOPS CARE AFCAPS/TexCAPS LIPID

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

1994
1995
1996
1998
MIRACLHPSPROSPER ALLHAT-LLT ASCOT CARDS ALLIANCE
PROVE IT A to Z

• Focus on other high-risk groups
• ACS, elderly, diabetes, hypertension

2001
2002
2003
2004

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

TNT IDEAL SPARCL

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

2005
2006
6
STATINS

• Goal of therapy
• Mechanisms of action of statins
• Regression of atherosclerosis?
• Non-lipid lowering effects

7
(No Transcript)
8
Effect of Intensive Compared With Moderate
Lipid-Lowering Therapy on Progression of Coronary
Atherosclerosis
JAMA, March 3, 2004Vol 291, No. 9 1071
9
Effect of 13 weeks of statin therapy on carotid
plaque composition
MMP-2
TIMP-1
control
pravastatin
Circulation 2001102928
10
Pleiotropic effects of statins
? Coagulation
? Endothelial progenitor cells
? Platelet activation
? Endothelial function
? Effects on collagen
? NO bioactivity
Statins
? Reactive oxygen species
? MMPs
? AT1 receptor
? VSMC proliferation
? Macrophages
? Inflammation
? Immunomodulation
? Endothelin
Liao JK. Am J Cardiol. 200596(suppl 1)24F-33F.
MMPs matrix metalloproteinases
11
Should low cholesterol be lowered in the high
risk patient? What is the goal for statin
therapy?
12
Elevated Cholesterol Levels AssociatedWith High
Risk of CHD
Adapted from Martin MJ, et al. Lancet.
19862933-936, with permission Reproduced from
Castelli WP. Am J Med. 1984764-12, with
permission
13
(No Transcript)
14
HMG-CoA Reductase Inhibitor Secondary Prevention
Relationship between LDL Levels and Event Rates
in Secondary Prevention Trials of Patients with
Stable CHD
Event()
LaRosa JC et al. N Engl J Med. 2005352.
15
Statin benefit independent of baseline lipids
Meta-analysis of 14 trials
Groups
Events ()
Treatment(45,054)
Control(45,002)
Controlbetter
Treatment better
Total-C (mg/dL)
13.5
0.76
16.6
201
0.79
13.9
gt201-251
17.4
0.80
gt251
15.2
19.7
LDL-C (mg/dL)
0.76
13.4
16.7
135
0.79
14.2
17.6
gt135-174
20.4
15.8
0.81
gt174
HDL-C (mg/dL)
0.78
22.7
35
18.2
18.2
gt35-43
0.79
14.3
14.2
gt43
11.4
0.79
TG (mg/dL)
0.79
13.4
16.8
124
0.78
18.0
gt124-177
13.8
0.80
15.3
18.8
gt177
0.79
Overall
17.8
14.1
1.5
1.0
0.5
Relative risk
CHD death, MI, stroke, coronary
revascularizationCholesterol Treatment
Trialists Collaboration
CTT Collaborators. Lancet. 20053661267-78.
16
Components of Secondary Prevention
Cigarette smoking cessation Blood pressure control Lipid management to goal Physical activity Weight management to goal Diabetes management to goal
Antiplatelet agents / anticoagulants
Renin angiotensin aldosterone system blockers
Beta blockers
17
Exercise Evidence Mortality 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
20001021358-1363
18
New lifestyle guidelines More exercise, fruits
and vegetables
2000 Report 2005 Report
Exercise
gt 30 min of moderate physical activity 5-7 days/week gt 30 min of moderate physical activity 5-7 days/week gt 30 min of moderately intense exercise every day 60 min to prevent weight gain
5 servings/day 5 servings/day gt 9 servings/day

Fruits and vegetables
www.healthierus.gov/dietaryguidelines. Feb 2005.
19
Adiposity predicts mortality
National Institutes of Health-AARP Diet and
Health Study 527,265 men and women age 50-71 years
3.0
2.5
2.0
Relative
risk of
1.5
death
1.0
0
0
20
25
30
35
40
45
Current BMI (kg/m2)
All men (n 313,047 42,173 deaths)All women (n
214,218 19,144 deaths)
Adams KF et al. New Engl J Med. 2006355763-78.
20
Weight Management Recommendations
Goal BMI 18.5 to 24.9 kg/m2 Waist Circumference
Men lt 40 inches (lt 35.4 or 90cm SA) Women lt
35 inches (lt 31.5 or 90cm SA)

• Assess BMI and/or waist circumference on each
  visit encourage weight maintenance
• physical 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 BMI25-30 kg/m2.
Obesity is defined by a BMI gt30 kg/m2.
21
Diet reduces mortality in primary prevention
trials

• 2002
• Physicians Health Study(N 20,551)

• 2003
• Cardiovascular Health Study(N 5,201)

• 2002
• Nurses Health Study(N 84,688)

• 2003
• European Prospective Investigation into Cancer
  and NutritionGreek cohort (N 22,043)

• 2005
• European Prospective Investigation into Cancer
  and Nutritionelderly cohort (N 74,607)

2004 The Healthy Aging A Longitudinal Study in
Europe (N 2339)
Parikh P et al. J Am Coll Cardiol.
2005451379-87. Trichopoulou A et al. BMJ.
2005330991-7. Knoops KTB et al. JAMA.
20042921433-9.
Blood levels of n-3 fatty acids inversely
related to death Greater adherence associated
with lower mortality
22
Nine Main Components of the Mediterranean diet

• 1) Abundance of plant food
• whole grain breads, pastas, cereals,
• Fruits and Vegetables
• Beans
• Nuts/Seeds
• 2) Minimally Processed Fresh Foods
• 3) Desserts composed mainly of fresh fruits with
  rare sweets containing refined sugars or honey
• 4) Olive Oil as principal source of fat
• 5) Daily Dairy product (cheese or yogurt) in low
  to moderate amounts
• 6) Fish and Poultry in low to moderate amounts
• 7) Up to four eggs weekly
• 8) Rare Red Meat
• 9) Wine in low to moderate amounts with meals

23
Components of Secondary Prevention
Cigarette smoking cessation Blood pressure control Lipid management to goal Physical activity Weight management to goal Diabetes management to goal
Antiplatelet agents / anticoagulants
Renin angiotensin aldosterone system blockers
Beta blockers
24
Aspirin Evidence Dose and Efficacy
Indirect Comparisons of Aspirin Doses on Vascular
Events in High-Risk Patients
Antithrombotic Trialists Collaboration. BMJ.
200232471-86
25

• Renin-Angiotensin-Aldosterone System Blockers
  Recommendations

26
CV and renal continuum RAAS as a mediator of
pathophysiology
Atherothrombosis progressive CVD
Tissue injury (MI, stroke,renal insufficiency,
PAD)
Early tissue dysfunction
Pathological remodeling
RAAS
Oxidative mechanical stress inflammation
Target organ damage
Vasoconstriction/Na/H2Oretention (High BP)
End-organ failure (CHF, ESRD)
Risk factors
Death
ESRD end-stage renal disease.
Adapted from Dzau V et al. Circulation.
20061142850-70.
27
EUROPA, HOPE, PEACE, QUIET Effect of ACEIs on
CV endpoints
EUROPA CV death/MI/cardiac arrest
HOPECV death/MI/stroke
Placebo
15
20
Placebo
22 RRR HR 0.78 (0.700.86) P lt 0.001
20 RRR HR 0.80 (0.710.91) P 0.0003
15
10
10
Ramipril 10 mg
Perindopril 8 mg
5
5
0
0
0
2
4
1
3
1
3
4
0
5
2
Patients ()
PEACECV death/MI/CABG/PCI
QUIETCV death/MI/cardiac arrest
Placebo
8
30
Placebo
5
13 RRR HR 0.87 (0.591.29)
4 RRR HR 0.96 (0.881.06) P 0.43
20
Trandolapril 4 mg
3
10
Quinapril 20 mg
1
0
0
0
1
2
3
1
2
3
4
5
6
Time (years)
Fox KM et al EUROPA study. Lancet.
2003362782-8. Yusuf S et al HOPE study. N Engl
J Med. 2000342145-53. Braunwald E et al PEACE
trial. N Engl J Med. 20043512058-68. Pitt B et
al QUIET study. Am J Cardiol. 2001871058-63.
Primary endpointSecondary endpoint
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VALIANT ACEI and ARB show similar effects in
post-MI patients with LV dysfunction
Death from any cause
Combined CV endpoint
0.4
0.4
0.3
0.3
Probability of event
0.2
0.2
0.1
0.1
0.0
0.0
0
6
12
18
24
30
36
6
12
18
24
30
36
0
Months
Months
Captopril n 4909
Valsartan/captopriln 4885
Valsartann 4909
CV death, reinfarction, or hospitalization for
HF.
Pfeffer MA et al. N Engl J Med. 20033491893-906.
29
ONTARGET Time to primary outcome
N 25,620 with vascular disease or high-risk
diabetes
0.20
0.15
Cumulative hazard ratio
0.10
0.05
0.00
0
1
2
3
4
5
Follow-up (years)
Ramipril
Telmisartan
Telmisartan plus ramipril
ONTARGET Investigators. N Engl J Med.
20083581547-59.
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AHA/ACC guidelines for secondary CVD
prevention2006 Update ACEI and ARB
ACEI
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.
2006472130-9.
LOE level of evidence
31

• b-blocker Recommendations

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b-blocker Evidence
Summary of Secondary Prevention Trials of
b-blocker Therapy
Total Patients
Phase of Treatment
RR (95 CI)
28,970
0.87 (0.77-0.98)
Acute treatment
24,298
0.77 (0.70-0.84)
Secondary prevention
53,268
0.81 (0.75-0.87)
Overall
0.5
1.0
2.0
RR of death
b-blocker better
Placebo better
CIConfidence interval, RRRelative risk
Antman E, Braunwald E. Acute Myocardial
Infarction. In Braunwald E, Zipes DP, Libby P,
eds. Heart Disease A textbook of Cardiovascular
Medicine, 6th ed., Philadelphia, PA W.B.
Sanders, 2001, 1168.
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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.
34
COURAGE Defining optimal care
Clinical Outcomes Utilizing Revascularization and
Aggressive Drug Evaluation
Intensive lifestyle intervention
Intensive medicaltherapy
Reduce symptomsTreat underlying disease
Revascularization?
35
COURAGE Study design
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)
Optimal medical therapy PCI (n 1149)
Optimal medical therapy(n 1138)
Randomized
Primary outcomes All-cause mortality, nonfatal MI
Secondary outcomes Death, MI, stroke ACS
hospitalization
Follow-up Median 4.6 years
Intensive pharmacologic therapy lifestyle
interventionCCS Canadian Cardiovascular Society
Boden WE et al. Am Heart J. 20061511173-9.
Boden WE et al. N Engl J Med. 20073561503-16.
36
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
Patients who underwent previous CABGP 0.01
Boden WE et al. N Engl J Med. 20073561503-16.
37
COURAGE Treatment effect on primary outcome
All-cause death, MI
1.0
0.9
0.8
Survival free of primary outcome
HR 1.05 (0.87-1.27) P 0.62
0.7
0.6
0.5
0
0
2
4
7
6
5
3
1
Years
Medical therapy PCI medical
therapy
No. at risk Medical therapy 1138 1017 959 834 638
408 192 30 PCI 1149 1013 952 833 637 417 200 35
Unadjusted, log-rank
Boden WE et al. N Engl J Med. 20073561503-16.
38
COURAGE Treatment effect on angina
NS
P 0.02
P lt 0.001
Angina-free()
NS
Years
Boden WE et al. N Engl J Med. 20073561503-16.
39
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

Boden WE et al. N Engl J Med. 20073561503-16.
40
Pfisterer and Gersh Lancet 2010
41
BARI 2D Study design
42
BARI 2D Enrollment, randomization, and treatments
43
BARI 2D All-cause death for medical therapy vs
type of revascularization
44
BARI 2D Death, MI, stroke for medical therapy vs
type of revascularization
45
BARI 2D All-cause death by type of insulin
therapy
46
BARI 2D Conclusions
47
BARI 2D Implications
48
Stable CAD Multiple treatment options
Aspirin Beta blockers Calcium
antagonists Ranolazine Lipid lowering ACE
inhibitors ARBs
Lifestyle intervention
Medicaltherapy
Reduce symptomsTreat underlying disease
CABG
PCI
Thank you