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
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
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)
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
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.
III IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIII IIaIIaIIa IIbIIbIIb IIIIIIIIIIIaIIaIIa IIbIIbIIb IIIIIIIII
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:
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
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*
Boden WE et al. N Engl J Med. 2007;356:1503-16.
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
Boden WE et al. N Engl J Med. 2007;356:1503-16.
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
Boden WE et al. N Engl J Med. 2007;356:1503-16.
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