1. Coronary Artery Disease Evolving Management Strategies Medicate, Dilate, or Operate?
Bunyad Haider, M.D.FACC;FACP
Professor and Chairman
Dept of Medicine
UMDNJ-New Jersey Medical School
Gordon A. Ewy, MD

2. CV disease: US prevalence
Myocardial ischemia 37 million*
Heart failure 5 million
Acute MI 865,000/year
Chest Pain
4.2 million emergency visits/year 6.4 million outpatient visits/year
Peripheral vascular disease 8 million
Stroke 5.7 million
CV disease: US prevalence
According to the American Heart Association (AHA), approximately 80 million people in the United States have >1 type of cardiovascular (CV) disease.
Mortality data from the National Health Center for Statistics (NCHS), 2006 show CV disease as the underlying cause of death in 36.3% of all 2,398,000 deaths in 2004, or one of every 2.8 deaths in the United States.
According to the NCHS, if all forms of major CV disease were eliminated, life expectancy would rise by almost 7 years.
*Symptomatic coronary artery disease (CAD) or angina pectoris.
American Heart Association. Heart Disease and Stroke Statistics—2007 Update.
Gordon A. Ewy, MD

3. 64-slice multidetectr CT
Gordon A. Ewy, MD

4. Angiography Cannot Detect Coronary Remodeling Intravascular Ultrasound (IVUS) Necessary
3.1 mm
We’ve seen the model, now here we see a living example of Glagov’s model at work
The angiogram at left shows a left anterior ascending coronary; the 2 arrows on the angiogram to the right would appear to indicate 2 similar, healthy arterial segments
The IVUS images of these segments to the right do corroborate that their luminal diameters are equivalent; however, the segment on top has a large atheroma area that was invisible to angiography because it is entirely extraluminal
3.1 mm
Gordon A. Ewy, MD

5. Coronary Artery Disease is Caused by Atherothrombosis
Inflammation
Lipid accumulation
Cell proliferation
Cell death &
Thrombosis
The result is obstruction of the
coronary arteries
Gordon A. Ewy, MD

6. Atherosclerosis: An Inflammatory Disease with or without infection
Slide III.2 C
MMP-9
Atherosclerosis: An Inflammatory Disease*
Atherosclerosis, once regarded largely as a disorder of lipid accumulation, is now generally viewed as an inflammatory disease. The process begins with endothelial dysfunction caused, for example, by modified LDL, an infectious microorganism, or free radicals associated with cigarette smoking. Modified LDL is a major cause of endothelial injury in patients with type 2 diabetes and results from such factors as oxidation and glycation.
Post-insult endothelial changes include increased leukocyte adhesion and migration into the arterial wall, increased permeability to lipoproteins and other plasma constituents, a switch from anticoagulant to procoagulant activity, and formation of cytokines, growth factors, and vasoactive molecules. As the inflammation continues, circulating monocytes and T lymphocytes migrate into the subendothelial space, and macrophages ingest oxidized LDL and are transformed into foam cells. The resulting fatty streak is augmented by migrating/proliferating smooth muscle cells and adherent/aggregating platelets to form an intermediate atherosclerotic lesion.
Activation of T lymphocytes and macrophages also leads to the release of hydrolytic enzymes, cytokines, chemokines, and growth factors, which induce further damage. Eventually, a fibrous cap, which represents a healing response, will form over the mixture of leukocytes, lipid, and debris to wall off the lesion from the lumen. The core of such an advanced lesion may become necrotic. Subsequent thinning and rupture of the fibrous cap appears to be caused by the continued influx and activation of macrophages. Their release of metalloproteinases and other proteolytic enzymes causes degradation of the matrix, followed by possible hemorrhage, thrombus formation, and arterial occlusion.
Ross R. N Engl J Med. 1999;340:
*An animated version of this slide is located in the folder “Animated Slides.”
III.2 © 2002 PPS®
Gordon A. Ewy, MD

7. Preventing CAD 1. Preventing endothelial dysfunction
Focus on risk factors that activate the endothelium
Gordon A. Ewy, MD

8. Arteriothrombotic Risk Factors are additive
Environmental Factors
Diet/Exercise/Drugs
Smoking
Gender
Hypertension
Aging
Thrombosis
Genetics
Arteriothrombotic Risk Factors are additive
as each activates endothelial cells
Gordon A. Ewy, MD

9. Goal Treat risk factors that activate endothelium
(most risk factors for CAD)
and
Treat dyslipidemia
Gordon A. Ewy, MD

10. Is Statin Therapy Alone Optimal?
25 studies (19 placebo controlled randomized trials) of 69,511 subjects
Statin therapy reduced all-cause mortality by 16%
Statin therapy reduced CHD mortality by 23%
Wilt et al. Arch Internal Medicine 2003; 164: 1427
Gordon A. Ewy, MD

11. Solutions? The LDL-C goal should be even lower
We need to treat high triglycerides and low HDL more aggressively
We need to decrease atherogenic chylomicrons
We need to treat non-lipid risk factors (including CRP) more aggressively
All of the above!
Gordon A. Ewy, MD

12. Log-linear relationship between LDL-C levels and relative risk for CHD
3.7
2.9
2.2
1.7
1.3
1.0
Relative
Risk for
Coronary
Heart
Disease
LDL-Cholesterol (mg/dL)
NCEP Report Circulation; 2004: 110:
Gordon A. Ewy, MD

13. Statin Titration Yields Minimal Incremental LDL-C Reduction
Doubling
2nd
Doubling
3rd
Doubling
Starting Dose of Statin
20%-46%
3-7%
3-7%
3-7%
Ezetemide
20%-46%
18-21%
Percent LDL-Cholesterol Reduction
Gordon A. Ewy, MD

14. Contraversis Surrounds Heart Drug
ENHANCE
Effects of Ezetimibe plus Simvastatin Versus Simvastatin alone in Atheroscelero Carotid Artery
JAMA ,2 2008

15. PCI vs. Medical Therapy for Coronary Artery Disease
STEMI: Primary PCI vs. thrombolysis
NTEMI and UAP: Early invasive approach vs. conservative care
Stable CAD: PCI + OMT vs. OMT
Gordon A. Ewy, MD

16. Ruptured plaque with occlusive thrombus
AMI: Pathophysiology
Ruptured plaque with occlusive thrombus
Gordon A. Ewy, MD 16 16

17. 23 Randomized Trials of PCI vs. Lysis
Keeley, Grines. Lancet 2003;361:13-20
Gordon A. Ewy, MD 17 17

18. 23 Randomized Trials of PCI vs. Lysis
Keeley, Grines. Lancet 2003;361:13-20
Gordon A. Ewy, MD 18 18

19. Schomig A et al. NEJM and Lancet
The STOPAMI Trials
STOPAMI-I: 140 pts with AMI rand. to acc t-PA v. stent/abcx STOPAMI-II: 162 AMI pts rand. to acc t-PA/abcx v. stent/abcx
P<0.001
P=0.001
Schomig A et al. NEJM and Lancet
Gordon A. Ewy, MD

20. Ruptured plaque with subocclusive thrombus
ACS: Pathophysiology
Ruptured plaque with subocclusive thrombus
Gordon A. Ewy, MD 20 20

21. ACC/AHA 2007: UA/NSTEMI guidelines: Initial invasive strategy algorithm
(Class: Level of evidence)
UA/NSTEMI diagnosis is likely or definite:
Initiate ASA (I:A) or clopidogrel if ASA intolerant (I:A)
Invasive strategy selected
Initiate anticoagulant Rx (I:A)
Acceptable options: Enoxaparin or UFH (I:A)
Bivalirudin or fondaparinux (I:B)
Prior to angiography
Initiate ≥1 (I:A) or both (IIa:B) Clopidogrel*, IV GP IIb/IIIa inhibitor*
Factors favoring administration of both:
Delay to angiography · High-risk features · Early recurrent ischemic discomfort
Proceed to diagnostic angiography
*GP IIb/IIIa inhibitor may not be needed if patient received preloading dose of ≥300 mg clopidogrel ≥6 hr earlier (I:B) plus bivalirudin (IIa:B)
Anderson JL et al. J Am Coll Cardiol. 2007;50:
Gordon A. Ewy, MD

22. ACC/AHA 2007: UA/NSTEMI guidelines: Initial conservative strategy algorithm
UA/NSTEMI diagnosis is likely or definite:
Initiate ASA (I:A) or clopidogrel if ASA intolerant (I:A)
Conservative strategy selected
Initiate anticoagulant Rx (I:A) Acceptable options: Enoxaparin or UFH (I:A) or fondaparinux (I:B), but enoxaparin or fondaparinux are preferable (IIa:B)
Initiate clopidogrel (I:A)
Consider adding IV eptifibatide or tirofiban (IIb:B)
(Continued)
UFH = unfractionated heparin
Anderson JL et al. J Am Coll Cardiol. 2007;50:
Gordon A. Ewy, MD

23. Meta-analysis of Conservative vs. Invasive Strategies in ACS
9,212 randomized pts in 7 trials
Composite death or MI from rand to latest FU
Composite of Death or Myocardial Infarction
No./Total (%)
Favors Routine
Invasive
Favors Selective
Invasive
Source
Routine invasive
Selective invasive
TIMI IIIB
86/740 (11.6)
101/733 (13.8)
VANQWISH
152/462 (32.9)
139/458 (30.3)
MATE
16/111 (14.4)
11/90 (12.2)
FRISC II
127/1222 (10.4)
174/1235 (14.1)
TACTICS
81/1114 (7.3)
105/1106 (9.5)
VINO
4/64 (6.3)
15/67 (22.4)
RITA
95/895 (10.6)
118/915 (12.9)
Total
561/4608 (12.2)
663/4604 (14.4)
0.1
1.0 10
18%
OR, 0.82
[ ]
P<0.001
Odds Ratio (95% Cl)
Mehta SR et al. JAMA 2005;293:
Gordon A. Ewy, MD

24. Stable Coronary Artery Disease
Fibrotic plaque
“Prior studies have shown only that PCI decreases the frequency of angina and improves short-term exercise performance”
Boden WE et al. NEJM 2007;356:
Gordon A. Ewy, MD

25. The First Coronary Angioplasty for Stable CAD; Sept. 16th, 1977
First coronary angioplasty lesion (circles) two days before (A),
immediately after (B), and one month after (C) balloon dilation
Gordon A. Ewy, MD

26. Gordon A. Ewy, MD

27. DRUG ELUTING CORONARY STENTS
Cypher(sirolimus)
Taxus(paclitaxel)
Xience( everolimus)
Endeaver(zotarolimus)
Gordon A. Ewy, MD

28. COURAGE: Clinical Outcomes Utilizing Revascularization and Aggressive Guideline-Driven Drug Evaluation
Boden W et al. NEJM 2007;356:
Gordon A. Ewy, MD

29. Background: Conventional Wisdom
“Thus, the long-term prognostic effect of PCI on cardiovascular events in pts with stable coronary artery disease remains uncertain” (!)
Hypothesis
In pts with stable CAD (symptomatic and asymptomatic), PCI + Optimal Medical Therapy will reduce death and nonfatal MI compared to Optimal Medical Therapy alone
Boden WE et al. NEJM 2007;356:
Gordon A. Ewy, MD

30. COURAGE: Background and rationale
In patients with stable CAD
Elective PCI procedures are common in the US (~ 85% of patients)
PCI decreases angina frequency but long-term prognostic effects on CV events are not known
Antianginal agents also provide symptom relief
ACEIs, ASA, β-blockers, and statins have been shown to prevent MI and death
COURAGE was designed to evaluate whether PCI plus optimal medical therapy reduces risk of major CV events compared with optimal medical therapy alone in stable CAD patients
Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation
Boden WE et al. N Engl J Med. 2007;356. Boden WE et al. Am Heart J. 2006;151:
Gordon A. Ewy, MD

31. COURAGE: Study design
AHA/ACC Class I/II indications for PCI, suitable coronary artery anatomy and ≥70% stenosis in ≥1 proximal epicardial vessel + objective evidence of ischemia or ≥80% stenosis + class III angina without provocation testing
Optimal medical therapy* + PCI (n = 1149)
Randomized
Optimal medical therapy (n = 1138)
Primary outcome: All-cause mortality, nonfatal MI
Follow-up: Median 4.6 years
*Intensive pharmacologic therapy + lifestyle intervention
Boden WE et al. N Engl J Med. 2007;356.
Gordon A. Ewy, MD

32. Key Inclusion and Exclusion Criteria
Inclusion criteria
1, 2, or 3 vessel disease (>70% visual stenosis of proximal coronary segment) amenable to PCI
CCS Class I-III angina (or asymptomatic)
Objective evidence of ischemia
ACC/AHA Class I or II indication for PCI
Exclusions
Uncontrolled unstable angina or complicated post-MI
Revascularization within 6 months
Ejection fraction <30% or cardiogenic shock/severe HF
Boden WE et al. NEJM 2007;356:
Gordon A. Ewy, MD

33. Survival Free from Death and MI (mean FU 4.6 yrs); N=2,287
1.0
Optimal Medical Therapy (OMT)
Death/MI
at 4.6 yrs
19.0%
18.5%
0.9
0.8
PCI + OMT
Freedom from
Death or MI (%)
0.7
Hazard ratio: 1.05
95% CI ( )
P = 0.62
0.6
0.5
0.0 1 2 3 4 5 6 7
Years
Number at Risk
Medical Therapy
PCI
Boden WE et al. NEJM 2007;356:
Gordon A. Ewy, MD

34. COURAGE: Summary and implications
In patients with stable CAD
PCI added to optimal medical therapy did not reduce risk of death, MI, or other major CV events compared to optimal medical therapy alone
Findings reinforce existing clinical practice guidelines
PCI can be safely deferred if intensive medical therapy is instituted and maintained
Some patients (~1/3) may require eventual revascularization
Initial management approach for many patients includes lifestyle modification + pharmacologic therapy
Boden WE et al. N Engl J Med. 2007;356.
Gordon A. Ewy, MD

35. Angina/QOL at 1 Year: Med Rx vs. PCI
8 prior randomized trials
Trial
QOL
Angina
ETT
ACME
PCI better
ACME 2
MASS
ACIP
RITA 2
AVERT
MASS II
TIME
Gordon A. Ewy, MD

36. Does COURAGE Represent PCI in the United States?
Canada
US VA
US non VA
962,732
(98.5%)
14,268
(1.5%)
Boden WE et al. NEJM 2007;356:
*US data of file, Boston Scientific
Gordon A. Ewy, MD

37. : COURAGE Projections: 3-year death/MI
21% (OMT) vs. 16.4% (PCI + OMT) (22%↓)
P≈0.02
Death/MI (%) at 4.6 years
27%↑ 
29%↓
Boden WE et al. NEJM 2007;356:
Gordon A. Ewy, MD 37 37

38. PCI Outcomes PCI success 1149 patients total
46 (4%) procedure not attempted
27 (2%) no lesions crossed
1077 patients (94%) had PCI attempted
1577/1688 lesions had PCI success (93%)
Few PCI pts received GPIIb/IIIa inhibitors or adequate clopidogrel pre-loading
787 patients (69%) had 2 or 3 vessel ds.
590 pts (59%) received 1 stent
416 pts (41%) received ≥2 stents
At least 371 of 787 pts (47%) with multivessel disease had incomplete revascularization
14% PTCA
only
86% stents
97% BMS
3% DES
PCI success
Really ~85%
Peri-PCI
MIs
revascularization
Complete
Gordon A. Ewy, MD 38

39. COURAGE Methodology
Patients were randomized in COURAGE after diagnostic angiography 
Many patients with severe disease who might have benefited were undoubtedly excluded
and thus
The results of COURAGE don’t imply that patients with angina and/or inducible ischemia should be managed medically, without diagnostic angiography!
Gordon A. Ewy, MD

40. Gordon A. Ewy, MD

41. Gordon A. Ewy, MD

42. Original Article Long-Term Outcomes with Drug-Eluting Stents versus Bare-Metal Stents in Sweden
Bo Lagerqvist, M.D., Ph.D., Stefan K. James, M.D., Ph.D., Ulf Stenestrand, M.D., Ph.D., Johan Lindbäck, M.Sc., Tage Nilsson, M.D., Ph.D., Lars Wallentin, M.D., Ph.D., for the SCAAR Study Group
N Engl J Med
Volume 356(10):
March 8, 2007
Gordon A. Ewy, MD

43. DES vs BMS: Effect on death or MI
Swedish Coronary Angiography and Angioplasty Registry (SCAAR)
0.20
DES
BMS
0.15
Adjusted cumulative risk of death or MI
Curve is an estimation from Cox regression model at mean level of the propensity score
0.10
0.05
0.00
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Years
No. at risk
Bare-metal stent (BMS)
12,880
11,706
11,432
8665
5520
2963 7
Drug-eluting stent (DES)
5770
5307
5158
3216
1608
580
Lagerqvist B et al. N Engl J Med. 2007;356:
Gordon A. Ewy, MD

44. Landmark analysis: Effect on death
Risk assessed during and after the prespecified 6-month landmark
0.10
0.08
DES
Adjusted cumulative risk of death
0.06
BMS
0.04
RR: 1.03
(0.84–1.26)
0.02
RR: 1.32 (1.11–1.57)
0.00
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Years
Propensity score-adjusted cumulative event rates at the mean level of the propensity score
Lagerqvist B et al. N Engl J Med. 2007;356:
Gordon A. Ewy, MD

45. Gordon A. Ewy, MD

46. Gordon A. Ewy, MD

47. Gordon A. Ewy, MD

48. Conclusion
Drug-eluting stents were associated with an increased rate of death, as compared with bare-metal stents
This trend appeared after 6 months, when the risk of death was 0.5 percentage point higher and a composite of death or myocardial infarction was 0.5 to 1.0 percentage point higher per year
The long-term safety of drug-eluting stents needs to be ascertained in large, randomized trials
Gordon A. Ewy, MD

49. Original Article A Pooled Analysis of Data Comparing Sirolimus-Eluting Stents with Bare-Metal Stents
Christian Spaulding, M.D., Joost Daemen, M.D., Eric Boersma, Ph.D., Donald E. Cutlip, M.D., and Patrick W. Serruys, M.D., Ph.D.
N Engl J Med
Volume 356(10):
March 8, 2007
Gordon A. Ewy, MD

50. Study Overview
Patients in four randomized trials comparing sirolimus-eluting coronary-artery stents and bare-metal stents were included in a pooled analysis
Gordon A. Ewy, MD

51. Conclusion
Stent thrombosis after 1 year was more common with both sirolimus-eluting stents and paclitaxel-eluting stents than with bare-metal stents
Both drug-eluting stents were associated with a marked reduction in target-lesion revascularization
There were no significant differences in the cumulative rates of death or myocardial infarction at 4 years
Gordon A. Ewy, MD

52. Gordon A. Ewy, MD

53. Gordon A. Ewy, MD

54. Gordon A. Ewy, MD

55. Gordon A. Ewy, MD

56. Gordon A. Ewy, MD

57. Original Article Drug-Eluting Stents vs
Original Article Drug-Eluting Stents vs. Coronary-Artery Bypass Grafting in Multivessel Coronary Disease
Edward L. Hannan, Ph.D., Chuntao Wu, M.D., Ph.D., Gary Walford, M.D., Alfred T. Culliford, M.D., Jeffrey P. Gold, M.D., Craig R. Smith, M.D., Robert S.D. Higgins, M.D., Russell E. Carlson, M.D., and Robert H. Jones, M.D.
N Engl J Med
Volume 358(4):
January 24, 2008
Gordon A. Ewy, MD

58. Study Overview
.In this New York State registry study, outcomes of patients with multivessel coronary disease treated with drug-eluting coronary stents or coronary-artery bypass grafting (CABG) were compared during 18 months of follow-up
The rates of death, death or myocardial infarction, and repeat revascularization were consistently lower after CABG than after treatment with drug-eluting stents
Gordon A. Ewy, MD

59. Conclusion
For patients with multivessel disease, CABG continues to be associated with lower mortality rates than does treatment with drug-eluting stents and is also associated with lower rates of death or myocardial infarction and repeat revascularization
Gordon A. Ewy, MD