Bunyad Haider, M.D.FACC;FACP Professor and Chairman Dept of Medicine UMDNJ-New Jersey Medical School...

Bunyad Haider, M.D.FACC;FACP

Professor and ChairmanDept of Medicine

UMDNJ-New Jersey Medical School

Coronary Artery DiseaseCoronary Artery DiseaseEvolving Management StrategiesEvolving Management StrategiesMedicate, Dilate, or Operate?Medicate, Dilate, or Operate?

CV disease: US prevalenceCV disease: US prevalence

American Heart Association. Heart Disease and Stroke Statistics—2007 Update.

Myocardial ischemia 37 million*

Acute MI 865,000/year

Heart failure

5 million

Peripheral vascular disease

8 million

Stroke5.7 million

Chest Pain

4.2 million emergency visits/year6.4 million outpatient visits/year

*Symptomatic coronary artery disease (CAD) or angina pectoris.

3.1 mm3.1 mm

3.1 mm3.1 mm

Angiography Cannot Detect Coronary RemodelingAngiography Cannot Detect Coronary RemodelingIntravascular Ultrasound (IVUS) Necessary

Coronary Artery Disease is Coronary Artery Disease is Caused by Caused by

AtherothrombosisAtherothrombosis Inflammation Lipid accumulation Cell proliferation Cell death & Thrombosis

The result is obstruction of thecoronary arteries

III.2© 2002 PPS®

C

MMP-9MMP-9

Atherosclerosis: An Inflammatory Atherosclerosis: An Inflammatory Disease with or without infectionDisease with or without infection

Preventing CADPreventing CAD1. 1. Preventing endothelial

dysfunction

Focus on risk factors that activate the endothelium

Environmental FactorsDiet/Exercise/Drugs

Genetics

Aging

Smoking Gender

Hypertension

Thrombosis

Arteriothrombotic Risk Factors are additiveArteriothrombotic Risk Factors are additiveas each activates endothelial cellsas each activates endothelial cells

GoalGoal

Treat risk factors that activate endothelium(most risk factors for CAD)

andTreat dyslipidemia

Is Statin Therapy Alone Is Statin Therapy Alone Optimal?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

Solutions?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!

Log-linear relationship between LDL-C levels Log-linear relationship between LDL-C levels and relative risk for CHDand relative risk for CHD

RelativeRisk for

CoronaryHeart

Disease

3.7

2.9

2.2

1.7

1.3

1.0

40 70 100 130 160 190

LDL-Cholesterol (mg/dL)

NCEP Report Circulation; 2004: 110:227-239

Statin Titration Yields MinimalStatin Titration Yields MinimalIncremental LDL-C Reduction Incremental LDL-C Reduction

Starting Dose of Statin

1st

Doubling2nd

Doubling3rd

Doubling

20%-46% 3-7% 3-7% 3-7%

20%-46% 18-21%

Ezetemide

Percent LDL-Cholesterol Reduction

Contraversis Surrounds Heart DrugContraversis Surrounds Heart Drug

ENHANCE Effects of Ezetimibe plus

Simvastatin Versus Simvastatin alone in Atheroscelero Carotid

ArteryJAMA ,2 2008

PCI vs. Medical Therapy PCI vs. Medical Therapy for Coronary Artery for Coronary Artery

DiseaseDiseaseSTEMI: STEMI: Primary PCI vs. Primary PCI vs.

thrombolysisthrombolysis

NTEMI and UAP: NTEMI and UAP: Early invasive Early invasive

approach vs. conservative careapproach vs. conservative care

Stable CAD: Stable CAD: PCI + OMT vs. OMTPCI + OMT vs. OMT

AMI: PathophysiologyAMI: Pathophysiology

Ruptured plaque with Ruptured plaque with occlusive thrombusocclusive thrombus

23 Randomized Trials of PCI vs. Lysis23 Randomized Trials of PCI vs. Lysis23 Randomized Trials of PCI vs. Lysis23 Randomized Trials of PCI vs. Lysis

p=0.0002 p=0.0003

N = 7,739N = 7,739

Keeley, Grines. Keeley, Grines. LancetLancet 2003;361:13-20 2003;361:13-20

23 Randomized Trials of PCI vs. Lysis23 Randomized Trials of PCI vs. Lysis23 Randomized Trials of PCI vs. Lysis23 Randomized Trials of PCI vs. Lysis

P<0.0001P<0.0001

N = 7,739N = 7,739

Keeley, Grines. Keeley, Grines. LancetLancet 2003;361:13-20 2003;361:13-20

P<0.0001P<0.0001

p=0.0002p=0.0002

26%41%

60%57%

0%

20%

40%

60%

80%

100%

STOPAMI-I STOPAMI-2

Myo

card

ial s

alva

ge

(% L

V m

yoca

rdiu

m)

t-PA +- Abcx Stent/Abcx

The STOPAMI TrialsThe STOPAMI Trials

Schomig A et al. Schomig A et al. NEJMNEJM and and LancetLancet

STOPAMI-I:STOPAMI-I: 140 pts with AMI rand. to acc t-PA v. stent/abcx 140 pts with AMI rand. to acc t-PA v. stent/abcx

STOPAMI-II:STOPAMI-II: 162 AMI pts rand. to acc t-PA/abcx v. stent/abcx 162 AMI pts rand. to acc t-PA/abcx v. stent/abcx

P<0.001P<0.001 P=0.001P=0.001

ACS: PathophysiologyACS: Pathophysiology

Ruptured plaque with subocclusive thrombusRuptured plaque with subocclusive thrombus

Proceed to diagnostic angiography

UA/NSTEMI diagnosis is likely or definite: Initiate ASA (I:A) or clopidogrel if ASA intolerant (I:A)

Invasive strategy selectedInitiate anticoagulant Rx (I:A)

Acceptable options: Enoxaparin or UFH (I:A) Bivalirudin or fondaparinux (I:B)

Prior to angiographyInitiate ≥1 (I:A) or both (IIa:B) Clopidogrel*, IV GP IIb/IIIa inhibitor*

ACC/AHA 2007: UA/NSTEMI guidelines: ACC/AHA 2007: UA/NSTEMI guidelines: Initial invasive strategy algorithmInitial invasive strategy algorithm

Anderson JL et al. J Am Coll Cardiol. 2007;50:652-726.

*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)

(Class: Level of evidence)

Factors favoring administration of both: Delay to angiography · High-risk features · Early recurrent ischemic discomfort

Initiate clopidogrel (I:A) Consider adding IV eptifibatide or tirofiban (IIb:B)

(Continued)

ACC/AHA 2007: UA/NSTEMI guidelines: ACC/AHA 2007: UA/NSTEMI guidelines: Initial conservative strategy algorithmInitial conservative strategy algorithm

Anderson JL et al. J Am Coll Cardiol. 2007;50:652-726.

Conservative strategy selectedInitiate anticoagulant Rx (I:A)

Acceptable options: Enoxaparin or UFH (I:A) or fondaparinux (I:B), but enoxaparin or fondaparinux are preferable (IIa:B)

UA/NSTEMI diagnosis is likely or definite: Initiate ASA (I:A) or clopidogrel if ASA intolerant (I:A)

UFH = unfractionated heparin

Mehta SR et al. Mehta SR et al. JAMAJAMA 2005;293:2908-2917 2005;293:2908-2917

Composite of Death or Myocardial InfarctionNo./Total (%)

SourceSourceRoutine Routine invasiveinvasive

Selective Selective invasiveinvasive

TIMI IIIBTIMI IIIB 86/740 (11.6)86/740 (11.6) 101/733 101/733 (13.8)(13.8)

VANQWISVANQWISHH

152/462 152/462 (32.9)(32.9)

139/458 139/458 (30.3)(30.3)

MATEMATE 16/111 (14.4)16/111 (14.4) 11/90 (12.2)11/90 (12.2)

FRISC IIFRISC II 127/1222 127/1222 (10.4)(10.4)

174/1235 174/1235 (14.1)(14.1)

TACTICSTACTICS 81/1114 (7.3)81/1114 (7.3) 105/1106 105/1106 (9.5)(9.5)

VINOVINO 4/64 (6.3)4/64 (6.3) 15/67 (22.4)15/67 (22.4)

RITARITA 95/895 (10.6)95/895 (10.6) 118/915 118/915 (12.9)(12.9)

TotalTotal 561/4608 561/4608 (12.2)(12.2)

663/4604 663/4604 (14.4)(14.4)

Odds Ratio (95% Cl)

Favors RoutineInvasive

Favors SelectiveInvasive

OR, 0.82[0.72-0.93]

P<0.001

0.1 1.0 10

Meta-analysis of Conservative vs. Meta-analysis of Conservative vs. Invasive Strategies in ACSInvasive Strategies in ACS

9,212 randomized pts in 7 trials9,212 randomized pts in 7 trialsComposite death or MI from rand to latest FUComposite death or MI from rand to latest FU

18%18%

Stable Coronary Artery Stable Coronary Artery DiseaseDiseaseFibrotic plaqueFibrotic plaque

• ““Prior studies have shown only that PCI Prior studies have shown only that PCI decreases the frequency of angina and decreases the frequency of angina and improves short-term exercise performance”improves short-term exercise performance”

Boden WE et al. Boden WE et al. NEJMNEJM 2007;356:1503-16 2007;356:1503-16

First coronary angioplasty lesion (circles) two First coronary angioplasty lesion (circles) two days before (A),days before (A),

immediately after (B), and one month after (C) immediately after (B), and one month after (C) balloon dilationballoon dilation

The First Coronary AngioplastyThe First Coronary Angioplasty for Stable CAD; for Stable CAD; Sept. 16Sept. 16thth, 1977, 1977

DRUG ELUTING CORONARY DRUG ELUTING CORONARY STENTSSTENTS

Cypher(sirolimus)Taxus(paclitaxel)

Xience( everolimus)Endeaver(zotarolimus)

COURAGE: COURAGE: CClinicallinical OOutcomesutcomes UUtilizingtilizing

RRevascularizationevascularization and and AAggressive ggressive GGuideline-uideline-

DrivenDriven Drug Drug EEvaluationvaluation

Boden W et al. NEJM 2007;356:1503-16.

In pts with stable CAD (symptomatic and In pts with stable CAD (symptomatic and

asymptomatic), PCI + Optimal Medical asymptomatic), PCI + Optimal Medical

Therapy will Therapy will reduce death and nonfatal MI reduce death and nonfatal MI

compared to Optimal Medical Therapy compared to Optimal Medical Therapy

alonealone

HypothesisHypothesis

““Thus, the long-term prognostic effect of PCI on Thus, the long-term prognostic effect of PCI on cardiovascular events in pts with stable coronary cardiovascular events in pts with stable coronary

artery disease remains uncertain” (!)artery disease remains uncertain” (!)

Background: Background: Conventional WisdomConventional Wisdom

Boden WE et al. NEJM 2007;356:1503-16Boden WE et al. NEJM 2007;356:1503-16

COURAGE: Background COURAGE: Background and rationaleand rationale

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

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

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

In patients with stable CAD

Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation

COURAGE: Study designCOURAGE: Study design

Boden WE et al. N Engl J Med. 2007;356.

Optimal medical therapy* + PCI (n = 1149)

Optimal medical therapy(n = 1138)

AHA/ACC Class I/II indications for PCI, suitable coronary artery anatomyand

≥70% stenosis in ≥1 proximal epicardial vessel + objective evidence of ischemia or

≥80% stenosis + class III angina without provocation testing

Primary outcome:All-cause mortality, nonfatal MI

Follow-up: Median 4.6 years

Randomized

*Intensive pharmacologic therapy + lifestyle intervention

Key Inclusion and Exclusion Key Inclusion and Exclusion CriteriaCriteria

Inclusion criteriaInclusion criteria

1, 2, or 3 vessel disease (>70% visual stenosis of 1, 2, or 3 vessel disease (>70% visual stenosis of proximal coronary segment) amenable to PCIproximal coronary segment) amenable to PCI

CCS Class I-III angina (or asymptomatic)CCS Class I-III angina (or asymptomatic)

Objective evidence of ischemia Objective evidence of ischemia

ACC/AHA Class I or II indication for PCIACC/AHA Class I or II indication for PCI

ExclusionsExclusions

Uncontrolled unstable angina or complicated post-MIUncontrolled unstable angina or complicated post-MI

Revascularization within 6 monthsRevascularization within 6 months

Ejection fraction <30% or cardiogenic shock/severe HFEjection fraction <30% or cardiogenic shock/severe HF


Number at RiskMedical Therapy 1138 1017 959 834 638 408 192 30PCI 1149 1013 952 833 637 417 200 35

Years0 1 2 3 4 5 6

0.0

0.5

0.6

0.7

0.8

0.9

1.0

PCI + OMT

Optimal Medical Therapy (OMT)

Hazard ratio: 1.05Hazard ratio: 1.0595% CI (0.87-1.27)95% CI (0.87-1.27)

P = 0.62P = 0.62

7

Survival Free from Death and Survival Free from Death and MI MI (mean FU 4.6 (mean FU 4.6

yrs); N=2,287 yrs); N=2,287

Fre

edo

m f

rom

De

ath

or

MI (

%)

Death/MIat 4.6 yrs

19.0%18.5%


COURAGE: Summary and COURAGE: Summary and implicationsimplications

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.

In patients with stable CAD

Angina/QOL at 1 Year: Med Rx Angina/QOL at 1 Year: Med Rx vs. PCIvs. PCI

TrialTrial QOLQOL AnginaAngina ETTETT

ACMEACME PCI PCI betterbetter

PCI PCI betterbetter


ACME 2ACME 2 MASSMASS PCI PCI

betterbetter

ACIPACIP PCI PCI betterbetter


RITARITA 22 PCI PCI betterbetter


AVERTAVERT PCI PCI betterbetter



MASS IIMASS II PCI PCI betterbetter


TIMETIME PCI PCI betterbetter



8 prior randomized 8 prior randomized trialstrials

Does COURAGE Represent PCI in Does COURAGE Represent PCI in the United States?the United States?

962,732(98.5%)

14,268(1.5%)

Canada US VA US non VA

Boden WE et al. NEJM 2007;356:1503-Boden WE et al. NEJM 2007;356:1503-1616

*US data of file, Boston Scientific*US data of file, Boston Scientific

::COURAGE Projections: COURAGE Projections: 3-year death/MI3-year death/MI

21% (OMT) 21% (OMT) vs. vs. 16.4% (PCI + OMT) 16.4% (PCI + OMT) (22%↓)(22%↓)D

ea

th/M

I (%

) at

4.6

D

ea

th/M

I (%

) at

4.6

y

ears

yea

rs

29%↓29%↓27%↑27%↑

P≈0.02

Boden WE et al. Boden WE et al. NEJMNEJM 2007;356:1503-16 2007;356:1503-16

Co

mp

lete

Co

mp

lete

rev

asc

ula

riza

tio

nre

vas

cu

lari

zati

onP

eri-

PC

IP

eri-

PC

IM

IsM

IsPCI OutcomesPCI Outcomes

1149 patients total1149 patients total

46 (4%) procedure not attempted46 (4%) procedure not attempted27 (2%) no lesions crossed27 (2%) no lesions crossed

1077 patients (94%) had PCI attempted1077 patients (94%) had PCI attempted

1577/1688 lesions had PCI success (93%)1577/1688 lesions had PCI success (93%)

Few PCI pts received GPIIb/IIIa inhibitors Few PCI pts received GPIIb/IIIa inhibitors or adequate clopidogrel pre-loadingor adequate clopidogrel pre-loading

787 patients (69%) had 2 or 3 vessel ds.787 patients (69%) had 2 or 3 vessel ds.590 pts (59%) received 1 stent590 pts (59%) received 1 stent

416 pts (41%) received ≥2 stents416 pts (41%) received ≥2 stentsAt least 371 of 787 pts (47%) with multivessel At least 371 of 787 pts (47%) with multivessel

disease had incomplete revascularization disease had incomplete revascularization

14% PTCA14% PTCAonlyonly

86% stents86% stents97% BMS97% BMS3% DES3% DES

Really Really ~85%~85%

PC

I su

cces

sP

CI s

ucc

ess

COURAGE MethodologyCOURAGE Methodology Patients were randomized in COURAGE Patients were randomized in COURAGE

after diagnostic angiographyafter diagnostic angiography Many patients with severe disease who Many patients with severe disease who

might have benefited were undoubtedly might have benefited were undoubtedly excludedexcluded

and thusand thus

The results of COURAGE The results of COURAGE don’t implydon’t imply that that patients with angina and/or inducible patients with angina and/or inducible ischemia should be managed medically, ischemia should be managed medically, without diagnostic angiography!without diagnostic angiography!

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 MedVolume 356(10):1009-1019

March 8, 2007

DES vs BMS: Effect on death or DES vs BMS: Effect on death or MIMI

Lagerqvist B et al. N Engl J Med. 2007;356:1009-19.

Swedish Coronary Angiography and Angioplasty Registry (SCAAR)

Curve is an estimation from Cox regression model at mean level of the propensity score

No. at riskBare-metal stent (BMS)Drug-eluting stent (DES)

70

2963580

55201608

86653216

11,4325158

11,7065307

12,8805770

Adjustedcumulative

risk of death or MI

0.10

0.15

0.05

0.000.0 0.5 1.0 1.5 2.0 2.5 3.0

Years

DESBMS

0.20

Landmark analysis: Effect Landmark analysis: Effect on deathon death

Lagerqvist B et al. N Engl J Med. 2007;356:1009-19.

Propensity score-adjusted cumulative event rates at the mean level of the propensity score

Risk assessed during and after the prespecified 6-month landmark

RR: 1.03 (0.84–1.26)

RR: 1.32 (1.11–1.57)

0.06

0.04

0.02

0.000.0 0.5 1.0 1.5 2.0 2.5 3.0

Years

DES

BMS

0.10

0.08

Adjustedcumulative

risk of death

ConclusionConclusion 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

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.


March 8, 2007

Study OverviewStudy Overview Patients in four randomized trials

comparing sirolimus-eluting coronary-artery stents and bare-metal stents were included in a pooled analysis

ConclusionConclusion 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

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.


January 24, 2008

Study OverviewStudy 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

ConclusionConclusion 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

Bunyad Haider, M.D.FACC;FACP Professor and Chairman Dept of Medicine UMDNJ-New Jersey Medical School...

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Transcript of Bunyad Haider, M.D.FACC;FACP Professor and Chairman Dept of Medicine UMDNJ-New Jersey Medical School...