Myocardial Ischemia Update

1
MyocardialIschemia Update
2
Chronic Ischemic Heart Disease Overview

• Highly prevalent
• 6.5-16.5 million in the US
• Multifactorial etiology
• CAD, hypertension, hypertrophic cardiomyopathy,
  valvular heart disease
• High socioeconomic burden
• Depression
• Quality of life
• High costs of care

Gibbons RJ et al. www.acc.org.
3
Repeat revascularization is common post-PCI/CABG
N 18,240 who underwent elective PCI or CABG
46
50
40
30
30
Patients()
20
10
0
Recurrentangina
2nd revascularization
Kempf J et al. Presented at ESC. 2007.
4
Angina increases cost of care
US managed care enrollees, n 140,001 with
asymptomatic CAD, n 23,535 with angina Dx
Average yearly cost/patient 11,530
(asymptomatic CAD) vs 22,004 (angina)
ED visits
Hospitalizations
ED visits
Prior to diagnosis
Following diagnosis
Kempf J et al. Presented at Scientific Forum on
Quality of Care and Outcomes Res in CV Disease.
2006.
And Rx nitrates and/or ß-blockers and/or CCBs
5
WISE Landmark study in women
Prospective cohort study conducted at 4 US sites

• Goals
• Improve diagnostic testing for ischemic heart
  disease in women
• Study pathophysiologic mechanisms for ischemia in
  the absence of epicardial coronary artery
  stenoses
• Evaluate the influence of menopausal status and
  reproductive hormone levels on diagnostic testing
  results

Womens Ischemia Syndrome Evaluation
Bairey Merz CN et al. J Am Coll Cardiol.
1999331453-61.
6
WISE Persistent chest pain in women predicts
future CV events

n 673 WISE participants with chest pain at
baseline
1
0.9
Without CAD HR 1.89 (1.063.39)P 0.03
Event-freesurvival ()
0.8
0.7
With CAD HR 1.17 (0.761.80)P 0.49
0.6
0
1
2
3
4
5
6
Years from PChP diagnosis (at one year)
Neither
PChPNo CAD
No PChPCAD
Both
PChP persistent chest pain
Johnson BD et al. Eur Heart J. 2006271408-15.
7
WISE Persistent chest pain associated with
diminished QOL
No obstructive CAD No obstructive CAD Obstructive CAD Obstructive CAD
No PChP PChP No PChP PChP
Angina symptoms
Typical presentation () 30 33 32 40
Intensity (range 1-5) 2.3 2.6 2.6 2.6
Daily frequency () 30 49 34 39
Psychological symptoms
Perceived QOL 7.3 6.6 7.1 6.6
Depression 8.8 12.2 9.3 12.9
Anxiety 18.0 20.1 17.7 20.1
Adjusted P 0.04 Range 1 - 10 (best) ?score
?trait
Johnson BD et al. Eur Heart J. 2006271408-15.
Bairey Merz CN et al. J Am Coll Cardiol.
1999331453-61.
8
WISE CAD imposes an economic burden
N 883 women with angiographic CAD
80
70



60

50
Cumulative observed direct costs (, thousands)
40

30
20
10
0
2
3
4
5
1
Follow-up (years)
Nonobstructive CAD
1 vessel CAD
2 vessel CAD
3 vessel CAD
P lt 0.0001 nonobstructive vs 1-3 vessel CAD
Shaw LJ et al. Circulation. 2006114894-904.
9
Contemporary clinical practice of ischemic heart
disease
Opportunity for early detection, risk
stratification, and medical therapy
Healthy population
Revas revascularization
Adapted from Timmis AD et al. Heart.
200793786-91.
10
Examining the Science Underlying Myocardial
Ischemia
11
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.
12
Major cardiac events occur in non-target areas
following successful PCI
20
15
Hazardrate ()
10
Non-target lesion event
5
Target lesion event
0
1
2
3 Year
4
5
Substantial number of cardiac events could be
prevented if non-obstructive, high-risk lesions
were identified
Cutlip DE et al. Circulation. 20041101226-30.
13
Local determinants of the natural history of
individual coronary lesions
Opportunities for identification and intervention
Local factors
Shear stress
Quiescent, stable plaque No symptoms

• Proliferation
• Inflammation
• Remodeling

Quiescence
Inflammation
Thin cap Fibroatheroma MI, sudden death
Proliferation Calcification
Fibrotic/ scarred plaque Angina
Courtesy of PH Stone, MD and R Gerrity, PhD.
14
Proposed classification scheme for
atherosclerotic plaque
Plaque trajectory Histopathology Progression rate Vascular remodeling Proclivity to rupture Clinical manifestation
Quiescent plaque Small lipid core Thick fibrous cap Minimal Compensatory expansive remodeling Low Asymptomatic
Stenotic plaque Small lipid core Very thick fibrous cap Gradual Constrictive remodeling Low Stable angina
High-risk plaque Large lipid core Thin and inflamed fibrous cap Increased Excessive expansive remodeling High ACS
Chatzizisis YS et al. J Am Coll Cardiol.
2007492379-93.
15
The spectrum of CAD
Inner curvatureLow ESS region(atherosclerosis-p
rone)
Physiologiccoronary artery
Low ESS
Early fibroatheroma
60
20
20
Fibroproliferation
Microruptures
Lower ESSVulnerabilityIntense inflammation
Physiologic ESS Limited inflammation
High ESS
Quiescent plaque
Stenotic plaque
Thin cap fibroatheroma
Erosion
Rupture
Asymptomatic
Stable angina
ACS
ESS endothelial shear stress
Chatzizisis YS et al. J Am Coll Cardiol.
2007492379-93.
16
Ventricular arrhythmogenesis in ischemic
myocardium

• Risk factors
• Age
• Heredity
• Gender
• Smoking
• Lipids
• Hypertension
• Diabetes
• Obesity

• Clinical or subclinical susceptibility
• Structural substrate present

High risk of transient acute ischemia reperfusion

• Substrate
• Vulnerable ischemic zone
• Intracoronary thrombus
• Autonomic influence
• Hemodynamic compromise

• Triggers
• VPC
• VT
• Reentry

Ventricular fibrillation

VPC ventricular premature contraction VT
ventricular tachycardia
Adapted from Luqman N et al. Int J Cardiol.
2007119283-90.
17
Causes and consequences of myocardial ischemia
New understanding
?O2 demand
Na and Ca2 overload
Electrical instability Myocardial dysfunction
Heart rate Blood pressure Preload Contractility
?O2 supply
Belardinelli L et al. Heart. 200692(suppl
IV)iv6-14.
18
Overview of the sodium channel
Na
Na
Na
Resting closed
Inactivated
Activated
out
Na
Na
in
Na
Na
Na 140 mM
Na
Na
Na
10mM
Ca2
Ca2
in
Ca2
Ca2
Na
Ca2
Ca2
out
Na/Ca2 Exchanger
Na
Ca2
Courtesy of L Belardinelli, MD.
19
Origin of late INa

• During the plateau phase of the action potential,
  a small proportion of sodium channels either do
  not close, or close and then reopen
• These late channel openings permit a sustained
  Na current to enter myocytes during systole

0
Sodiumcurrent
Late
Peak
Belardinelli L et al. Heart. 200692(suppl
IV)iv6-14.
20
Myocardial ischemia causes enhanced late INa
0
Ischemia
Sodiumcurrent
Late
Peak
Enhanced late INa appears to be a major
contributor to increased intracellular Na during
ischemia
Belardinelli L et al. Heart. 200692(suppl
IV)iv6-14.
21
Role of altered ion currents in adverse
consequences of myocardial ischemia
Disease(s) and pathological states linked to
imbalance of O2 supply/demand
?Late INa
?Na entry (Nai)
NCX
?Cytosolic Ca2

• Mechanical dysfunction
• Abnormal contraction and relaxation
• ?Diastolic tension

• Electrical instability
• Afterpotentials
• Beat-to-beat ?APD
• Arrhythmias (VT)

Nai intracellular NaNCX Na/Ca2
exchanger APD action potential duration
Belardinelli L et al. Heart. 200692(suppl
IV)iv6-14.
22
Diastolic relaxation failure adversely affects
myocardial O2 supply and demand

• Sustained contraction of ischemic tissue during
  diastole
• Increases MVO2
• Compresses intramural small vessels
• Reduces myocardial blood flow

Exacerbates ischemia
MVO2 myocardial oxygen consumption
Courtesy of PH Stone, MD.
23
Late INa inhibition blunts Ca2 accumulation
0.30
12
ATX-II
RAN
0.25
Indo fluorescence(F405/F485 ratio)
8

LV work(L/min per mm Hg)

0.20

4

0.15
ATX-II
RAN
0.10
0
0
10
20
30
40
50
0
10
20
30
40
50
Time of perfusion (min)
ATX-II alone (n 11) ATX-II ranolazine 4 µM
(n 9) or 9 µM (n 9)

P lt 0.05 vs ATX-II aloneATX-II sea anemone
toxin (selectively ?late INa)
Fraser H et al. J Mol Cell Cardiol.
2006411031-8.
24
Ranolazine blunts sotalol-induced action
potential prolongation in dogs
Transmembrane action potentials (superimposed)
Control
50 mV
1 sec
Antzelevich C et al. Circulation 2004110904-10.
25
Issues in chronic myocardial ischemia treatment
Implications for clinical trials
Pathophysiology of angina is complex
relationship of angina to ACS is unclear
Despite existing treatments, ischemic episodes
frequently occur
PCI is one approach to reduce angina frequency
Trials of all proven noninterventional therapies
alone and in combination are needed
Bhatt AB, Stone PH. Curr Opin Cardiol.
200621492-502.Boden WE et al. Am Heart J.
20061511173-9.
26
Stable CAD Multiple treatment options
Lifestyle intervention
Medicaltherapy
Reduce symptomsTreat underlying disease
CABG
PCI
27
SAFE-LIFE Evaluation of intensive lifestyle
intervention
N 101 with CAD
Advice on Mediterranean diet
Stress management30 min daily
Encouraged to ?physical activity
3-day nonresidential retreat
Weekly 3-hr meetings x 10 weeks
Biweekly 2-hr meetings x 9 months
Control group received printed lifestyle advice
only
Michalsen A et al. Am Heart J. 2006151870-7.
28
SAFE-LIFE Reduction in angina at 1 year with
intensive lifestyle intervention
P 0.015
P 0.01
Michalsen A et al. Am Heart J. 2006151870-7.
29
Chronic ischemic heart disease Treatment gaps

• Most patients have relative intolerances to
  maximum doses of traditional antianginal agents
  (?-blockers, CCBs, and nitrates)

• Patients continue to experience myocardial
  ischemia
• ?-blockers and many CCBs have similar depressive
  hemodynamic and electrophysiologic effects

• Antianginal drugs without these limitations are
  needed

Pepine CJ et al. Am J Cardiol. 199474226-31.
Gibbons RJ et al. www.acc.org.
30
Novel anti-ischemic strategy
?O2 demand
Ca2 overload
Heart rate Blood pressure Preload Contractility
Electrical instability Myocardial dysfunction
?O2 supply
Nitrates, ß-blockers, CCBs
Ranolazine (late Na current inhibition)
Courtesy of PH Stone, MD and BR Chaitman, MD.
2006.
31
Ranolazine clinical trial program
Stable angina
Unstable angina
Myocardial infarction
Heart failure
Silent CAD
Death
NSTEMI
STEMI
MERLIN-TIMI 36
Courtesy of BR Chaitman, MD.
32
Ranolazine clinical trial program in chronic
stable angina
Study N Ranolazine dosing (mg bid) Background antianginal therapy
MARISA 191 50010001500 No
CARISA 823 7501000 Amlodipine 5 mgAtenolol 50 mgDiltiazem 180 mg
ERICA 565 1000 Amlodipine 10 mg
Monotherapy Assessment of Ranolazine In Stable
Angina Combination Assessment of Ranolazine In
Stable Angina Efficacy of Ranolazine In Chronic
Angina
Chaitman BR et al. J Am Coll Cardiol.
2004.Chaitman BR et al. JAMA. 2004.Stone PH et
al. J Am Coll Cardiol. 2006.
33
MARISA, CARISA, ERICA main findings

• As monotherapy, ranolazine improves exercise
  performance in the absence of clinically
  meaningful pathophysiologic effects
• These studies provide evidence of additional
  antianginal and anti-ischemic efficacy in
  patients who remain symptomatic on standard
  therapies or maximal amlodipine therapy

Chaitman BR et al. J Am Coll Cardiol.
2004.Chaitman BR et al. JAMA. 2004.Stone PH et
al. J Am Coll Cardiol. 2006.
34
Antianginal efficacy by gender
Improved exercise duration
MARISA
CARISA

60
150


NS
NS

NS
NS
NS
40
100
Exercise duration, sec(? from placebo)
Exercise duration, sec(? from baseline)

20
50
0
0
500 mg
1000 mg
1500 mg
Placebo
750 mg
1000 mg
Ranolazine
Ranolazine
Women
Men
P 0.014, P lt 0.001, P 0.037 vs placebo
Wenger NK et al. Am J Cardiol. 20079911-8.
35
Antianginal efficacy by gender
Improved angina score
NS
30
P 0.016
20
SAQ angina frequency score (? from baseline)
10
0
Placebo amlodipine
Ranolazine amlodipine
Women
Men
ERICA studySAQ Seattle Angina Questionnaire
Wenger NK et al. Am J Cardiol. 20079911-8.
36
Antianginal efficacy by diabetes status

Placebo
Ranolazine 750 mg bid
Ranolazine 1000 mg bid
CARISA studyP 0.81 (interaction between
diabetes status and treatment effect)
Timmis AD et al. Eur Heart J. 20062742-8.
37
CARISA Reductions in A1C (diabetes substudy)
n 131 with diabetes (n 31 on insulin)
AIC change from baseline

• Possible mechanisms ?Insulin sensitivity
• ?Physical activity

Least squares mean()


Placebo
Ranolazine 750 mg bid
Ranolazine 1000 mg bid
Cooper-DeHoff R, Pepine CJ. Eur Heart J.
2006275-6.Timmis AD et al. Eur Heart J.
20062742-8.
P 0.008 vs placebo
38
Summary Ranolazine in challenging populations

• Antianginal efficacy independent of
• Gender
• Age
• Diabetes status
• Also associated with ?A1C in patients with
  diabetes

Wenger NK et al. Am J Cardiol. 2007.Stone PH et
al. J Am Coll Cardiol. 2006.Timmis AD et al. Eur
Heart J. 2006.
39
ROLE Long-term safety and tolerability in stable
CAD patients
N 746 ranolazine patients who completed MARISA
or CARISA
2.8-year mean follow-up gt80 entered open-label
extension

• Adverse events
• Most common dizziness (11.8) and constipation
  (10.9)
• Discontinuation dizziness (0.9), constipation
  (0.6)
• Total of 72 patients (9.7) discontinued due to
  adverse events
• ECG findings
• Mean QTc prolongation 2.4 ms (P lt 0.001 vs
  baseline)
• QTc gt500 ms in 10 patients (1.2)
• No cases of Torsades de Pointes

Ranolazine Open-Label Experience
Koren MJ et al. J Am Coll Cardiol.
2007491027-34.
40
MERLIN-TIMI 36 Study design
Patients with non-ST-elevation ACStreated with
standard medical/interventional therapiesN 6560
IV/oral ranolazine
Placebo
RandomizedDouble-blind
Primary efficacy endpointCV death, MI,
recurrent ischemia Safety endpointsAll-cause
death, CV hospitalization, symptomatic documented
arrhythmia, clinically significant arrhythmia on
Holter during first 7 days
Metabolic Efficiency with Ranolazine for Less
Ischemia in Non-St-Elevation Acute Coronary
Syndromes
Morrow DA et al. JAMA. 20072971775-83.
41
MERLIN-TIMI 36 Effect on primary endpoint
Ranolazine vs placebo within 48 hrs of ischemic
symptom onset
30
CV death, MI, or recurrent ischemia ()
20
HR 0.92(95 CI 0.83-1.02)Log-rank P 0.11
10
0
0
180
360
540
Days
Placebo
Ranolazine
No. at risk Placebo Ranolazine
3281 3279
2454 2450
1223 1223
268 269
Morrow DA et al. JAMA. 20072971775-83.
42
MERLIN-TIMI 36 Components of primary endpoint
n 3279 ranolazine group, n 3281 placebo group
CV death or MI
Recurrent ischemia
HR 0.99(95 CI 0.85-1.15)Log-rank P 0.87
HR 0.87(95 CI 0.76-0.99)Log-rank P 0.03
Placebo 16.1
20
20
Placebo 10.5
15
15
Cumulativepercentage
10
10
Ranolazine 13.9
Ranolazine 10.4
5
5
0
0
0
180
360
540
0
180
360
540
Days
Event rates at 12 months
Morrow DA et al. JAMA. 20072971775-83.
43
MERLIN-TIMI 36 Efficacy results in major
subgroups
Primary endpoint
Subgroup
Favors ranolazine
Favors placebo
n
Pinteraction
Gender
Men Women
4269 2291
0.12
0.80
Age
lt75 years 75 years
5406 1154
Diabetes
No DM DM
4340 2220
0.39
TIMI Risk
0-3 4-7
3601 2959
0.16
Index event
UA NSTEMI
3067 3342
0.85
STD 1 mm
No Yes
4255 2304
0.23
Overall
6560
0.6
0.8
1.4
1.2
1.6
HR (95 CI)
STD ST-segment depression
Morrow DA et al. JAMA. 20072971775-83.
44
MERLIN-TIMI 36 Primary arrhythmia endpoints
Rate () Rate () Rate ()
Ranolazine Placebo P
Ventricular events Ventricular events
VT 3 beats VT 3 beats 52.1 60.6 lt0.001
Supraventricular events Supraventricular events
SVT 4 beats SVT 4 beats 44.7 55.0 lt0.001
New-onset AF New-onset AF 1.7 2.4 0.08
Bradycardiac events Bradycardiac events
Bradycardia, heart block, pause 2.5 sec Bradycardia, heart block, pause 2.5 sec 39.8 46.6 lt0.001
Bradycardia Bradycardia 35.6 43.0 lt0.001
Pause 3 sec Pause 3 sec 3.1 4.3 0.01
SVT supraventricular tachycardia
Scirica BM et al. Circulation. 2007116.
45
MERLIN-TIMI 36 Reduction in VT lasting 8 beats
10
8.3
8
RR 0.65 P lt 0.001
Placebo
5.3
RR 0.67 P 0.008
Incidence()
6
4
Ranolazine
2
RR 0.63 (0.52-0.76) P lt 0.001
0
0
24
48
72
96
120
144
168
Hours from randomization
Scirica BM et al. Circulation. 2007116.
46
MERLIN-TIMI 36 Incidence of VT 8 beats in
high-risk subgroups
Ranolazine ()
Placebo ()
P
EF 40
5.3
7.3
0.011
EF lt40
8.8
16.6
0.005
QTc 450 msec
5.2
7.8
lt0.001
QTc gt450 msec
5.6
10.5
0.002
TRS 0-4
8.2
lt0.001
5.5
TRS 5-7
4.4
8.9
0.001
No prior HF
5.2
8.1
lt0.001
Prior HF
5.4
9.3
0.013
No ischemia on cECG
5.0
8.3
lt0.001
Ischemia on cECG
6.3
8.3
0.12
0.1
1
10
RR (95 CI)
TRS TIMI risk scorecECG continuous ECG
Scirica BM et al. Circulation. 2007116.
47
MERLIN-TIMI 36 Ventricular tachycardia events
Ranolazine () Placebo () P
Polymorphic VT 8 beats 1.2 1.4 0.40
Sustained VT (30 sec) 0.44 0.44 0.98
Monomorphic VT 0.13 0.22 0.37
Polymorphic VT 0.32 0.22 0.46
Scirica BM et al. Circulation. 2007116.
48
MERLIN-TIMI 36 Major safety outcomes
Event rate () Event rate ()
Ranolazine(n 3268) Placebo(n 3273) P
All-cause death 5.3 5.4 0.91
Sudden cardiac death 1.7 1.8 0.43
All-cause death or CV hospitalization 33.2 33.4 0.53
Symptomatic documented arrhythmia 3.0 3.1 0.84
Clinically significant arrhythmia on Holter 73.7 83.1 lt0.001
VT 3 beats, SVT 120 bpm, new AF, bradycardia
lt45 bpm, CHB, or pulse gt2.5 sec
Morrow DA et al. JAMA. 20072971775-83.
49
MERLIN-TIMI 36 Sudden cardiac death by subgroup
Ranolazine () Placebo () P
Overall 1.7 1.8 NS
EF 40 1.5 1.5 0.48
EF lt40 2.7 4.9 0.07
QTc 450 msec 1.4 1.6 0.86
QTc gt450 msec 3.0 3.0 0.27
TRS 0-4 1.2 1.3 0.47
TRS 5-7 3.5 3.9 0.73
No prior HF 1.2 1.3 0.63
Prior HF 4.1 4.3 0.58
Scirica BM et al. Circulation. 2007116.
50
MERLIN-TIMI 36 Summary and implications

• In patients with ACS, ranolazine added to
  standard therapy was associated with
• No difference in
• Composite efficacy endpoint of CV death, MI,
  recurrent ischemia
• Safety endpoints of all-cause death, all-cause
  death or CV hospitalization, symptomatic
  documented arrhythmia
• Significant reduction in arrhythmias detected by
  Holter monitoring during first 7 days

Findings do not support use of ranolazine in ACS
but add to previous safety data and provide
additional support for ranolazine as antianginal
therapy in stable CAD
Morrow DA et al. JAMA. 20072971775-83.
51
Stable CAD Multiple treatment options
Lifestyle intervention
Medicaltherapy
Reduce symptomsTreat underlying disease
CABG
PCI
52
ACIP Study design
Angiographic CAD (50 stenosis in 1 major
vessel or branch) suitable for revascularization
ischemia during exercise or pharmacologic
stress testing and 1 asymptomatic episode during
48-hr AECG
Angina-guided strategy(n 183)
Ischemia-guided strategy(n 183)
Revascularization strategy(n 192)
Primary outcome Absence of ischemia at 12
weeksSecondary outcomes Death, MI, recurrent
hospitalization for cardiac disease, nonprotocol
revascularization at 1 and 2 years
Pepine CJ et al. J Am Coll Cardiol.
1994241-10.Davies RF et al. Circulation.
1997952037-43.
Asymptomatic Cardiac Ischemia Pilot
53
ACIP Baseline characteristics
Angina-guided Ischemia-guided Revascularization
Age (years) 61 62 61
Women () 10 15 17
Diabetes () 11 19 18
Heart failure () 3 2 4
Hypertension () 32 41 39
Family history () 45 36 43
Smoking () 19 17 13
Prior MI () 38 40 43
Davies RF et al. Circulation. 1997952037-43.
54
ACIP Two-year cumulative all-cause mortality
rates for the treatment strategies
8
6.6
Angina guided
6
P 0.34
4.4
Ischemia guided
P lt 0.005
4
Percent
P lt 0.05
2
1.1
Revascularization
0
24
20
15
12
8
4
0
Follow-up (months)
Davies RF et al. Circulation. 1997952037-43.
55
COURAGE Defining optimal care
Clinical Outcomes Utilizing Revascularization and
Aggressive Drug Evaluation
Intensive lifestyle intervention
Intensive medicaltherapy
Reduce symptomsTreat underlying disease
Revascularization?
56
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.
57
Patient expectations about elective PCI for
stable CAD
N 52 consecutive patients scheduled for first
elective PCI semi-structured questionnaire
completed prospectively
Do you think the angioplasty will prevent a heart attack? Do you think the angioplasty will prevent a heart attack?
Yes 75
Do you think the angioplasty will help you live longer? Do you think the angioplasty will help you live longer?
Yes 71
Holmboe ES et al. J Gen Intern Med. 200015632-7.
58
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.
59
COURAGE Lifestyle intervention and risk factor
goals

• Smoking cessation
• Exercise program
• 30 min moderately intensive exercise 5x/week
• Nutrition counseling
• Total dietary fat lt30 of calories
• Saturated fat lt7 of calories
• Dietary cholesterol lt200 mg/day
• Weight control
• BMI lt25 kg/m2 (if baseline BMI 25.0-27.5)
• 10 relative weight loss (if baseline BMI gt27.5)

• LDL-C (mg/dL)
• 60-85
• HDL-C (mg/dL)
• 40
• Triglycerides (mg/dL)
• lt150
• BP (mm Hg)
• lt130/85
• lt130/80 if diabetes or renal disease present
• A1C ()
• lt7.0

Boden WE et al. Am Heart J. 20061511173-9.
60
COURAGE Pharmacologic therapy

• Antiplatelet
• Aspirin
• Clopidogrel in accordance with established
  practice standards
• Dyslipidemia
• Simvastatin ezetimibe, ER niacin, or fibrates
• ACEI, ARB, or diuretic
• Lisinopril or losartan

• ?-blocker
• ER metoprolol
• Calcium channel blocker
• Amlodipine
• Nitrate
• Isosorbide 5-mononitrate

Boden WE et al. Am Heart J. 20061511173-9. Boden
WE et al. N Engl J Med. 20073561503-16.
61
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.
62
COURAGE Baseline angina
PCI medical therapy(n 1149) Medical therapy(n 1138)
CCS class () 0 I II III 12303623 13303719
Median duration (mo) Interquartile range 51-15 51-15
Median episodes/week Interquartile range 31-6 31-6
Boden WE et al. N Engl J Med. 20073561503-16.
63
COURAGE Inducible ischemia at baseline
PCI medical therapy(n 1149) Medical therapy(n 1138)
Nuclear imaging, (n) 70 (685) 72 (708)
Single reversible defect, (n) 22 (154) 23 (161)
Multiple reversible defects, (n) 65 (444) 68 (483)
Boden WE et al. N Engl J Med. 20073561503-16.
64
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.
65
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.
66
COURAGE Treatment effect in CV and diabetes
subgroups
Baseline characteristics
Medical therapy better
PCI better
Myocardial infarction
Yes
No
Extent of CAD
Multivessel disease
Single-vessel disease
Diabetes
Yes
No
Angina
CCS 0-I
CCS II-III
Ejection fraction
50
gt50
Previous CABG
No
Yes
0.25
0.50
1.00
2.00
1.75
1.50
Hazard ratio (95 CI)
Boden WE et al. N Engl J Med. 20073561503-16.
67
COURAGE Change in quality-of-life scores
After 1 year, both strategies associated with
comparable improvement
90
85
80
75
SAQ QOL score
70
65
60
55
50
Baseline
6
24
48
Time (months)
PCI medical therapy
Medical therapy
WS Weintraub, MD. Presented at ACC. 2007.
68
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.
69
New Guidelines for Myocardial Ischemia Management
70
AHA Scientific Statement Pharmacologic treatment
of hypertension in stable angina
I
IIa
IIb
III
ß-blocker (prior MI), ACEI/ARB (diabetes and/or
LV dysfunction), and diuretic If ß-blocker
contraindicated or side effects occur, substitute
a nonDHP CCB Add long-acting DHP CCB to
ß-blocker, ACEI/ARB, diuretic regimen if angina
or BP remains uncontrolled Target BP is lt130/80
mm Hg or lt120/80 mm Hg if LV dysfunction is
present
A
B
B
B
Rosendorff C et al. Circulation. 20071152761-88.
71
CVD prevention in high-risk women Class I
recommendations

• BP lt120/80 mm Hg
• LDL-C lt100 mg/dL
• Antiplatelet therapy
• ß-Blocker
• ACEI or ARB
• A1C lt7
• Aldosterone blocker (select women)

• Smoking cessation
• Heart-healthy eating pattern
• Regular physical activity
• Weight management

Mosca L et al. Circulation. 20071151481-1501.
72
CVD prevention in high-risk women Class II
recommendations

• Consider
• LDL-C lt70 mg/dL (very-high-risk women)
• HDL/non-HDL therapy
• Omega-3 fatty acid supplementation
• Depression referral and treatment

Mosca L et al. Circulation. 20071151481-1501.
73
Optimal patient care in stable CAD Summary

• Establish aggressive treatment goals
• Utilize intensive, multifaceted therapy to
  achieve and maintain treatment goals
• Lifestyle modification
• Risk factor reduction
• Antianginal therapy

74
Risk Stratification In Patients With Chronic
Myocardial Ischemia
75
Available methods for risk stratification in CAD
patients

• Clinical parameters
• ECG
• Chest x-ray
• Noninvasive testing
• Resting LV function
• Exercise test
• Stress imaging
• Coronary angiography

Gibbons RJ et al. www.acc.org.
76
High-risk criteria
gt3 annual mortality rate

• Severe resting LV dysfunction (LVEF lt35)
• High-risk treadmill score (-11)
• Severe exercise LV dysfunction (LVEF lt35)
• Stress-induced large perfusion defect (esp
  anterior)
• Multiple, moderate-sized perfusion defects
• Large, fixed perfusion defect with LV dilation or
  increased lung uptake (thallium-201)
• Stress-induced moderate perfusion defect with LV
  dilation or increased lung uptake (thallium-201)
• Echocardiographic wall motion abnormality (gt2
  segments) at low dobutamine dose (10 mg/kg per
  min) or low HR (lt102 bpm)
• Stress echocardiographic evidence of extensive
  ischemia

Gibbons RJ et al. www.acc.org.
77
Intermediate-risk criteria
1-3 annual mortality rate

• Mild/moderate resting LV dysfunction (LVEF
  35-49)
• Intermediate-risk treadmill score (-11 lt score lt
  5)
• Stress-induced moderate perfusion defect without
  LV dilation or increased lung intake
  (thallium-201)
• Limited stress echocardiographic ischemia with a
  wall motion abnormality only at higher doses of
  dobutamine involving 2 segments

Gibbons RJ et al. www.acc.org.
78
Low-risk criteria
lt1 annual mortality rate

• Low-risk treadmill score (5)
• Normal or small myocardial perfusion defect at
  rest or with stress
• Normal stress echocardiographic wall motion or no
  change of limited resting wall motion
  abnormalities during stress

Gibbons RJ et al. www.acc.org.
79
Comparison of 3 different risk scores
N 460 consecutive patients with NSTE-ACS
PURSUIT risk score
GRACE risk score
TIMI risk score
30
30
30
25
25
25
20
20
20
Deathor MI()
15
15
15
10
10
10
5
5
5
0
0
0
lt96
96-112
113-133
gt133
lt10
10-12
13-14
gt14
0-2
3-4
5-7
30 days 1 year
Death/MI
de Araújo Gonçalves P et al. Eur Heart J.
200526865-72.
80
Summary

• Chronic IHD continues to impose a high
  socioeconomic burden
• Mechanistic understanding has undergone a
  paradigm shift
• Traditional focus Determinants of myocardial O2
  supply/demand
• Contemporary focus Changes in Na and Ca2
  currents during ischemia
• Contemporary management
• Aggressive treatment of multiple risk factors
• Multifactorial treatment of symptoms
• Renewed interest in the role of optimal medical
  therapy vs PCI