Contemporary Management of Myocardial Ischemia

1
Contemporary Management of Myocardial Ischemia
2
Epidemiology of chronic ischemia (angina)

• 6.516.5 million Americans suffer with angina
  pectoris
• Despite therapeutic advances
• gt13 million episodes of angina per week in the US
• gt1000 episodes of angina every minute
• Growing prevalence of chronic ischemia (angina)
  due to residual CAD after PCI and CABG
• Improved treatment of recurring ischemia (angina)
  is an important goal

AHA. Heart Disease and Stroke Statistics2006
Update. Gibbons RJ et al. ACC/AHA 2002
guidelines. www.acc.org/clinical/guidelines/stabl
e/stable.pdf. Pepine CJ et al. Am J Cardiol.
199474226-31.
3
Persistent ischemia (angina) despitecurrent drug
therapy

• Despite use of traditional antianginal agents
  (?-blockers, CCBs, and nitrates), patients
  reported a median of 2 anginal attacks/week
• A significant percentage of patients have
  relative intolerance to full doses of ?-blockers,
  CCBs, and nitrates
• ?-blockers and many CCBs have similar depressive
  effects on BP, HR and/or AV nodal conduction
• Antianginal drugs without these limitations are
  needed

Gibbons RJ et al. ACC/AHA 2002 guidelines.
www.acc.org/clinical/guidelines/stable/stable.pdf
Pepine CJ et al. Am J Cardiol. 199474226-31.
4
Persistent ischemia (angina) despite PCI
N 1620 consecutive NHLBI Dynamic Registry
patients 1 year post-PCI

• Despite adjunctive antianginal therapy, 26 of
  patients reported recent angina

Holubkov R et al. Am Heart J. 2002144826-33.
5
Myocardial ischemia Significant clinical burden
Coronary artery disease
Hypertension
Hypertrophic cardiomyopathy
Valvular heart disease
6.516.5 million patients with stable angina1,2
1.9 billion in direct costs3
1. AHA. Heart Disease and Stroke Statistics2006
Update. 2. Gibbons RJ et al. ACC/AHA 2002
guidelines. www.acc.org/clinical/guidelines/stabl
e/stable.pdf 3. Javitz HS et al. Am J Manag Care.
200410(suppl)S358-69.
6
Coexistence of myocardial ischemia and depression
N 1957 7 months post-discharge following MI/UA
History of depression ()
Angina frequency
Rumsfeld JS et al. Am Heart J. 2003145493-9.
Seattle Angina Questionnaire
7
Causes of inadequate myocardial O2 supply

• Limited flow in epicardial coronary arteries
• Flow-limiting lesion(s) in conduit vessels
• Exacerbated by impaired endothelium-dependent
  response to stress
• Reduced dilation
• Constriction
• Impaired microvascular coronary flow reserve
• Resistance vessel (lt200 µm diameter) dysfunction
• Disordered VSMC activation/contraction
• Abnormal motility
• Abnormal growth
• Inflammation
• Extravascular compression

Pepine CJ et al. J Am Coll Cardiol.
20064730S-5. Reis SE et al. J Am Coll Cardiol.
1999331469-75. Kerins DM et al. In Goodman and
Gilmans The Pharmacological Basis of
Therapeutics. 10th ed.
8
Ischemia is related to myocardial O2 supply and
demand
Heart rate
Diastolic time
Spasm/ autoreg.
Oxygen demand
Oxygen supply
Contractility
Coronary blood flow
Collaterals
Wall tension
AoP LVED gradient
Systolicpressure
Volume
LVEDP
Ao dias. pressure
Ischemia
Adapted from Morrow DA et al. In Braunwalds
Heart Disease. 7th ed.
9
Obstructive plaque and ischemia
Obstructiveatheroscleroticplaque
Fattystreak
Increasedplaque
Normal
Plaque
Exertionalangina
Noninvasive tests normal
Noninvasive tests abnormal
? Vasodilator response to stress
Adapted from Abrams J. N Engl J Med.
20053522524-33.
10
New Mechanistic Approaches to Myocardial Ischemia
11
New mechanistic approaches to myocardial ischemia

• Rho kinase inhibition (fasudil)
• Metabolic modulation (trimetazidine)
• Preconditioning (nicorandil)
• Sinus node inhibition (ivabradine)
• Late Na current inhibition (ranolazine)

12
Rho kinase inhibition Fasudil
Rho kinase triggers vasoconstriction through
accumulation of phosphorylated myosin
Agonist
Ca2
Ca2
Receptor
PLC
PIP2
VOC
ROC
IP3
SR Ca2
Myosin
Myosin phosphatase
MLCK
Ca2
Myosin-P
Calmodulin
Adapted from Seasholtz TM. Am J Physiol Cell
Physiol. 2003284C596-8.
13
Metabolic modulation (pFOX) Trimetazidine

• O2 requirement of glucose pathway is lower than
  FFA pathway
• During ischemia, oxidized FFA levels rise,
  blunting the glucose pathway

Myocytes
Glucose
FFA
Acyl-CoA
Pyruvate
ß-oxidation
Trimetazidine
Acetyl-CoA
Energy for contraction
MacInnes A et al. Circ Res. 200393e26-32. Lopasc
huk GD et al. Circ Res. 200393e33-7. Stanley
WC. J Cardiovasc Pharmacol Ther. 20049(suppl
1)S31-45.
pFOX partial fatty acid oxidation FFA free
fatty acid
14
Preconditioning Nicorandil

• Activation of ATP-sensitive K channels
• Ischemic preconditioning
• Dilation of coronary resistance arterioles

O
N
HN
NO2
O

• Nitrate-associated effects
• Vasodilation of coronary epicardial arteries

IONA Study Group. Lancet. 20023591269-75. Rahman
N et al. AAPS J. 20046e34.
15
Late Na current inhibition Ranolazine
Myocardial ischemia
? Late INa
Na Overload
Ca2 Overload
Mechanical dysfunction ? LV diastolic tension ?
Contractility
Electrical dysfunctionArrhythmias
Belardinelli L et al. Eur Heart J Suppl.
20068(suppl A)A10-13.Belardinelli L et al. Eur
Heart J Suppl. 2004(6 suppl I)I3-7.
16
Na/Ca2 overload and ischemia
Myocardial ischemia
Intramural small vessel compression(? O2
supply) ? O2 demand
? Late Na current
Na overload
? Diastolic wall tension (stiffness)
Ca2 overload
Adapted from Belardinelli L et al. Eur Heart J
Suppl. 20068(suppl A)A10-13.
17
Myocardial ischemia Sites of action of
anti-ischemic medication
? O2 Demand Heart rate Blood pressure Preload Cont
ractility ? O2 Supply
Ca2 overload Electrical instability Myocardial
dysfunction(?systolic function/ ?diastolic
stiffness)

• Traditional
• anti-ischemic
• medications
• ß-blockers
• Nitrates
• Ca2 blockers

Courtesy of PH Stone, MD and BR Chaitman, MD.
2006.
18
Ranolazine Key concepts

• Ischemia is associated with ? Na entry into
  cardiac cells Na efflux in recovery by
  Na/Ca2 exchange results in ? cellular Ca2i
  and eventual Ca2 overload Ca2 overload may
  cause electrical and mechanical dysfunction
• ? Late INa is an important contributor to the
  Nai - dependent Ca2 overload
• Ranolazine reduces late INa

Belardinelli L et al. Eur Heart J Suppl.
20068(suppl A)A10-13.Belardinelli L et al. Eur
Heart J Suppl. 2004(6 suppl I)I3-7.
19
Clinical Management of Chronic Stable Angina
20
Older antianginal drugs Pathophysiologic effects
O2 Demand
O2 Supply
Coronary blood flow
Arterial pressure
Venous return
Myocardial contractility
Heart rate
Drug class
ß-blockers DHP CCBs Non-DHP CCBs Long-acting
nitrates

/
Boden WE et al. Clin Cardiol. 20012473-9.
Gibbons RJ et al. ACC/AHA 2002 guidelines.
www.acc.org/clinical/guidelines/stable/stable.pdf
Kerins DM et al. In Goodman and Gilmans The
Pharmacological Basis of Therapeutics. 10th ed.
CCB calcium channel blocker DHP
dihydropyridine Except amlodipine
21
Older antianginal drugs Clinical conditions that
may limit use
Treated with PDE5 inhibitors Nondihydropyridine
CCBs
Gibbons RJ et al. ACC/AHA 2002 guidelines.
www.acc.org/clinical/guidelines/stable/stable.pdf
22
Unmet needs in antianginal therapy

• Despite medical therapy and/or revascularization,
  some patients continue to experience angina
• Current treatment options for recurrent angina
  are limited
• Consensus on role of newer treatments is pending
• How best to manage symptomatic patients?

23
New Therapeutic Options for Chronic Stable Angina
24
Ranolazine Pathophysiologic effects vs older
antianginals
O2 Demand
O2 Supply
Myocardial contractility
Venous return
Arterial pressure
Heart rate
Coronary blood flow
Drug class
?

?
?

ß-blockers
?

?
?
?
DHP CCBs
?

?
?
?
Non-DHP CCBs

?
?
? /
?
Long-acting nitrates





Late Na current inhibitors(ranolazine)
Boden WE et al. Clin Cardiol. 20012473-9.
Gibbons RJ et al. ACC/AHA 2002 guidelines.
www.acc.org/clinical/guidelines/stable/stable.pdf
Kerins DM et al. In Goodman and Gilmans The
Pharmacological Basis of Therapeutics. 10th ed.
Except amlodipineRanolazine No direct effect
butmay prevent ischemia-related decline
25
MARISA Study overview
Monotherapy Assessment of Ranolazine In Stable
Angina
Objective Assess the antianginal effects of
ranolazine as monotherapy in stable
angina Design Randomized, double-blind,
placebo-controlled, crossover Population N
191 with stable angina Treatment Ranolazine
SR 500 mg, 1000 mg, or 1500 mg bid Placebo Prima
ry outcome Total exercise duration at
trough Follow-up 3 active treatment periods,
each lasting 1 week 1-week placebo period
1-year open-label follow-up
Chaitman BR et al. J Am Coll Cardiol.
2004431375-82.
26
MARISA Study design
Single-blind placebo qualifying phase
Double-blind phase
Post-study follow-up
1 week
2 weeks
4 weeks
Pre-visit 1
Visit 1
Visit 7
Randomized, 1-week periods, crossover, placebo,
ranolazine SR 5001500 mg bid
Qualifying ET
ET each week at trough and 4 hours post-dose
Chaitman BR et al. J Am Coll Cardiol.
2004431375-82.
ET exercise test (treadmill)
27
MARISA Dose-related increase in exercise
duration with ranolazine
N 175 evaluable patients with stable angina



Ranolazine SR bid
Chaitman BR et al. J Am Coll Cardiol.
2004431375-82.
P 0.003 vs placebo P lt 0.001 vs placebo
28
MARISA Tolerability of treatments
Dose-related adverse events
Occurring in 3 of patientsExceeds
recommended dose
Chaitman BR et al. J Am Coll Cardiol.
2004431375-82.
29
MARISA Summary

• Compared with placebo, ranolazine SR 5001500 mg
  bid significantly improved
• Total exercise duration
• Time to angina onset
• Time to 1 mm ST ?
• No clinically significant ? in HR or BP at rest
  or during exercise
• 7 (13/191) of ranolazine patients discontinued
  due to adverse events, mostly (11/13) at the
  highest dose
• No effect on QT dispersion
• No patient discontinued because of QTc
  prolongation

Ranolazine monotherapy is associated with
increased exercise performance in the absence of
any clinically meaningful pathophysiologic effects
Chaitman BR et al. J Am Coll Cardiol.
2004431375-82.
? gt30 from baseline
30
CARISA Study overview
Combination Assessment of Ranolazine In Stable
Angina
Objective Assess the antianginal effects of
ranolazine when added to standard antianginal
therapy Design Randomized, double-blind,
placebo-controlled, parallel-group Population
N 823 with angina/ischemia despite standard qd
doses of amlodipine 5 mg, atenolol 50 mg, or
diltiazem 180 mg Treatment Ranolazine SR 750
mg or 1000 mg bid Placebo Primary outcome
Total exercise duration at trough Follow up 12
weeks
Chaitman BR et al. JAMA. 2004291309-16.
31
CARISA Study design
Background CCB or ?-blocker plus nitrates prn
Ranolazine SR 1000 mg bid (n 275)
Single-blind placeboqualifying phase
Ranolazine SR 750 mg bid (n 279)
1 week
ET
Placebo (n 269)
2 weeks
4 weeks
6 weeks
ET
ET
ET
ET
ET Exercise test (treadmill)ET at trough and
4 hours post-dose
Chaitman BR et al. JAMA. 2004291309-16.
32
CARISA Ranolazine increases exercise duration

Background CCB or ?-blocker plus nitrates prn


(n 258)
(n 272)
(n 261)
Ranolazine SR bid
Chaitman BR et al. JAMA. 2004291309-16.
P 0.03 vs placebo
33
CARISA Ranolazine reduces angina frequency

Background CCB or ?-blocker plus nitrates prn
P lt 0.001
P 0.006
Anginal episodes per week
Placebo
Ranolazine SR750 mg bid
Ranolazine SR1000 mg bid
Chaitman BR et al. JAMA. 2004291309-16.
34
CARISA Ranolazine reduces nitrate consumption

Background CCB or ?-blocker plus nitrates prn
P lt 0.001
Number per week
Nitroglycerin use
Placebo
Ranolazine SR750 mg bid
Ranolazine SR1000 mg bid
Chaitman BR et al. JAMA. 2004291309-16.
35
CARISA Ranolazine benefits patients with and
without diabetes

Placebo
Ranolazine SR750 mg bid
Ranolazine SR1000 mg bid
Timmis AD et al. Eur Heart J. 20062742-8.
Pinteraction 0.81
36
CARISA Ranolazine reduces A1C
N 189 with diabetes on background antianginal
therapy

• Possible mechanisms include
• Improved insulin sensitivity
• Increased physical activity

P 0.008
P 0.0002
Cooper-DeHoff R and Pepine CJ. Eur Heart J.
2006275-6.Timmis AD et al. Eur Heart J.
20062742-8.
R ranolazine SRn 31/189 also receiving
insulin
37
CARISA Summary

• Ranolazine SR added to standard therapy
  significantly improved
• Total exercise duration, time to angina onset,
  time to 1 mm ST ?
• Anginal frequency and nitroglycerin consumption
• No clinically significant changes in HR or BP at
  rest or during exercise
• Small QTc increases with no effect on QT
  dispersion

Ranolazine provides additional antianginal and
anti-ischemic efficacy in patients who remain
symptomatic on standard therapies
Chaitman BR et al. JAMA. 2004291309-16.
38
ERICA Study design
Evaluation of Ranolazine in Chronic Angina
Stable angina on amlodipine 10 mgN 565
Ranolazine SR 1000 mg bid
Placebo
RandomizedDouble-blind
7 weeks
Primary outcomeAngina frequency
Stone PH et al. Circulation. 2005112(suppl
II)II-748-9.
39
ERICA Ranolazine reduces angina frequency and
nitrate consumption
N 565
6
5
P 0.028
4
Mean
P 0.014
number
3
per
week
2
1
0
Baseline
Week 7
Baseline
Week 7
Anginal attacks
Nitroglycerin use
Placebo
Ranolazine SR 1000 mg bid
Stone PH et al. Circulation. 2005112(suppl
II)II-748-9.
40
ERICA Summary

• Added to maximum-dose amlodipine, ranolazine SR
  1000 mg bid significantly reduced anginal
  frequency and nitroglycerin use
• No change in HR or BP
• Early withdrawal rate due to adverse events was
  comparably low in both groups
• 1.1 ranolazine
• 1.4 placebo

Ranolazine provides additional, well-tolerated
antianginal efficacy in patients who remain
symptomatic despite maximal CCB therapy
Stone PH et al. Circulation. 2005112(suppl
II)II-748-9.
41
Ranolazine Long-term use
Exercise-induced chronic angina Successfully
completed 1 of 2 treadmill studiesN 746
Open label Ranolazine titrated to 1000 mg
bid 2.96 years mean follow-up
Results Overall mortality 2.8 per
patient year (PPY) SCD mortality 0.6 PPY QTc
gt500msec 10 patients Torsade de Pointes 0
patients Ranolazine discontinuation due to AEs
9.7 in first 2 years Age gt64 years and prior Hx
of HF were significant predictors of
AE-associated discontinuation
Koren MJ et al. J Am Coll Cardiol. 200647(suppl
A)Abstract 999-253.
SCD sudden cardiac death
42
Antianginals Effects on exercise duration
1. Chaitman BR et al. J Am Coll Cardiol.
2004431375-82. 2. Davies RF et al. J Am Coll
Cardiol. 199525619-25. 3. Go M et al. Am J
Cardiol. 198453669-73. 4. Stone PH et al.
Circulation. 1990821962-72.
bid
43
Ranolazine extended-release tabletsApproved Jan
31, 2006

• Ranolazine is indicated for the treatment of
  chronic angina
• Because ranolazine prolongs the QT interval, it
  should be reserved for patients who have not
  achieved an adequate response with other
  antianginal drugs
• Ranolazine should be used in combination with
  amlodipine, ß-blockers or nitrates
• Effects on angina rate and exercise tolerance
  appear to be smaller in women

FDA. http//www.fda.gov/bbs/topics/news/2006/NEW01
306.html.Ranolazine extended-release tablets
prescribing information.
44
Ranolazine extended-release tablets Dosing

• Dosing should be initiated at 500 mg bid and
  increased to 1000 mg bid, as needed, based on
  clinical symptoms
• The maximum recommended daily dose of ranolazine
  is 1000 mg bid

Ranolazine extended-release tablets prescribing
information.
45
Ranolazine Drug interactions
Inhibitors of CYP3A increase ranolazine plasma
levels and QTc prolongation and should not be
coadministered with ranolazine

• Ketoconazole and other azole antifungals
• Diltiazem
• Verapamil
• Macrolide antibiotics
• HIV protease inhibitors
• Grapefruit juice or grapefruit-containing products

Ranolazine extended-release tablets prescribing
information.
46
Ranolazine No apparent proarrhythmic
characteristics

• No potential for early afterdepolarizations
  (EADs)
• Did not cause EADs
• Suppressed EADs induced by proarrhythmic agents
• Does not cause ? dispersion of ventricular
  repolarization
• Concentration-dependent ? transmural dispersion
  of APD (cardiomyocytes)
• No effect on QT dispersion in humans
• No torsade de pointes reported in clinical trials

Antzelevitch C et al. Circulation.
2004110904-10. Cobbe S. Eur Heart J Suppl.
20046(suppl I)I9-11. Chaitman BR et al. J Am
Coll Cardiol. 2004431375-82.
47
Current nonpharmacologic antianginal strategies

• Exercise Training
• Enhanced external counterpulsation (EECP)
• ? Endothelial function
• Promotes coronary collateral formation
• ? Peripheral vascular resistance
• ? Ventricular function
• Placebo effect

• Transmyocardial revascularization (TMR)
• Sympathetic denervation
• Angiogenesis
• Spinal cord stimulation (SCS)
• ? Neurotransmission of painful stimuli
• ? Release of endogenous opiates
• Redistributes myocardial blood flow to ischemic
  areas

Allen KB et al. N Engl J Med. 19993411029-36. Bo
netti PO et al. J Am Coll Cardiol.
2003411918-25.Murray S et al. Heart.
200083217-20.
48
Potential cardioprotective benefits of exercise
NO production
ROS generation
ROS scavenging
Other mechanisms
Vasculature
Thrombosis
Myocardium
Domenech R. Circulation. 2006113e1-3. Kojda G
et al. Cardiovasc Res. 200567187-97. Shephard
RJ et al. Circulation. 199999963-72.
49
Exercise vs PCI in low-risk CAD
N 101 men with CCS class IIII angina
PCI
20 min bicycle ergometry daily
Assessed at 12 months
Exercise vs PCI
Lower resting HR (P lt 0.01) Greater improvement
in maximal O2 uptake (P lt 0.001)
Fewer rehospitalizations Lower cost
Hambrecht R et al. Circulation. 20041091371-8.
gt80 had 1- or 2-vessel disease
50
Summary

• Many patients continue to experience angina
  despite medical therapy and/or revascularization
• Late Na blockade is a potentially effective new
  antianginal option with a mechanism of action
  complementary to traditional agents
• Potential clinical application in broad range of
  patients unresponsive to current treatment
  options
• Elderly
• Diabetes
• LV dysfunction or heart failure

51
Practical Considerations in Chronic Ischemic
Heart Disease Management
52
Angina treatment Objectives

• Reduce ischemia and relieve anginal symptoms
• Improve quality of life
• Prevent MI and death
• Improve quantity of life

Gibbons RJ et al. ACC/AHA 2002 guidelines.
www.acc.org/clinical/guidelines/stable/stable.pdf

53
ACC/AHA guidelines Chest pain evaluation
Contraindications to stress testing
Yes
Consider angiography
No
Symptoms/clinical findings warrant angiography
Yes
No
Low/intermediate risk
No
Pharmacologic imaging study
Patient able to exercise
Yes
Treatment
Previous coronary revascularization
Yes
Exercise imaging study
No
High risk
Consider angiography
Resting ECG interpretable
No
Consider angiography/revascularization
Yes
High risk
Exercise test
Consider imaging study/angiography
Treatment
Gibbons RJ et al. ACC/AHA 2002 guidelines. www.acc
.org/clinical/guidelines/stable/stable.pdf.
If adequate information on diagnosis/prognosis
available
54
ACC/AHA guidelines Chronic stable angina
treatment
Sublingual NTG
Patient education
CCB,Long-acting nitrate
Yes
Prinzmetal angina?
Medications/conditions that provoke/exacerbate
angina?
Yes
Treat appropriately
No
ß-blocker
Routine follow-up
Serious contraindication or unsuccessful
treatment
Add/substitute CCB
Consider revascularization
Serious contraindication or unsuccessful
treatment
Add long-acting nitrate
Gibbons RJ et al. ACC/AHA 2002 guidelines. www.acc
.org/clinical/guidelines/stable/stable.pdf.
Unsuccessful treatment
55
Substantial growth in PCI
5 national sample of Medicare beneficiaries
Adapted from Lucas FL et al. Circulation.
2006113374-9.
Adjusted for age, gender, race
56
Stable CAD PCI vs conservative medical management
Meta-analysis of 11 randomized trials N 2950
Favors medical management
Favors PCI
0
1
2
Risk ratio(95 Cl)
Katritsis DG et al. Circulation. 20051112906-12.
57
Selective vs routine catheterization Cost
reduction
N 11,249 consecutive stable angina patients
Myocardial perfusion plus selective cath
Routine early cath
Pretest clinical risk
Shaw LJ et al. J Am Coll Cardiol. 199933661-9.
Includes diagnostic and follow-up costs
58
Chronic stable angina Pharmacotherapy
ACC/AHA guidelines
Aspirin ß-blockers in patients with prior
MI ß-blockers in patients without prior
MI Lipid-lowering therapy in patients with
suspected CAD and LDL-C gt130 mg/dL (target LDL-C
lt100 mg/dL) ACEI in all patients with CAD who
have diabetes and/or LV systolic dysfunction
Gibbons RJ et al. ACC/AHA 2002 guidelines. www.acc
.org/clinical/guidelines/stable/stable.pdf.Grundy
SM et al. Circulation. 2004110227-39.
Optional goal of lt70 mg/dL in patients at very
high risk (ATP III Update)
59
CRUSADE Nonpharmacologic interventions at
discharge
N 35,897 patients with UA/NSTEMI Oct 2004Sept
2005


Patients ()


CRUSADE. www.crusadeqi.com
Can Rapid risk stratification of Unstable angina
patients Suppress ADverse outcomes with Early
implementation of the ACC/AHA guidelines
60
CRUSADE Discharge medications following UA/NSTEMI
N 35,897 patients without contraindications
Patients ()
CRUSADE. www.crusadeqi.com
Oct 2004Sept 2005
61
AHA guidelines Chest pain evaluation in women
Diabetes, abnormal rest ECG, questionable
exercise capacity
Normal rest ECG, able to exercise
Intermediate risk
Stress cardiac imaging
Exercise treadmill test
Able to exercise or symptoms with low-level
exercise
Low risk
Unable to exercise
Exercise stress
Pharmacologic stress
Moderately/severely abnormal test Reduced LVEF
Normal or mildly abnormal testNormal LVEF
Risk factor modification anti-ischemic Rx
Cardiac catheterization
Mieres JH et al. Circulation. 2005111682-96.
62
IHD vasculopathy Gender differences

• Structural features (macro- and microvessels)
• Smaller size
• Increased stiffness (fibrosis, remodeling, etc)
• More diffuse disease
• More plaque erosion vs rupture
• Rarefaction (drop out), disarray, microemboli,
  etc
• Functional features (macro- and microvessels)
• Endothelial dysfunction
• Smooth muscle dysfunction (Raynauds, migraine,
  CAS)
• Vasculitis (Takayasus, rheumatoid, SLE, CNSV,
  giant cell, etc)

CAS coronary artery spasm SLE systemic lupus
erythematosis CNSV central nervous system
vasculitis
Pepine CJ et al. J Am Coll Cardiol. 20064730S-5.
63
Ischemia in women Microvascular dysfunction

• Diminished coronary flow reserve
• Microvascular dysfunction exists in 50 of
  women presenting with chest pain and normal or
  near-normal coronary angiograms who had flow
  reserve measured

Reis SE et al. J Am Coll Cardiol.
1999331469-75. Reis SE et al. Am Heart J.
2001141735-41. Pepine CJ et al. J Am Coll
Cardiol. 20064730S-5.
Womens Ischemia Syndrome Evaluation (WISE) study
cohorts
64
Women have more adverse outcomes vs men
Angina 2x ? morbidity/mortality
MI 1.5x ? 1-year mortality
CABG 2x ? morbidity/mortality
CAD
Heart failure 2x ? incidence
Pepine CJ. J Am Coll Cardiol. 2004431727-30.
65
Less obstructive CAD Women vs men
Patients undergoing elective diagnostic
angiography for angina
Women
Men
ACC-National Cardiovascular Data Registry. J Am
Coll Cardiol. 2006.
66
Higher incidence of major CV events in women
Euro Heart Survey of Stable Angina n 1547
women, n 2478 men
Overall angina population
Women
Men
Angina with angiographic CAD
Women
Incidence ()
Men
Daly C et al. Circulation. 2006113490-8.
67
Increased risk of death/MI in women with CAD
Euro Heart Survey of Stable Angina n 718 men,
n 276 women with angiographic CAD
Log rank P 0.02
Cumulative event probability
0
3
6
9
12
15
18
Time since entry (months)
Men
Women
Daly C et al. Circulation. 2006113490-8.
68
CRUSADE Gender and discharge medications
N 35,897 patients with UA/NSTEMI
100
80
60
Patients ()
40
20
0
Aspirin
?-blocker
ACEI
Statin
Clopidogrel
Discharge medications
Men
Women
Oct 2004Sept 2005 P values not reported
CRUSADE. www.crusadeqi.com
69
Ongoing Trials in Managing Myocardial Ischemia
70
MERLIN-TIMI 36 Study design
Metabolic Efficiency with Ranolazine for Less
Ischemia in Non-ST elevation acute coronary
syndromeThrombolysis In Myocardial Infarction 36
Patients with non-ST elevation ACStreated with
standard medical/interventional therapiesN 5500
IV/oral ranolazine
Placebo
RandomizedDouble-blind
Anticipated completion 2006
Primary outcomeCV death, MI, recurrent ischemia
Lüscher T. Eur Heart J Suppl. 20046(suppl
I)I17-8. MERLIN-TIMI 36 Study Group.
www.clinicaltrials.gov.
71
COURAGE Study design
Clinical Outcomes Utilizing Revascularization and
Aggressive druG Evaluation
Boden WE et al. Am Heart J. 2006.
72
BARI 2D Study design
Bypass Angioplasty Revascularization
Investigation 2 Diabetes
Patients with type 2 diabetes and angina or
asymptomatic myocardial ischemiaN 2322
Aggressive pharmacologic CV therapy
Aggressive pharmacologic CV therapy coronary
revascularization
Randomize
Randomize
Insulinsensitizer-based antidiabetic therapy
Insulin-based antidiabetic therapy
5 years
Primary outcome All-cause deathSecondary
outcome All-cause death, Q-wave MI, stroke
Double-blind, 2x2 factorial
Sobel BE et al. Circulation. 2003107636-42.
73
Stem cell therapy for intractable anginaStudy
design

Patients with intractable CCS class III or IV
angina not suitable for CABG or PCI N 24
5 days GCSF (plus ASA, clopidogrel,
statin)/apheresis/CD34 cell selection
Double-blind, placebo-controlled
Saline control
1 x 105/kg
5 x 104/kg
5 x 105/kg
Injected into hibernating/ischemic myocardium
Cross-over permitted at 6 months(CCS class III
or IV, abnormal SPECT, ETT lt 6 min)
Losordo DW et al. VBWG US chapter meeting. March
2006 Atlanta, Ga.
Sub-therapeutic dose in preclinical studies GCSF
granulocyte colony-stimulating factor
74
Summary

• Despite availability of effective medical and
  interventional modalities, patients with stable
  CAD continue to experience ischemic events
• In special populations (eg, women) CAD needs to
  be more aggressively diagnosed and treated
• Ongoing trials may help better define the role of
  aggressive medical therapy with/without PCI