This document discusses the value of viability studies in patients with coronary artery disease (CAD) and low ejection fraction (EF). It summarizes several studies on the topic and discusses their limitations. A key trial was the STICH trial, which found no significant difference in outcomes between revascularization and medical therapy alone, challenging the belief that revascularization benefits those with viable myocardium. The document concludes that while viability concepts are biologically plausible, recent trials create confusion and there is no consensus on how to apply viability testing in practice.

1. ©2015 MFMER | 3417831-1
CAD and Low EF
Does Viability Assessment Matter?
ACC 15
64th Annual Scientific Session & Expo
March 16, 2014
Lyle D. Joyce MD, PhD
Mayo Clinic Rochester

2. ©2015 MFMER | 3417831-2
Surgical Consult
47 yr old male
Major complaint dyspnea on exertion
ECHO shows 20% EF
LVEDd 67 cm
CI 1.9
Angio: Reasonable targets

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Mortality Rates in Patients Undergoing
CABG in New York State From 1997 to 1999
6.5
4.6
4.1
2.82.7
1.9
1.4
1.0
0
1
2
3
4
5
6
7
In-hospital mortality Early mortality
Veli K, Topkara et al: Circulation 112:I-344-I, 2005
EF 20
EF 21-30
EF 31-40
EF >40
%

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Velazquez EJ et al: JACC 65(6):615, 2015
Favors Medical Therapy
Favors CABG + Medical Therapy
Severe Renal Insufficiency
Smaller LVESVI (<79 mL/m2)
Higher LVEF (>28%)
Single-Vessel Coronary Disease
Limited Functional Capacity
(6MWD <300 meters, KCCQ
Physical Ability Score 55)
More Viable Myocardium
Ischemic Burden
Biomarker Level (BNP, STNFR-1)
Less Viable Myocardium
Increased MI Risk
Increased Risk of Sudden Cardiac Death
Moderate to Severe Mitral Regurgitation
Preserved Functional Capacity
(6MWD 300 meters, KCCQ
Physical Ability Score >55)
Lower LVEF (27%)
Three-Vessel Coronary Disease
Larger LVESVI (79 mL/m2)

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Outline – Value of viability studies
1. Look at the traditional experience with
CABG in low EF
2. Review the data on the subject
3. Discuss what one might conclude going
forward

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Mechanisms of LV dysfunction in CAD
patients are complex
• Ischemic LV dysfunction may be sustained by
repetitive ischemia leading to infarction
or
• Myocardial stunning and hibernation
and
therefore, completely or partially reversible in a
substantial number of patients who undergo
revascularization

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What we want to Believe
• In revascularizing patients with CAD and
severe LV dysfunction, the presence of a large
amount of dysfunctional but viable myocardium
identifies patients with the best prognosis
• The concepts of myocardial viability and viability
testing are logical and mechanistically sound
• Assessment of myocardial viability should be
used to predict improvement in LV function after
CABG and thus help select patients for CABG

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Furthermore….
Reasonable, though non-definative, evidence
from more than 100 nonrandomized studies of
more than 3,000 patients with viability testing in
the last 2 decades has consistently demonstrated
its usefulness

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3.2
7.7
16
6.2
0
5
10
15
20
Viable Nonviable
J Am Coll Cardiol 39: 1151, 2002
J Am Coll Cardiol Img 5(5):550, 2012
Revascularization
Medical therapy
Deathrate(%peryear)
23.0% 2=1.43
P=0.23
-79.6% 2=147
P<0.0001
In the presence of viability, a 79.6% reduction in mortality was noted with
revascularization vs medical therapy; without myocardial viability, there was
no significant difference in mortality between the 2 treatment groups
Death Rates for Patients With and Without Myocardial
Viability Treated by Revascularization or Medical Therapy

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Stratified patients with severe LV systolic
dysfunction (presumed ischemic) to
recent angiography or not then
randomized to PET-guided management
vs standard care without PET

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Unfortunately, the clinicians who enrolled
patients in this particular trial did not always
follow the recommendations of the positron
emission tomography (PET) findings, leaving
the interpretation of the study fairly flexible
and pointing out the difficulty of pulling off a
study with such a complex design

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“Survival Curves” (on the Basis of Time to First
Occurring Outcome of the Composite Event)
0.0
0.2
0.4
0.6
0.8
1.0
0 100 200 300
Days
Standard arm
PET arm
Mantel-Haenszel (log-rank) test for differences between 2 survival curves; chi square = 2.1;
HR=0.78; 95% CI 0.58-1.1; P=0.15; PET=positron emission tomography

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When only patients adhering to PET
guided recommendations were
included, the PET adherence group
had significantly better outcome than
the standard care

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“Survival Curves” (on the Basis of Time to First
Occurring Outcome Out of the Composite Event)
0.0
0.2
0.4
0.6
0.8
1.0
0 100 200 300
Days
Standard arm
PET arm
The positron emission tomorgraphy adherence group vs standard care arm; Mantel-Haenszel (log-
rank) test for differences between 2 survival curves; adjusted HR=0.62; 95% CI 0.42-0.93; P=0.019

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“Survival Curves” (on the Basis of Time
to Cardiac Death) for All Subjects
0.0
0.2
0.4
0.6
0.8
1.0
0 100 200 300
Days
Standard arm
PET arm
Mantel-Haenszel (log-rank) test for differences between 2 survival curves; chi square = 1.3;
HR=0.72; 95% CI 0.4-1.3; P=0.25; PET=positron emission tomography

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PARR-2 Conclusion
• The data suggest that many patients with severe
LV dysfunction and suspected CAD might not
always benefit from FDG PET imaging
• However, there is potential value for FDG PET,
particularly in a high-risk patient population where
decisions for therapy are most difficult
• When patients adhere to FDG PET
recommendations, a reduction in events
might be realized

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STICH Revascularization Hypothesis
• The first prospective randomized trial testing the
hypothesis that CABG improves survival in
patients with ischemic LV dysfunction compared
to outcome with aggressive medical therapy
• Provided the first opportunity to assess the
interaction between myocardial viability and
survival in randomized patients who were all
eligible for medical management alone and also
eligible for CABG

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Crossover Occurred in
• 17% of patients assigned to medical therapy
• 9% of patients assigned to CABG potentially
reducing the treatment effect

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Kaplan-Meier Estimates of Death from any Cause
on an As-Treated Basis or on a Per-Protocol Basis
0.0
0.2
0.4
0.6
0.8
1.0
0 1 2 3 4 5 6
Years from randomization
MED
CABG
Mortalityrate
MED 537 471 430 381 276 139 72
CABG 555 487 452 428 319 167 89
0 1 2 3 4 5 6
Years from randomization
595 516 464 412 297 146 74
620 548 509 482 355 182 97
HR
0.76
95% CI
0.62-0.92
P
0.005
HR
0.70
95% CI
0.58-0.84
P
<0.001
Per Protocol As Treated

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Viability Study Limitations Include That…
1. It was a substudy
2. Use of viability testing was not randomized
nor the results blinded
3. There were differences in baseline
characteristics of the patient groups
4. Nonviable group was relatively small

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Kaplan-Meier Analysis of the Probability of
Death, According to Myocardial Viability Status
0.0
0.2
0.4
0.6
0.8
1.0
0 1 2 3 4 5 6
Years since randomization
With viability
Without viability
The comparison that is shown has not been adjusted for other prognostic baseline variables;
after adjustment for such variables on multivariable analysis, the between-group difference
was not significant (P=0.21)
Probabilityofdeath
HR 0.64 (95% CI 0.48-0.86)
P=0.003
Without viability 114 99 85 80 63 36 16
With viability 487 432 409 371 294 188 102

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Myocardial Viability and Mortality
0.0
0.2
0.4
0.6
0.8
1.0
0 1 2 3 4 5 6
Years from randomization
MED (33 deaths)
CABG (25 deaths)
Mortalityrate
MED 60 51 44 39 29 14 4
CABG 54 48 41 41 34 22 12
Without Viability
0 1 2 3 4 5 6
Years from randomization
MED (95 deaths)
CABG (83 deaths)
243 219 206 179 146 94 51
244 213 203 192 148 94 51
With Viability
56%
42%
35%
31%

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STICH Trial Conclusion
We did not find a significant interaction between
myocardial-viability status and medical vs
surgical treatment with respect to the rates of
death from any cause or from cardiovascular
causes or hospitalization for cardiovascular
causes

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Key Points
• The STICH trial results have challenged conventional
thinking that, firstly, revascularization is superior to
medical therapy alone for the treatment of ICM and,
secondly, that viability testing is necessary in this patient
population
• Following publication of the STICH trial results, there
has been considerable debate about the validity of the
findings given the numerous methodological limitations,
both in the main trial and also in the viability substudy
• Further observational studies using echocardiography,
nuclear cardiology, cardiac MRI and cardiac CT have
been published in the last 18 months, demonstrating
ability to predict functional recovery and, in some cases,
patient outcomes – but in a nonrandomized setting

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Imaging Techniques for Assessment
of Myocardial Viability
Echocardiography
• End-diastolic wall thickness
• Dobutamine echocardiography
• MCE
• TDI
• STE
Radionuclide imaging
• Thallium scintigrpahy
• Technetium scintigraphy
• Positron emission tomogrpahy
(eg, FDG-PET)
• Combined PET/SPECT
CMR
• EDWT
• Dobutimaine CMR
• LGE
CCT
• Contrast CT: Delayed
enhancement imaging
• Noncontrast CT: Hypodense
myocardium

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Clinicians are now presented with the
dilemma of reconciling plausible biological
concepts already incorporated into
practice with the opposing findings of
recent clinical trials

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To add further confusion…
The clinical parameters in the opening case are
identical to the mean parameters in our last 117
ischemic cardiomyopathy patients that received
an LVAD. As survival improves, one may want to
go straight to a mechanical support device.

31. ©2015 MFMER | 3417831-31
Velazquez EJ et al: JACC 65(6):615, 2015
Favors Medical Therapy
Favors CABG + Medical Therapy
Severe Renal Insufficiency
Smaller LVESVI (<79 mL/m2)
Higher LVEF (>28%)
Single-Vessel Coronary Disease
Limited Functional Capacity
(6MWD <300 meters, KCCQ
Physical Ability Score 55)
More Viable Myocardium
Ischemic Burden
Biomarker Level (BNP, STNFR-1)
Less Viable Myocardium
Increased MI Risk
Increased Risk of Sudden Cardiac Death
Moderate to Severe Mitral Regurgitation
Preserved Functional Capacity
(6MWD 300 meters, KCCQ
Physical Ability Score >55)
Lower LVEF (27%)
Three-Vessel Coronary Disease
Larger LVESVI (79 mL/m2)

32. ©2015 MFMER | 3417831-32
Velazquez EJ et al: JACC 65(6):615, 2015
Favors Medical Therapy
Favors CABG + Medical Therapy
Severe Renal Insufficiency
Smaller LVESVI (<79 mL/m2)
Higher LVEF (>28%)
Single-Vessel Coronary Disease
Limited Functional Capacity
(6MWD <300 meters, KCCQ
Physical Ability Score 55)
More Viable Myocardium
Ischemic Burden
Biomarker Level (BNP, STNFR-1)
Less Viable Myocardium
Increased MI Risk
Increased Risk of Sudden Cardiac Death
Moderate to Severe Mitral Regurgitation
Preserved Functional Capacity
(6MWD 300 meters, KCCQ
Physical Ability Score >55)
Lower LVEF (27%)
Three-Vessel Coronary Disease
Larger LVESVI (79 mL/m2)

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Questions & Discussion

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Methodological Limitations of the STICH Trial
Main STICH trial
• Most patients had angina, not dyspnea, as predominant symptom and majority
were in NYHA class I-II
• Selection bias: Openly acknowledged by several investigators; average
recruitment rate was just two patients per site per year
• Left main stem patients excluded, a group in whom revascularization would have
shown a survival benefit
• Cross over: 17% OMT patients had CABG and 9% of CABG patients never
actually has surgery
• 6% patients in OMT group had PCI but no counted as revascularization
• Outcome of screened (but not enrolled) patients unknown
STICH viability substudy
• Nonrandomized: Use of viability testing left to physician discretion
• Significant differences in baseline characteristics between those with and without
viability (especially incidence of prior MI and LV cavity volumes)
• Binary classification of patients as ‘viable’ or ‘nonviable’ with use of controversial
thresholds, and different cut offs for SPECT and DbE
• Revascularization not guided by presence of myocardial viability

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Algorithm Suggesting how to Integrate Viability and
Ischemic Testing into Contemporary Denied Practice
Diagnosis of ischemic cardiomyopathy
Concurrence optimal medical therapy
Dominant symptom: Angina Dominant symptom: Dyspnea
Asses co-morbidities and risks of revascularization
Procedural risk
High Int Low HighIntLow
Viability ±ischemia testing
based on CAD severity
Optimize anti-
anginal therapy
Persistent
symptoms
Mild – moderate CAD Severe CAD
V – Yes
I – Yes
V – Yes
I – No
V – No
I – No
V – No V – Yes
OMT ± CRT
Persistent symptoms
Revascularization