Cad and low ef does viability assessment matter

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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

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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

2.8 2.7

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

Death

rate

(%

per

year)

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

Mo

rta

lity r

ate

MED 537 471 430 381 276 139 72

CABG 555 487 452 428 319 167 89

0 1 2 3 4 5 6


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)

Pro

ba

bili

ty o

f de

ath

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


MED (33 deaths)

CABG (25 deaths)

Mo

rta

lity r

ate

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


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.

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Higher LVEF (>28%)




Ischemic Burden



Increased MI Risk




Lower LVEF (27%)



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Higher LVEF (>28%)




Ischemic Burden



Increased MI Risk




Lower LVEF (27%)



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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 High Int Low

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

Healthcare

Cad and low ef does viability assessment matter