-Dr Akshay Mehta

Dr B Nanavati HospitalAsian Heart Institute

STICH Trial-A Critical Appraisal

Background 1

CAD is the commonest substrate for HF

The role of CABG for Rx of CAD with HF not clearly established.

Landmark trials in the 1970s comparing CABG with medical therapy alone, were predominantly in pts with chronic stable angina.

Background 2 These trials excluded patients with severe LV

dysfunction (patients with an ejection fraction of <35%).

A meta-analysis of the trials showed that 7.2% of the patients who underwent randomization had an EF of 40% or less

Only 4.0% had primary symptoms of heart failure rather than angina

Predate the major developments in medical therapy and cardiac surgery

Two Hypotheses

Surgical Revascularization

Hypothesis

LV restoration hypothesis

Surgical Treatment for Ischemic Heart Failure –STICH Trial

I II

I] Surgical Revascularization Hypothesis

Primary Hypothesis: In patients with HF, LVD and CAD amenable to surgical

revascularization, CABG added to intensive medical therapy (MED) will decrease all-cause mortality compared to MED alone.

Secondary hypothesis: Presence and extent of dysfunctional but viable myocardium,

as defined by radionuclide imaging, dobutamine stress echocardiography, or both, will identify patients with greatest survival advantage of MED + CABG compared with MED alone.

II] LV restoration hypothesis

In patients with dominant anterior wall LV akinesia or dyskinesia, LV shape and size optimization by SVR combined with CABG and MED improves long-term survival free of cardiac hospitalization compared with CABG and MED without SVR.

Original Article Coronary-Artery Bypass Surgery in Patients

with Left Ventricular Dysfunction

Eric J. Velazquez, M.D., Kerry L. Lee, Ph.D., Marek A. Deja, M.D., Ph.D., Anil Jain, M.D., George Sopko, M.D., M.P.H., Andrey Marchenko, M.D., Ph.D.,

Imtiaz S. Ali, M.D., Gerald Pohost, M.D., Sinisa Gradinac, M.D., Ph.D., William T. Abraham, M.D., Michael Yii, M.S., F.R.C.S., F.R.A.C.S., Dorairaj

Prabhakaran, M.D., D.M., Hanna Szwed, M.D., Paolo Ferrazzi, M.D., Mark C. Petrie, M.D., Christopher M. O'Connor, M.D., Pradit Panchavinnin, M.D.,

Lilin She, Ph.D., Robert O. Bonow, M.D., Gena Roush Rankin, M.P.H., R.D., Robert H. Jones, M.D., Jean-Lucien Rouleau, M.D., for the STICH

Investigators

N Engl J MedVolume 364(17):1607-1616

April 28, 2011

STICH Revascularization Hypothesis

HF, LVD and CAD amenable to CABG

1212Randomized MED only

602

Randomized CABG610

All-Cause Mortality

Adjusted HR 0.82 (0.68,0.99)Adjusted P = 0.039

Thus Primary End Point:

As randomized, CABG led to a 14% RRR in all-cause mortality compared to MED

(not significant)

Has CABG no role in Ischemic HF ?

“We were unable to show a significant benefit for CABG in our primary analysis, but if you dive deeper, the data are much more supportive of bypass surgery,”

-Dr Eric J. Velazquez, M.D.

Cardiovascular Mortality

HR 0.81 (0.66, 1.00)

P = 0.050

Adjusted HR 0.77 (0.62, 0.94)

Adjusted P = 0.012

• Death from any cause adjusted outcomes models. Model 1: surgical ventricular reconstruction eligibility (i.e., enrollment stratum); Model 2: Model 1 + age, sex, race, baseline New York Heart Association heart failure class, myocardial infarction history, previous revascularization, best available core lab ejection fraction; Model 3: Model 2+ number of diseased vessels, presence of chronic renal insufficiency, mitral regurgitation grade, stroke history, atrial fibrillation or flutter.

Death or Cardiovascular Hospitalization-nt done

HR 0.74 (0.64, 0.85)

P < 0.001

Adjusted HR 0.70 (0.61, 0.81) P <

0.001

Death or Cardiovascular hospitalization

Time-varying Hazard Ratios

0.25 0.5 1 2 4

CABG group better

MED group better

STICH Revascularization HypothesisEffect of Actual Treatment Received

As treated: MED (592) vs. CABG (620) Per protocol: MED (537) vs. CABG (555)

1212

RandomizedCABG

Randomized MED only

610602

Received MED

Received CABG

555537

Received MED

5565

All-Cause Mortality — As Treated (nt done)

HR 0.70 (0.58 – 0.84)

P < 0.001

All cause mortality-as treated

All-Cause Mortality— As Per Protocol (nt done)

HR 0.76 (0.62, 0.92)

P = 0.005

All-cause mortality: as per protocol

Conclusions STICH trial supports bypass surgery on top of best medical

therapy vs medical therapy alone to reduce cardiovascular morbidity and mortality

“Although the totality of information supports CABG, there is

an early hazard A fair approach is to evaluate each patient’s prognosis. If they

have a low likelihood of living two years or don’t want to take the risk of having surgery medical therapy may be a good option.”

- Dr Eric Velazquez

Also, as a start, aggressive medical therapy should be initiated and optimized, according to evidence-based guidelines.

For patients with persistent or progressive symptoms, revascularization can be offered.

Patients who are being treated for HF should be evaluated for coronary disease

Heart failure without angina shouldn't exclude patients from an angiographic evaluation.

Myocardial Viability and Survival in Ischemic Left Ventricular Dysfunction

Robert O. Bonow, MD

On behalf of the STICH Trial Investigators

STICH Viability Hypothesis

In this prospective substudy, we tested the hypothesis that assessment of myocardial viability identifies

patients with CAD and LV dysfunction who have the greatest survival benefit with CABG compared to

aggressive medical therapy

STICH Viability

Viability testing was optional at enrolling sites and was not a prerequisite for enrollment.

SPECT protocols:

•Thallium-201 stress-redistribution-reinjection• Thallium-201 rest-redistribution•Nitrate-enhanced Tc-99m perfusion imaging

Dobutamine echo protocols:

•Staged increase in dobutamine starting at 5 μg/kg/min

Patients randomized

1212

594

611

618

601

17

Patients with no myocardial viability test

Patients with no usable myocardial viability test

Patients with myocardial

viability test

Patients with usable myocardial

viability test

Unusable test • Timing • Poor quality

1212

150321 130

611

SPECTn=471

Dobutamine echo n=280

114Nonviable

487Viable

Patients with no usable myocardial viability test

Patients with usable myocardial

viability test

Patients randomized in STICH Revascularization Hypothesis

601

STICH Viability Results

…demonstrate that association between myocardial viability and survival, is non-significant when subjected to a multivariable analysis that includes other baseline variables.

STICH Viability

Implications:

In patients with CAD and LV dysfunction, assessment of myocardial viability does not identify patients who will have the greatest survival benefit from adding CABG to aggressive medical therapy

However, Limitations of the Trial

Patients were selected for viability testing individually at the physicians' discretion

Patients represent a subpopulation of STICH (<50%)

The number of patients without substantial viability was small(114) which limited statistical power

Use of two different imaging methods for assessing myocardial viability and their limitations of specificity/sensitivity.

Analysis limited to SPECT and dobutamine echo, not PET or cardiac MRI

while the analysis looked at "substantial viability" as an "all-or-none" variable, decisions whether to revascularize or not have generally depended on the extent of viability—that is, as a continuous variable.

Take home message:Despite all its imperfections the viability

study suggests that assessment of myocardial viability alone may not be

the deciding factor in selecting the best therapy for patients with ischemic

heart disease and LV dysfunction.

Besides viability one should also look at other factors like target vessels,

LV volumes, EF etc. This is specially true if

SPECT or Dobutamine echo only are used for viability

testing.Whether they have viability or not, STICH like

patients benefit from coronary bypass and we

shouldn't be using viability studies such as these to exclude patients from

cardiac surgery.We should await similar randomized studies with

other methods of viability detection like MRI etc.

Myocardial Viability and Mortality

Without viabilityWith viability

Variables associated with mortality

Chi-square p

Risk score 33.26 <0.001

LV ejection fraction 24.80 <0.001

LV EDVI 35.36 <0.001

LV ESVI 33.90 <0.001

Myocardial viability 8.54 0.003

1.0

0.8

0.6

0.4

0.2

0.0

Mo

rtal

ity

Rat

e

Years from Randomization0 1 2 3 4 5 6

50%

33%

Chi-square p

Risk score 33.26 <0.001LV ejection fraction 24.80 <0.001LV EDVI 35.36 <0.001LV ESVI 33.90 <0.001Myocardial viability 8.54 0.003

HR 95% Cl PO.65 0.48 0.86 0.003

Myocardial Viability and Mortality

Variable No.Univariate Multivariable

Chi-square p value Chi-square p value

SPECT and/or DE 601 8.54 0.003 1.57 0.210

SPECT alone 471 7.35 0.007 0.58 0.444

DE alone 280 1.18 0.277 0.42 0.518

Myocardial Viability and Mortality

Univariate Multivariable Chi-square p value Chi-square p value

8.81 0.003 0.91 0.339

HR 95% Cl P0.61 0.44 0.84 0.003

Myocardial Viability and Cardiovascular Mortality

Univariate Multivariable

Chi-square p value Chi-square p value

20.27 <0.001 8.60 0.003

Myocardial Viability and Mortality + CV Hospitaliztion

Patients with viability tests

Patients without myocardial viability

Patients with myocardial

viability

CABG50.1%

CABG47.4%

MED49.9%

MED52.6%

601

487

243 244

114

60 54

Myocardial Viability and Mortality

Subgroup

Without viability

With viability

N Deaths HR 95% CI

114 58 0.70 0.41, 1.18

487 178 0.86 0.64, 1.16

1 20.50.25

CABGbetter

MEDbetter

InteractionP value

0.528

56%

42%

35%

31%

the patients without substantial viability, "who had perhaps less likelihood of functional recovery [than those with substantial viability], did as well from CABG as patients who did. . . . I think that's what we have to take away from this: we shouldn't be using [viability] studies to exclude patients from cardiac surgery

-Dr Eric Velazquez

Surgical Treatment for Ischemic Heart Failure –STICH Trial

HypothesesIn patients with HF, LVD < 35% and CAD

amenable to CABG, CABG +MED will decrease all-cause mortality compared to

MED alone+ (Viability Substudy)

In pts with dominant anterior wall LV akinesia or dyskinesia, SVR + CABG + MED >

hosp free survival compared with CABG + MED without SVR.

I

II

For management of patients withHF with surgically revascularizable CAD

and decreased LV function

(1) Is contemporary CABG surgery superior to contemporary medical/secondary prevention

therapy in prolonging survival in these pts?

(2) Among patients with significant anterior wall dysfunction, does the addition of surgical ventricular reconstruction (SVR) to CABG

improve hospitalization-free survival?

Surgical Treatment for Ischemic Heart Failure trial stratum and treatment assignment.

CADEF <= 0.35

Medical eligibility

SVR eligible?

SVR eligible? Not in trial

Stratum AStratum B

Stratum C

MED

MED

CABG

CABGCABGCABG + SVR

CABG + SVR

YES

YESYES

NO NO

NO

Hypotheses :

In patients with heart failure, left ventricular EF of 0.35 or less

(1) coronary artery bypass grafting with intensive medical therapy improves long-term survival compared with survival with medical therapy alone, and

(2) in patients with anterior left ventricular dysfunction, surgical ventricular reconstruction to a more normal left

ventricular size plus coronary artery bypass grafting improves survival free of subsequent hospitalization for cardiac cause when compared with that with coronary artery bypass grafting alone.

Major STICH hypotheses

Primary Hypotheses

H1 Coronary revascularization hypothesis● Improvement in myocardial perfusion by CABG combined with MED improves long-term survival

compared with MED alone.

H2: LV restoration hypothesis● In patients with dominant anterior wall LV akinesia or

dyskinesia, LV shape and size optimization by SVR combined with CABG and

MED improves long-term survival free of cardiac hospitalization compared with CABG and MED without SVR.

The conclusions that can be drawn from this substudy are limited by a

number of factors Viability data were not available for all the patients who were

enrolled in the STICH main trial.3 The substudy patients represent slightly less than 50% of the randomized group.

Furthermore, viability testing was not performed on a randomly selected subgroup of patients but, rather, was

obtained according to test availability and the judgment of the recruiting investigator. Third, the possibility cannot be

excluded that the results of viability testing could have influenced subsequent clinical decision-making

Despite the goal of uniform testing in this trial, the nonrandom and nonblinded selection for viability testing of only 601 of the 1212 eligible patients (49.6%) introduces considerable biases. Moreover, viability was defined in a binary fashion, and revascularization was not guided by the presence of viable myocardium within specific coronary-artery territories. In addition, the study is underpowered in the group with nonviable myocardium (i.e., 60 patients who received medical therapy and 54 patients who underwent CABG). Finally, viability assessment was restricted to single-photon-emission computed tomography (SPECT) and dobutamine echocardiography, which have well-known limitations in their ability to detect viability.1 We believe there is need for a randomized study of revascularization versus medical therapy after viability assessment with a standard technique such as contrast-enhanced magnetic resonance imaging (MRI) or positron-emission tomography (PET),1-3 which would allow targeted revascularization based on the presence of viable myocardium within specific coronary-artery territor

"The analysis of intention-to-treat vs actual treatment is interesting, but the biological effect that our patients feel is what treatment they receive, and under that analysis, as a surgeon, you must conclude that patients with left ventricular dysfunction should receive coronary bypass." - Dr Steven Bolling (University of Michigan Cardiovascular Center, Ann Arbor)

Study Design

Randomized controlled trial, non-blinded 99 clinical sites in 22 countries Investigator-initiated and led National Heart, Lung and Blood Institute funded Duke Clinical Research Institute managed Independent Data and Safety Monitoring Committee Clinical Events Adjudication Committee Blinded Core Laboratories

Endpoints

Primary Endpoint– All-cause mortality

Major Secondary Endpoints– Cardiovascular mortality– Death (all-cause) + cardiovascular hospitalization

Important Inclusion Criteria

LVEF ≤ 0.35 within 3 months of trial entry CAD suitable for CABG MED eligible

– Absence of left main CAD as defined by an intraluminal stenosis of ≥ 50%

– Absence of CCS III angina or greater (angina markedly limiting ordinary activity)

Major Exclusion Criteria

Recent acute MI (within 30 days) Cardiogenic shock (within 72 hours of randomization) Plan for percutaneous intervention Aortic valve disease requiring valve repair or replacement History of more than 1 prior CABG Non-cardiac illness with a life expectancy of less than 3 years or

imposing substantial operative mortality

Surgical Treatment for Ischemic Heart Failure trial stratum and treatment assignment.

CADEF <= 0.35

Medical eligibility

SVR eligible?

SVR eligible? Not in trial

Stratum AStratum B

Stratum C

MED

MED

CABG

CABGCABGCABG + SVR

CABG + SVR

YES

YESYES

NO NO

NO

+ CABG amenable

STICH Viability

• All randomized patients were eligible for viability testing with SPECT myocardial perfusion imaging or dobutamine echo.

• Viability testing was optional at enrolling sites and was not a prerequisite for enrollment.

STICH Viability

Criteria for myocardial viability were prospective and pre-specified

SPECT: • 17 segment model• ≥11 segments manifesting viability based on relative

tracer activity

Dobutamine echo:• 16 segment model• ≥5 segments with dysfunction at rest manifesting

contractile reserve with dobutamine

STICH Viability

Primary endpoint: ▪ All-cause mortality

Secondary endpoints:

▪ Mortality plus cardiovascular hospitalization ▪ Cardiovascular mortality

Intention-to-treat analysis

VariableViable

(n=487)Non-Viable

(n=114) P value

Age 61 ± 10 61 ± 9 NS Multivessel CAD 73% 73% NS

Proximal LAD stenosis 64% 70% NS

Risk score 12.4 ± 8.7 12.9 ± 9.3 NS

Previous MI 76.6% 94.7% <0.001 LV ejection fraction (percent) 28 ± 8 23 ± 9 <0.001

LV end-diastolic volume index (ml/m2) 117 ± 37 147 ± 53 <0.001

LV end-systolic volume index (ml/m2) 86 ± 33 116 ± 50 <0.001

Baseline CharacteristicsPatients With and Without Myocardial Viability

*

*

Significant covariates in risk model: Age, renal function, heart failure,ejection fraction, CAD index, mitral regurgitation, stroke

Background• LV dysfunction in patients with CAD is not always an

irreversible process, as LV function may improve substantially after CABG

• Assessment of myocardial viability is often used to predict improvement in LV function after CABG and improvement in survival

THANK YOU!!