Critical appraisal of Stitch Trial by Dr. Akshay Mehta
1. STICH Trial-
A Critical Appraisal
-Dr Akshay Mehta
Dr B Nanavati Hospital
Asian Heart Institute
2. 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.
3. 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
4. Surgical Treatment for Ischemic
Heart Failure –STICH Trial
Two Hypotheses
I
II
Surgical
LV restoration
Revascularization
hypothesis
Hypothesis
5. 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.
6. 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.
7. 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 Med
Volume 364(17):1607-1616
April 28, 2011
10. Thus Primary End Point:
As randomized, CABG led to a 14% RRR in all-cause
mortality compared to MED
(not significant)
11. 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.
12. Cardiovascular Mortality
HR 0.81 (0.66, 1.00)
P = 0.050
Adjusted HR 0.77 (0.62, 0.94)
Adjusted P = 0.012
13. • 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.
14. Death or Cardiovascular
Death or Cardiovascular hospitalization
Hospitalization-nt done
HR 0.74 (0.64, 0.85)
P < 0.001
Adjusted HR 0.70 (0.61, 0.81) P <
0.001
16. STICH Revascularization Hypothesis
Effect of Actual Treatment Received
1212
Randomized 602 610 Randomized
MED only CABG
537 65 555 55
Received Received Received
MED CABG MED
Per protocol: MED (537) vs. CABG (555)
As treated: MED (592) vs. CABG (620)
19. 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
20. 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.
21. Myocardial Viability and Survival
in Ischemic Left Ventricular Dysfunction
Robert O. Bonow, MD
On behalf of the STICH Trial Investigators
22. 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
23. STICH Viability
Viability testing was optional at enrolling sites and was not a
prerequisite for enrollment.
Dobutamine echo
SPECT protocols:
protocols:
• Thallium-201 stress- • Staged increase in
redistribution- dobutamine starting
reinjection at 5 μg/kg/min
• Thallium-201 rest-
redistribution
• Nitrate-enhanced Tc-
99m perfusion
imaging
24. Patients randomized
Patients with no
Patients with no usable myocardial
myocardial viability test viability test
594 611
Unusable test
1212 17 • Timing
• Poor quality
618 601
Patients with Patients with usable
myocardial myocardial
viability test viability test
25. Patients randomized in STICH
Revascularization Hypothesis
1212
SPECT Dobutamine echo
n=471 n=280
321 150 130
Patients with no
611 usable myocardial
viability test
Patients with
usable myocardial 601
viability test 114
Nonviable
487
Viable
26. 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.
…fail to demonstrate a significant interaction
between myocardial viability and medical
versus surgical treatment with respect to
mortality, whether assessed according to
treatment assigned (intention to treat) or to
the treatment actually received.
27. 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
28. 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.
29. 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.
31. Myocardial Viability and Mortality
Univariate Multivariable
Variable No.
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
32. Myocardial Viability and Cardiovascular Mortality
Univariate Multivariable
Chi-square p value Chi-square p value
HR 95% Cl P
0.61 0.44 0.84 0.003
8.81 0.003 0.91 0.339
33. Myocardial Viability and Mortality + CV Hospitaliztion
Univariate Multivariable
Chi-square p value Chi-square p value
20.27 <0.001 8.60 0.003
34. Patients with viability tests
601
Patients with Patients
myocardial without
viability 487 114 myocardial
viability
243 244 60 54
MED CABG MED CABG
49.9% 50.1% 52.6% 47.4%
35. Myocardial Viability and Mortality
56%
35%
42%
31%
Subgroup N Deaths HR 95% CI Interaction
P value
Without viability 114 58 0.70 0.41, 1.18 0.528
With viability 487 178 0.86 0.64, 1.16
0.25 0.5 1 2
CABG MED
better better
36. 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
37. Surgical Treatment for Ischemic
Heart Failure –STICH Trial
In patients with HF, LVD < 35% and
CAD amenable to CABG, CABG +MED
will decrease all-cause mortality
I compared to MED alone+ (Viability
Substudy)
Hypotheses
In pts with dominant anterior wall LV
II akinesia or dyskinesia, SVR + CABG +
MED > hosp free survival compared with
CABG + MED without SVR.
38. For management of patients with
HF 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?
39. Surgical Treatment for Ischemic Heart Failure
trial stratum and treatment assignment.
CAD
EF <=
0.35
SVR YES NO NO
Medical SVR
eligible? Not in trial
eligibility eligible?
NO
YES
YES
Stratum A
Stratum B
Stratum C
CABG + SVR
MED CABG
CABG + SVR CABG
MED CABG
40. 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.
41. Major STICH hypotheses
Primary Major secondary
Hypotheses hypotheses
H1 Coronary revascularization
hypothesis Presence and extent of
dysfunctional but viable
● Improvement in myocardial myocardium, as defined by
perfusion by CABG combined radionuclide imaging,
with MED improves long-term dobutamine stress
survival compared with MED echocardiography, or both,
alone. will identify patients with
greatest survival advantage
H2: LV restoration hypothesis of MED and CABG compared
● In patients with dominant anterior with MED alone.
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.
42. 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
43. 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
44. "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)
45. 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
46. Endpoints
Primary Endpoint
– All-cause mortality
Major Secondary Endpoints
– Cardiovascular mortality
– Death (all-cause) + cardiovascular hospitalization
47. 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)
48. 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
49. Surgical Treatment for Ischemic Heart Failure
trial stratum and treatment assignment.
CAD
EF <= + CABG amenable
0.35
SVR YES NO SVR NO
Medical
eligible? eligible? Not in trial
eligibility
NO
YES
YES
Stratum A
Stratum B
Stratum C
CABG + SVR
MED CABG
CABG + SVR CABG
MED CABG
50. 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.
51. 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
54. 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
Difference statistically significant after allowing for baseline differences Model 3 Covariate adjusted – all variables prospectively specified in STICH protocol or with significant prognostic effect. Stratum, age, gender, race, HF class at baseline, MI history, previous revascularization, best available EF, number of diseased vessels, chronic renal insufficiency, MR, stroke hx, AF hxHR 0.83 (0.68, 0.99) p = 0.039.
