European Heart Journal (2023) 00, 1–3 VIEWPOINT

https://doi.org/10.1093/eurheartj/ehad488 Heart failure and cardiomyopathies

REVIV(E)ing the ischaemic paradigm in heart

failure: STICHes are needed

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1,2,3
Luis E. Rohde * and John J.V. McMurray1,2,3
1
Medical School, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil; 2Cardiovascular Division, Hospital de Clínicas de Porto Alegre and Hospital Moinhos de Vento, Porto
Alegre, Brazil; and 3British Heart Foundation Cardiovascular Research Centre, School of Cardiovascular and Metabolic Health at the University of Glasgow, Glasgow, UK

Graphical Abstract

REVIV(E)ing the ischaemic paradigm in heart failure: STICHes are needed

STICH(ES) & REVIVED-BCIS2 REVIVED-BCIS2 Trial STICH(ES) Trial

Trials asked a similar question Sample size 700 1212
Does revascularization of patients with CAD and left Year of enrolment 2013–2020 2002–2007
ventricular dysfunction improve clinical outcomes?
Mode of revascularization Percutaneous Surgical

NYHA class III-IV 26% 37%

Main findings were conflicting
Angina pectoris 33% 64%
CABG reduced all-cause mortality in STICHES
after extended follow-up Previous MI 53% 77%
PCI did not reduce all-cause mortality or HF
LVEF 27% 27% (CABG); 28% (medical)
hospitalization in REVIVED-BCIS2
Left main disease 13.6% 2.6%

Several possible explanations Three-vessel CAD 40% 60%

Patient profile, mode of revascularization, sample Medical therapy
size and follow-up were different in each trial
Beta blockers 91% 85%
CAD might be a “bystander” rather than cause
of systolic dysfunction in some patients ACEi or ARBs 84% 90%

Mineralocorticoid antagonist 49% 46%

What advice to patients?
What is to come? ICD 21% 2.4%*

Both PCI and CABG continue to be important Primary outcome All-cause death or HF hospitalization All-cause death
treatments for symptomatic myocardial ischaemia
Mortality rate in GDMT group 33% over 41 months 41% over 56 months †
CABG has a specific indication in selected
patients to improve outcomes in HF Deaths in GDMT group 115 244 †
STICH-3 will compare PCI & CABG Follow-up, median 3.4 years 4.7 years † & 9.3 years ‡

Critical comparison between REVIVED-BCIS2 and STICH(ES) trials. NYHA, New York Heart Association; MI, myocardial infarction; LVEF, left ventricu-
lar ejection fraction; CAD, coronary artery disease; ACEi, angiotensin converting enzyme inhibitor; ARBs, angiotensin receptor blockers; ICD, implan-
table cardio-defibrillator; HF, heart failure; GDMT, guideline directed medical therapy. *Only baseline ICD was reported. †Based on the 2011
publication. ‡Based on the extended follow-up 2016 publication.

* Corresponding author. Tel: + 55 51 33598342, Email: rohde.le@gmail.com

© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
2 Viewpoint
Over recent decades, heart failure with reduced ejection fraction
(HFrEF) has been transformed from a highly lethal disorder with a short
life expectancy to a more chronic condition with much-improved qual-
ity and quantity of life.1 Most of these successful therapies modulate
homeostatic systems that are deleteriously activated after an index insult
to the heart. Despite unquestionable benefits, our therapeutic actions
are primarily restricted to ameliorating the secondary consequences of
reduced cardiac contractility. However, therapeutic strategies aimed at
preventing recurrent direct myocardial injury, e.g. due to further coron-
ary artery occlusion, should also be a priority. Moreover, in patients with
severe obstructive coronary artery disease (CAD), chronic myocardial
hypoperfusion may cause or exacerbate left ventricular (LV) systolic dys-
function (hibernating myocardium), and this might be reversible with res-
toration of coronary blood flow.2 The logical extension of this
conceptual framework, if correct, is that diagnosis and treatment of
CAD should be central to the management of patients with HFrEF.
Surprisingly, however, few randomized clinical trials have evaluated the
efficacy and safety of coronary revascularization in patients with HFrEF.
The Surgical Treatment for Ischaemic Heart Failure (STICH) trial was
designed to evaluate the role of cardiac surgery in the treatment of pa-
tients with CAD and LV systolic dysfunction. One of the central hy-
potheses of STICH was that coronary artery bypass surgery (CABG)
and medical therapy would reduce overall mortality compared to med-
ical therapy alone. In 2011, the initial results of STICH showed that the
primary outcome—the rate of death from any cause—occurred in 244
of 602 patients (41%) in the medical-therapy group and 218 of 610 pa-
tients (36%) in the CABG group, representing a 14% non-significant
relative risk reduction over a median follow-up of 56 months.3 Based
in part on the results of STICH, international heart failure (HF) guide-
lines in 2013 made only a weak recommendation supporting CABG
in HF patients with severe systolic dysfunction.4 Five years later, the
publication of the extended follow-up study (STICHES) rekindled inter-
est in coronary revascularization as a treatment for HFrEF patients.
Over a median follow-up of 9.8 years, CABG reduced rates of death
from any cause, death from cardiovascular causes, and the rates of
the combined endpoint of death from any cause or hospitalization
for cardiovascular causes significantly.5 Although much more time
had been necessary to unequivocally demonstrate the difference be-
tween treatment groups, the magnitude of benefit was not trivial—
only 14 patients needed surgery to avoid one death.
Recently, a second trial clouded the picture once again. The
Revascularization for Ischaemic Ventricular Dysfunction (REVIVED) trial
tested a similar hypothesis to the STICH trial. The REVIVED investigators
hypothesized that revascularization with percutaneous coronary interven-
tion (PCI) in addition to optimal medical therapy, as compared with opti-
mal medical therapy alone, would improve event-free survival (and ejection
fraction) in patients with severe ischaemic LV systolic dysfunction and
myocardial viability confirmed by cardiac imaging. Unfortunately, neither
of these benefits was demonstrated. Over a median of 41 months, the
rate of the primary outcome—death from any cause or hospitalization
for HF—was similar between groups, occurring in 129 of 347 patients
(37%) in the PCI group and 134 of 353 patients (38%) in the
optimal-medical-therapy group. Left ventricular ejection fraction increased
in both groups but did not differ meaningfully by treatment assignment.6
Central to one of the hypothesized benefits of coronary revascular-
ization is the existence of significant amounts of viable but dysfunctional
myocardium in patients with HFrEF and CAD, that this can be accurate-
ly identified and quantified, and that it is reversible after improvement in
coronary perfusion.7 The association between myocardial viability and
LV recovery, and between viability and prognosis, has also been
evaluated in sub-studies of REVIVED and STICHES.8,9 At face value,
findings from both trials do not support the concept that using pre-
sumed myocardial viability to guide myocardial revascularization leads
to better outcomes in ischaemic cardiomyopathy. In STICHES, the
presence of viable myocardium was associated with improvement in
LV systolic function, but such improvement was not related to long-
term survival. The opposite was observed in REVIVED where dysfunc-
tional viable myocardial did not predict LV recovery. However, the
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presence of greater scar burden seemed to identify patients with re-
duced likelihood of improvement LV function (and improvement in
LVEF was a predictor of better outcome). It is important to note
that both these subs-studies were small, and their results are unreliable.
Unfortunately, most other clinical studies that tried to address the role
of viability-guided revascularization have used nonrandomized designs,
heterogenous protocols, and different imaging techniques. The incon-
sistent results in these reports highlight the uncertainty around the def-
inition and quantification of myocardial viability and whether attempting
to assess myocardial viability is worthwhile in clinical practice.
Clinicians now face the difficult task of reconciling these two apparently
conflicting trial outcomes and confusing findings related to myocardial via-
bility and deciding what to advise their patients. In comparing these trials,
we need to consider the patients enrolled, their background treatment,
the randomized intervention used, and the size and power of the
trial (Graphical Abstract). Although the eligibility criteria for both trials
were similar—extensive CAD associated with severe systolic dysfunc-
tion—the participants enrolled had different clinical profiles. Most
STICH patients had symptomatic CAD, previous myocardial infarction,
and three-vessel disease, while the participants in REVIVED had asymp-
tomatic or mildly symptomatic CAD and two-vessel disease. Although pa-
tients were selected to be at high risk of acute coronary occlusion (as well
as having potentially hypoperfused but viable myocardium), it is worth re-
membering that the contribution of coronary events to adverse outcomes
even in patients with HFrEF is small. Effective pharmacological therapies
preventing plaque rupture (rosuvastatin)10 and thrombosis (rivaroxa-
ban)11 had little if any impact on HF outcomes, particularly death, sudden
death, and HF hospitalization (which constitute most adverse events in pa-
tients with HFrEF).
Any difference in outcome between the two trials probably cannot
be explained by concomitant medical therapy which was similar in each
study. Although use of device therapy was lower than expected in both
studies, it was much better in REVIVED than STICH which may have
reduced the background mortality rate in the former trial. Regarding
the randomized intervention, incomplete revascularization has historic-
ally been the Achilles heel of percutaneous intervention, although the
completeness of revascularization was reported to be high in the PCI
group in REVIVED. Similarly, the durability of revascularization with ar-
terial grafting is superior compared to percutaneous intervention.
Bypass surgery also seems to offer greater protection against myocar-
dial infarction than PCI, and prevention of further ischaemic injury
might have resulted in greater protection in STICH than REVIVED.
The clinical profile of the participants and the potential advantages of
surgery plus the larger sample size and longer follow-up may have led
to the difference in outcome between the two trials. Due to the low
rate of coronary events in patients with HFrEF alluded to above, it
would be necessary to follow a large number of patients for a longer
time before the benefit of an effective treatment could be identified.
Another subtle but fundamentally important question is how much
the patient’s CAD in each trial was contributing to their ventricular
dysfunction, HF symptoms, or both? From a practical perspective,
we should consider that the historical delineation of ischaemic vs.
Viewpoint
non-ischaemic cardiomyopathy may not be as simple as previously
thought. Was CAD patho-physiologically linked to myocardial hypoperfu-
sion and systolic dysfunction or essentially a ‘bystander’ with respect to
ventricular function (e.g. stenosed vessels supply predominantly scar tissue
or stenosed vessels that do not truly cause myocardial ischaemia)? Did the
patients in STICH, with more severe and symptomatic CAD, have more
‘recoverable’ myocardium? It is not possible to answer all these questions
from the data available, but it could be crucial to explaining the different
outcomes between the two trials.
Finally, neither STICH nor REVIVED had sufficient statistical power to
detect more than a large effect of treatment on mortality. This was espe-
cially true of REVIVED, which was much smaller than STICH with many
fewer deaths (115 vs. 244) in the respective medical therapy groups. The
apparent mortality reduction in the extended follow-up of STICHES,
with a corresponding increase in the number of deaths over time, lends sup-
port to the view that the original trial was underpowered. Notably, viability
sub-studies were even more underpowered for treatment effect on clinical
events. From this perspective, we cannot conclude that the findings of
STICH and REVIVED are truly different, and longer follow-up of
REVIVED with accrual of more deaths is necessary to get a better assess-
ment of whether the two interventions resulted in different outcomes.
So, what is the current role of coronary revascularization in patients
with HFrEF? First, both percutaneous and surgical coronary revasculariza-
tion continue to be important treatments for symptomatic myocardial is-
chaemia i.e. angina pectoris. However, the role of percutaneous coronary
revascularization as a treatment for HF per se, to reduce the risk of death
and HF hospitalization, is unproven. Even in current guidelines, surgical
coronary revascularization has a limited and specific indication to improve
mortality in HF only in carefully selected individuals (e.g. young non-frail
patients with few comorbid conditions).12 A recent meta-analysis of ran-
domized clinical trials of revascularization strategies in HF supports this
recommendation but suggest lack of statistical robustness.13 So, overall,
the ischaemic paradigm remains alive in HF, and REVIVED has not changed
the cautious recommendations based upon STICHES. At present, the role
of pre-treatment evaluation of myocardial viability and hibernation in guid-
ing treatment and predicting benefit from myocardial revascularization
can be neither convincingly affirmed nor refuted, and this should remain
a key area of research.14 Unquestionably, we need further trials to give
more definitive answers about how to identify patients who might benefit
from coronary revascularization and how coronary revascularization is
best performed. An international consortium (STICH-3) has recently in-
itiated a randomized clinical trial (NCT05761067) to determine whether
CABG is superior to PCI in terms of all-cause mortality in patients with
severe CAD and LV systolic dysfunction.15 Unfortunately, however,
STICH-3 does not have a medically treated group, and there is no pre-
defined viability protocol or viability eligibility criteria. It seems remarkable
that in 2023, we do not have a robust and clear answer to such important
questions about the intersection between the two most important pro-
blems we encounter in modern cardiology.
Supplementary data
Supplementary data are not available at European Heart Journal online.
Declaration
Disclosure of Interest
L.E.R. has received consulting or personal lecture fees from Aché,
AstraZeneca, Bayer, Boehringer Ingelheim, Merck Serono, and
3
Novartis. J.M. reports payments through Glasgow University from
work on clinical trials, consulting and other activities from: Amgen,
AstraZeneca, Bayer, Cardurion, Cytokinetics, GSK, KBP Biosciences,
and Novartis. Personal consultancy fees from: Alnylam Pharma.,
Bayer, BMS, George Clinical PTY Ltd., Ionis Pharma., Novartis,
Regeneron Pharma., and River 2 Renal Corporation. J.M. reports per-
sonal lecture fees from Abbott, Alkem Metabolics, Astra Zeneca,
Blue Ocean Scientific Solutions Ltd., Boehringer Ingelheim, Canadian
Downloaded from https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehad488/7234447 by guest on 06 August 2023
Medical and Surgical Knowledge, Emcure Pharma. Ltd., Eris
Lifesciences, European Academy of CME, Hikma Pharmaceuticals,
Imagica health, Intas Pharma, J.B. Chemicals & Pharma. Ltd., Lupin
Pharma, Medscape/Heart.Org, ProAdWise Communications,
Radcliffe Cardiology, Sun Pharma., The Corpus, Translation Research
Group, and Translational Medicine Academy. J.M. is a director of
Global Clinical Trial Partners Ltd.
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