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Two trials of stem cells fail to meet primary
endpoints but improve health status
Two trials of regenerative therapy for heart failure failed to meet their primary endpoints but brought
clinically relevant benefits.
Trial 1: A phase 2, randomised,
single-blind, placebo-controlled,
crossover, multicentre study
Javed Butler MD, of The State Univer-
sity of New York at Stony Brook, reported
on the first trial. He and a colleague de-
livered a single dose of mesenchymal
stem cells intravenously to patients with
chronic nonischaemic cardiomyopathy.
Significant cardiac structural or functional
improvement did not occur but several
clinically relevant benefits were observed.
Dr Butler said the trial “demonstrated
that a more convenient and less invasive
infusion strategy is safe, well-tolerated
and shows improvements in multiple
measurements of patient health status.”
Previous work in this field has focused
almost exclusively on the more invasive
approach of injecting stem cells directly
into the heart.
Dr Butler and his colleague used “is-
chaemia tolerant” mesenchymal stem
grown under chronic hypoxic conditions,
with the aim of enhancing their potential
benefits.
He explained, “The premise was that
stem cells may exert immune modulatory
properties, which are enhanced when
grown under hypoxic conditions.” This
potential immune modulation and anti-
inflammatory effect also opens the door
to new methods of delivery.
“Virtually all studies of stem cell therapy
for heart failure have centred on the con-
cept that the cells must be injected di-
rectly into the heart to trigger new growth,
but if stem cells yield anti-inflammatory
benefits, direct cardiac delivery may not
be necessary to repair and stimulate the
dysfunctional viable myocardium.”
Patients with nonischaemic cardiomyo-
pathy and left ventricular ejection fraction
≤
40% were randomised to intravenous
ischaemia-tolerant mesenchymal stem
cell therapy (n=10) or placebo (n=12)
for 90 days and then crossed over to the
other treatment. Stem cells were donated
by a health volunteer and grown
under hypoxic conditions from
the moment of extraction.
At 90-days post infusion, no
major differences in primary
safety endpoints of all-cause
mortality, all-cause hospitalisa-
tion, and adverse events were
observed.
Secondary endpoints of car-
diac remodelling (left ventricular
ejection fraction and ventricular
volumes), assessed by cardiac
magnetic resonance imaging,
did not differ between groups
at 90-days. Ischaemia-tolerant
mesenchymal stem cell adminis-
tration did result in the second-
ary endpoints of better health
status and functional capacity,
however.
Specifically, compared with
placebo, ischaemia-tolerant
mesenchymal stem cell therapy
resulted in statistically signifi-
cant improvements in 6-min-
ute walk test (an estimated
36 m more than placebo, P =
0.02) and Kansas City Cardio-
myopathy Questionnaire scores
(clinical summary score +5.22, P = 0.02,
and functional status scores +5.65, P =
0.06) at 90-days post infusion.
Additionally, ischaemia-tolerant mes-
enchymal stem cell infusion resulted in
significant alterations in several inflamma-
tory cells, “supporting the immunomodu-
latory and anti-inflammatory mechanisms
of ischaemia-tolerant mesenchymal stem
cells,” noted Dr Butler.
Dr Butler concluded, “To our knowl-
edge, this trial represents the first expe-
rience with intravenously administered
ischaemia-tolerant mesenchymal stem
cells in patients with any type of chronic
cardiomyopathy. Further studies should
explore the efficacy of serial dosing to
produce more sustained immunomodula-
tory effects and thereby perhaps facilitate
improvement in left ventricular structure
and function, and in clinical outcomes.”
Trial 2: CHART-1, the largest
cardiac regenerative therapy trial
to date
Jozef Bartunek, MD, PhD, of OLV Hos-
pital, Aalst, Belgium, presented results of
the Congestive Heart failure cardiopoi-
etic Regenerative Therapy (CHART-1).
This trial used bone-marrow stem cells
to promote heart repair. The cells did not
significantly improve the primary outcome
over a sham procedure among patients
with congestive heart failure, but results
revealed critical new insights.
Dr Bartunek explained that thought
results were neutral in the overall patient
population, an exploratory analysis iden-
tified a subgroup of patients who may
benefit from cardiopoietic cell therapy.
“Within a well-defined patient population,
based on baseline heart failure severity, this
therapy showed benefit,” he said. “Lessons
learned from CHART-1 will now provide
the foundation for the design of the ensu-
ing CHART-2 trial, which will target these
patients.”
Cardiopoietic cell therapy involves the
isolation of mesenchymal stem cells from
a patient’s own bone marrow. Exposing
these cells to a “cardiogenic cocktail” turns
them into cardiopoietic cells, which are
then injected into damaged heart tissue.
The CHART-1 study randomised pa-
tients with symptomatic ischaemic heart
failure from 39 hospital centres in Europe
and Israel. Patients received either a sham
procedure (n=151) or cardiopoietic cells
(n=120).
At 39 weeks, no significant difference
between groups was observed for the
primary efficacy endpoint, a composite of
all-cause mortality, worsening heart failure
events, Minnesota Living withHeart Failure
Questionnaire total score, 6-minute walk
distance, and left ventricular end-systolic
volume and ejection fraction.
A subgroup analysis of patients with se-
vere heart enlargement at baseline (left ven-
tricular end-diastolic volumes between 200
and 370 mL), however, suggested a positive
effect of the cell treatment over sham.
Dr Bartunek concluded, “Outcomes for
all components of the composite endpoint,
including mortality and worsening heart
failure, were ‘directionally consistent.’”
He, added that “the effect was also related
to clinically meaningful improved quality
of life, greater 6-minute walk distance,
and reduced left ventricular end-systolic
volume for cell treatment vs sham.”
“We observed a modifying effect of
treatment intensity, with suggestion of a
greater benefit with a lower number of
injections. Overall safety was demon-
strated across the study cohort, with no
difference in adverse clinical outcomes
observed between groups.”
Ongoing analyses will evaluate
12-month clinical outcomes. Dr Bartunek
said, “Insights from the CHART-1 trial
carry implications for targeting the patient
population that should be considered for
cardiopoietic cell therapy in future clini-
cal trials or for broader clinical consid-
erations. More generally, indexes of heart
failure severity and optimised therapeutic
intensity should be considered.”
N-acetylcysteine
reduces post-MI
infarct size by
a third
The addition of intravenous N-acetyl-
cysteine to intravenous glyceryl trinitrate
reduced infarct size by approximately one
third in patients undergoing percutaneous
coronary intervention after ST-segment el-
evation acute myocardial infarction. This
outcome of N-AcetylCysteine In Acute
Myocardial infarction (NACIAM), a placebo-
controlled, double-blind trial, was reported
at the 2016 ESC Congress.
S
ivabaskari Pasupathy, BS, of the University of Ad-
elaide, Australia, explained, “Timely and effective
myocardial reperfusion by percutaneous coronary
intervention is the treatment of choice for limiting my-
ocardial infarct size and improving clinical outcomes
in patients presenting with ST-segment elevation acute
myocardial infarction, additional pharmacological in-
terventions may help reduce infarct size further. Any
intervention that reduces myocardial infarct size by
approximately a third might reasonably be expected to
substantially improve long-term outcomes.”
NACIAM included 112 patients with ST-segment
elevation acute myocardial infarction (mean age 64
years) from three Australian hospitals. All underwent
emergency percutaneous coronary intervention and
received low dose intravenous glyceryl trinitrate.
They were randomised before the percutaneous
coronary intervention to receive either high-dose
(15 g/24 h) N-acetylcysteine or placebo, both deliv-
ered intravenously over 48 h, “the hypothesis being
that N-acetylcysteine might reduce infarct size, ei-
ther by potentiating the effects of glyceryl trinitrate
or via ‘scavenging’ of reactive oxygen species,” said
Ms Pasupathy.
Cardiac magnetic resonance imaging performed
within 1 week (early) and again 3 months post myo-
cardial infarction (late) showed that patients who
received N-acetylcysteine experienced reductions in
infarct size of 33% and 50%, respectively, compared to
placebo (P = 0.02 for both). A similar but not signifi-
cant trend toward reduction in creatine kinase release
was observed.
Additionally, myocardial salvage, measured at
1 week, approximately doubled in patients who re-
ceived N-acetylcysteine (60% vs
27%, P < 0.001). Evidence of ac-
celerated tissue reperfusion and
hypochlorous acid “scavenging”
was also observed. Over 2 years of
follow-up, the combination of car-
diac readmissions and deaths was
less frequent in N-acetylcysteine-
treated (three vs 16 patients, P <
0.01).
Safety endpoints including hy-
potension, bleeding, and contrast-
induced nephropathy were similar
in both groups.
Ms Pasupathy concluded, “In-
travenous N-acetylcysteine ad-
ministration was associated with
more rapid chest pain resolution,
improved myocardial salvage, a fa-
vourable in-hospital safety profile,
sustained infarct size reduction at
3 months post ST-segment eleva-
tion acute myocardial infarction,
and promising clinical outcomes
at 2 years. While the results were
encouraging, NACIAM should
be regarded as the precursor to a
follow-up study sufficiently sized
to meet clinical endpoints.”
© ESC Congress 2016 – International Center for Documentary Arts (ICDA)
CONFERENCE COVERAGE
ESC 2016
PRACTICEUPDATE CARDIOLOGY
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