the causes are multifactorial and likely related to
the rapid adoption of LVADs for DT since 2010. In
their recent review, Mancini and Colombo listed the
possible causes: “Less frequent use of perioperative
heparin use, lower target INR ranges due to the high
incidence of bleeding, inadequate antiplatelet therapy,
overestimate of effective anticoagulation by the partial
prothrombin time, abnormal angulation of inflow or
outflow cannulas, infection, use of erythropoeietic factors, and/or other factors not yet identified.”
“The noise level seems to be somewhat down in
the thrombus issue,” said Thoratec CEO Keith Grossman in a quarterly (Q3) 2014 earnings call, but it
adds to the overall adverse event issue. “The discussion that I’m hearing is no longer really about one
specific type of adverse event, with one pump, but
adverse events generally speaking and where we are
now and where we should be as an industry.”
Another adverse event relates to the deleterious
cognitive effects of LVADs. Timothy Fendler, MD,
Saint Luke’s Mid America Heart Institute, Kansas City,
MO, and colleagues just reported using the Interagency Registry for Mechanically Assisted Circulatory Support to evaluate cognitive function in nearly
1,200 patients who underwent LVAD implantation.9
The cumulative incidence of cognitive decline in the
year after LVAD implantation was 29.2%. In adjusted
analysis, older age (≥70 versus <50 years; hazard
ratio, 2.24) and destination therapy (hazard ratio,
1.42) were significantly associated with greater risk
of cognitive decline. The possible mechanism: major,
minor, and mini strokes that occur due to blood clots
caused by the device.
Interestingly, cognition often improved for those
patients without cognitive decline, supporting the notion that LVADs improve cerebral perfusion, unless a
patient experiences an ischemic event, which is a big
if given that these events occur commonly. Brahmajee
Nallamothu, MD, MPH, chair of Quality of Care and
Outcomes Research for the American Heart Association, said, “We need to understand these complications if we’re going to start broadening their use.”
However, he noted that Dr. Fendler’s research only
showed an association—not a proven link—between
LVADs and mental decline in some patients.
“These are really sick patients, and they have a lot of
reasons to suffer cognitive decline,” said Dr. Nallamothu. “These are people who otherwise without the
device in all likelihood would die within a short time
period. That’s a real key point.”
A second new study, this one much smaller,
looked at 176 LVAD patients who were tested using
the MoCA (Montreal Cognitive Assessment), a simple
screening tool sensitive to mild cognitive impairment.
Pre -LVAD implantation, cognitive impairment was
seen in 67% of the study cohort. In the 56 patients
re-evaluated at 8 months post-implantation, total
MoCA score as well as the visuospacial, executive, and
delayed recall cognitive domains were significantly
improved as a group.10
Stem Cell Therapies in HF
They really don’t seem to work
If you are anticipating that cell therapy will get patients out of this mess, you have a long wait ahead.
At ACC.15, Robb MacLellan, MD, the Robert
A. Bruce Chair in Cardiovascular Research at the
University of Washington Medical Center, Seattle,
WA, said that while cell therapies have been shown
to be beneficial after myocardial infarction (MI) in
multiple animal species at multiple times post-MI,
there are “very limited data that cell therapies work
in established HF models, work on a background of
appropriate medical therapy, or are durable.”
Indeed, after more than 10 years of research
evaluating bone marrow stem cells, he noted:
• Engraftment is very poor (typically <1%).
• Durability of transplanted cells is questionable.
• Improvements in left ventricular function are at
most modest.
• It is very unlikely that bone marrow-derived
cells directly result in myocyte regeneration.
But hope springs eternal, and in a late-breaking tri-
26 CardioSource WorldNews
als session at the recent Heart Failure 2015 (a meeting of the European Society of Cardiology), a novel
gene therapy treatment called JVS-100 was found
to improve left ventricular ejection fraction (LVEF) in
some patients with ischemic cardiomyopathy and
low ejection fraction.
The results of the phase II STOP-HF trial were
presented by Marc Penn, MD, PhD, founder and
chief medical officer of Juventas and director of
cardiovascular research and cardiovascular medicine fellowship at Summa Health in Akron, OH, and
e-published in the European Heart Journal.1
The JVS-100 gene therapy is a non-viral plasmid
that encodes for stromal cell-derived factor-1 (SDF1). JVS-100 allows cardiac cells to begin expressing
SDF-1 protein, which acts as a beacon to attract the
patient’s own stem cells to the heart.
The STOP-HF randomized, double blind, placebo controlled trial was performed in 93 symptomatic
patients with LVEF ≤40%. Patients received either
placebo or 15 endomyocardial injections of JVS-100
15 or 30 mg (during a single treatment).
The trial missed its primary endpoint of change
in composite score (6-minute walk distance and
quality of life) at 4 months, but prespecified analy-
Another notable adverse event after implantation
of a continuous-flow LVAD is gastrointestinal bleeding (GIB). In an abstract presented at Heart Failure
2015, researchers at the University of Texas Health
Science Center, Houston, TX, showed that GIBs occur
in about 24% of patients receiving CF-LVADs, with
no difference in incidence in regard to device type,
INTERMACS score, or blood types.11 On regression
analysis, the only significant risk factor for GIB was
the presence of chronic kidney disease, giving clinicians little information for preventing this adverse
event or its recurrence.
Continual Technological Evolution
There are currently two U.S. Food and Drug Administration (FDA)-approved MCS devices for adults: The
HeartMate II (Thoratec Corporation, Pleasanton, California) CF pump (IMAGE 1) was approved for bridge-totransplant therapy (BTT) in 2008 and for DT in 2010.
The HeartWare HVAD (HeartWare International, Inc.,
Framingham, MA; the H stands for HeartWare) was
approved for BTT in November 2012. (One pediatric
device has also been approved: the MicroMed DeBakey Child ventricular assist device.)
Three more second-generation devices—the
Jarvik 2000 (Jarvik Heart), Incor (Berlin Heart), and
HeartAssist 5 (ReliantHeart)—are commercially available in Europe but investigational in the U.S.
In April 2015, Thoratec Corporation announced
approval from the FDA to broaden enrollment of its
ses demonstrated a greater effect of JVS-100 on
patients with higher-risk HF defined by lower ejection fraction. Patients with the worst heart failure
who were given the higher dose of the study drug
showed a 7% increase in LVEF as compared to a 4%
decrease in the placebo group (p < 0.05).
“The confluence of change in this group, in
LVEF, NTproBNP, LV end-systolic volume, and the
composite score and stroke volume are consistent
with a meaningful change in high-risk patients,”
concluded Dr. Penn. He added that the degree of
heart remodeling induced by SDF-1 overexpression
should give a greater than 80% chance of mortality
benefit in future trials. We’ll see.
In mid-May 2015, the U.S. FDA granted JVS-100
Fast Track status and approved a phase IIb, doubleblind, sham-controlled trial of the agent. STOP-HF2
will evaluate the safety and efficacy of two administrations of 30 mg doses of JVS-100 in HF patients
with LVEF ≤ 35% and N-terminal pro–B-type natriuretic peptide ≥500 pg/ml. The first dose will be
delivered at enrollment and the second 6 months
later, each delivered by endomyocardial injection
catheter to the left ventricle of the heart.
REFERENCE:
1. Chung ES, Miller L, Patel AN, et al. Eur Heart J. 2015; June
7 [Epub ahead of print].
July 2015