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The novel finding that low-
molecular-weight heparin acutely
modified the endothelial function
of pregnant women at high risk of
preeclampsia supports the rationale
tomount an adequately powered
trial to determine the effectiveness
of low-molecular-weight heparin
for prevention of early-onset
preeclampsia inwomen at highest risk.
Reconstituted
apolipoprotein A-I CSL112
enhances cholesterol
efflux after acute MI
The reconstituted, infusible, plasma-derived
apolipoprotein A-I has been shown to enhance
cholesterol efflux after acute myocardial
infarction, with no significant alterations in liver
or kidney function or other safety concerns
reports the Apo-I Event Reducing in Ischaemic
Syndromes I (AEGIS-I) trial.
M
ichael Gibson, MS, MD,
of Beth Israel Deaconess
Medical Center, Boston,
assachusetts, explained that
human or recombinant apolipo-
protein A-I has been shown to
increase high-density lipoprotein
– mediated cholesterol efflux
capacity and to regress atheroscle-
rotic disease in animal and clinical
studies. CSL112 is an infusible,
plasma-derived apolipoproteinA-I
that has been studied in normal
subjects or those with stable coro-
nary artery disease.
AEGIS-I was a multicentre,
randomised, double-blind,
placebo-controlled, dose-ranging
phase 2b trial. Patients with
myocardial infarction were
stratified by renal function and
randomised 1:1:1 to CSL112 (2
g apolipoprotein A-I per dose)
and high-dose CSL112 (6 g
apolipoprotein A-I per dose),
or placebo for four consecutive
weekly infusions.
Coprimary safety endpoints were
the occurrence of either a hepatic
safety event (an increase in alanine
transaminasemore than three times
the upper limit of normal or an
increase in total bilirubinmore than
twice the upper limit of normal) or
a renal safety event (an increase in
serum creatinine >1.5 times the
baseline value or a new requirement
of renal replacement therapy).
A total of 1258 patients were
randomised, and 91.2% received
all four infusions. The difference
in incidence rates for an increase
in alanine transaminase or total
bilirubin between both CSL112
arms and placebo was within the
protocol-defined noninferiority
margin of 4%.
Similarly, the difference in
incidence rates of an increase
in serum creatinine or a new
requirement for renal replacement
therapy was within the protocol-
defined noninferiority margin
of 5%. CSL112 was associated
with increases in apolipoprotein
A-I and ex vivo cholesterol efflux
similar to that achieved in patients
with stable coronary artery
disease.
With regard to the secondary
efficacy endpoint, the risk for
the composite of major adverse
cardiovascular events among the
groups was similar.
Dr Gibson concluded that among
patients with acute myocardial
infarction, four weekly infusions
of CSL112 were shown to be
feasible, well tolerated, and not
associated with any significant
alterations in liver or kidney
function or other safety concern.
The ability of CSL112 to acutely
enhance cholesterol efflux
was confirmed. The potential
benefit of CSL112 to reduce
major adverse cardiovascular
events needs to be assessed in an
adequately powered phase 3 trial.
assessments. High-risk women were then randomised to low-
molecular-weight heparin or saline placebo (30 mg IV bolus
and 1 mg/kg subcutaneous dose, respectively). Cardiovascular
function was assessed 1 and 3 h post randomisation. In
vitro endothelial effects of patient serum and exogenous
low-molecular-weight heparin on human umbilical venous
endothelial cells were determined.
High-risk women demonstrated reduced cardiac output and
a high-resistance haemodynamic profile with impaired radial
artery flow-mediated dilation versus controls. Low-molecular-
weight heparin increased flow-mediated dilation in high-risk
women 3-h following randomisation versus baseline and
increased plasma levels of placental growth factor, soluble
fms-like tyrosine kinase-1, and myeloperoxidase.
Serum from high-risk women impaired endothelial cell
angiogenesis and increased placental growth factor-1 and -2
transcription versus serum from low-risk controls. Coexposure
of high-risk serum with low-molecular-weight heparin improved
the in vitro angiogenic response such that it was equivalent to
that of low-risk serum and promoted placental growth factor
secretion.
Dr Kingdom concluded that in vivo and in vitro findings
demonstrated that pregnant women at high-risk of preeclampsia
demonstrate significant cardiovascular abnormalities versus
low-risk women at 24 weeks of gestation. The study provided
the first human documentation that low-molecular-weight
heparin acutely modifies the endothelial function and
circulating angiogenic proteins of pregnant women at high-
risk of preeclampsia.
In parallel, in vitro endothelial function was also influenced
by low-molecular-weight heparin, with significant angiogenic
responses and effects on placental growth factor secretion.
Placental growth factor may help mediate endothelial function
in pregnant women.
The novel finding that low-molecular-weight heparin acutely
modified the endothelial function of pregnant women at
high risk of preeclampsia supports the rationale to mount
an adequately powered trial to determine the effectiveness
of low-molecular-weight heparin for prevention of early-
onset preeclampsia in women at highest risk. Early-onset
preeclampsia can be predicted with reasonable accuracy by
the second trimester with multiparameter screening, providing
an opportunity to initiate preventative therapies prior to the
onset of clinical symptoms.
DECEMBER 2016
AHA 2016
27