PracticeUpdate: Cardiology

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EXPERT OPINION
Dr Peter Libby on the
GLAGOV study
Written by Peter Libby MD
The introduction of antibodies that inhibit proprotein
convertase subtilisin kexin type 9 (PCSK9) inhibitors promises
to revolutionise the treatment of hypercholesterolaemia
due to elevations in low-density lipoprotein (LDL). Numerous
studies have shown the ability of these new agents to lower LDL
profoundly even in patients well treated with statins. Preliminary
compilations of data from smaller studies provide encouraging
evidence regarding clinical benefit. Two large-scale outcome trials
in progress will inform us within the next few years regarding the
ability of these monoclonal antibody therapies that target PCSK9
to lower cardiovascular events in patients at risk.
The Global Assessment of Plaque Regression With a PCSK9
Antibody as Measured by Intravascular Ultrasound (GLAGOV)
study furnishes insight into how treatment with anti-PCSK9
agents might alter atherosclerotic plaques and the mechanisms
by which they might provide clinical benefit. In this clinical trial,
968 patients with coronary disease, almost all treated with statins,
received the anti-PCSK9 monoclonal antibody evolocumab or
placebo for 76 weeks and underwent serial intravascular ul-
trasound (IVUS) study to quantify coronary atheroma volume.
The evolocumab-treated group had reduced LDL concentra-
tions compared to those receiving placebo (36.6 vs 93.0mg/dL).
Those receiving placebo slightly increased the mean percent
atheroma volume over the approximately 18-month observation
period (+0.05%) while the evolocumab-treated group showed a
reduction in this measure of plaque volume (−0.95%, P < 0.02
vs placebo).
GLAGOV shows that beyond statin treatment, the additional
LDL lowering altered plaque volume about 1%, on the same order
of reduction of statin treatment versus placebo in prior ultrasound
studies. Statin treatment confers a disproportionate reduction
in clinical events (~20–45%) compared to the small percent-
age improvement in mean plaque volume (~1%). This finding
indicates that changes in qualitative features of plaques invisible
to ultrasound, not just quantity of plaque, may influence the
ability of LDL-lowering agents to prevent cardiovascular events.
Experimental studies have shown that lipid lowering can re-
duce plaque inflammation and reinforce the plaque’s extracellular
matrix, thus altering functional characteristics of plaques related
to their liability to cause clinical complications. Indeed, some
of the clinical benefit of statins likely derives from direct anti-
inflammatory actions independent of LDL lowering. In contrast
to statins, this and other studies show that anti-PCSK9 agents
do not lower the marker of inflammation, C-reactive protein
(CRP). We must await analysis of the ongoing large-scale clinical
endpoints studies to ascertain whether the decrement in LDL
conferred by adding anti-PCSK9 agents to statins will yield
a further reduction in clinical events out of proportion to the
relatively modest decrease in plaque volume, as in the case of
statin treatment.
In GLAGOV, about half of the statin-treated patients showed
atheroma regression by the ultrasound metrics evaluated. With
the addition of the biologic agent, about two-thirds of patients
showed regression over the 18-month study duration. While
longer treatment with the stringent lipid-combination would
likely produce further regression of lesion volume, the authors
point out that shrinking atherosclerotic plaques by targeting LDL
alone may reach diminishing returns. With the remarkable lipid
lowering enabled by the combination of statin and anti-PCSK9
antibodies, we may be wringing as much “milk out of the stone”
as we can by lessening lipid accumulation in the atheroma. This
consideration indicates that we may be plumbing the limits of
clinically beneficial LDL lowering with the remarkable therapies
we have at hand today. In an era of striving for “precision” medi-
cine, we should prepare to address a residual burden of events
in patients despite extreme LDL lowering by targeting other
potential drivers of cardiovascular risk including inflammation
or other lipid risk factors such as triglyceride-rich glycoproteins.
Dr Libby is Chief of Cardiovascular Medicine,
Brigham and Women’s Hospital and
Mallinckrodt Professor of Medicine, Harvard
Medical School in Boston, Massachusetts.
Ticagrelor no more effective than
clopidogrel in patients with prior lower
extremity revascularisation for peripheral
artery disease
In the Examining Use of tiCagreLor In paD (EUCLID) trial, ticagrelor did not reduce the primary
composite endpoint of cardiovascular mortality, myocardial infarction, or ischaemic stroke
versus clopidogrel in patients with peripheral artery disease and a history of lower extremity
revascularisation.
Schuyler Jones, MD, of the Duke
University School of Medicine,
Durham, North Carolina,
explained that peripheral artery disease
is considered a systemic manifestation
of atherosclerosis. It affects the
arteries of the lower extremities,
and is often thought to constitute a
coronary heart disease risk equivalent
due to associated high cardiovascular
morbidity and mortality.
He said, “Considering the
uncertainty about long-term risk
reduction after vascular intervention
and dramatic variation in antiplatelet
use after vascular intervention, we
were interested in ascertaining patient
risk after pulmonary vein isolation and
whether we could demonstrate (in the
largest subgroup of EUCLID patients)
ticagrelor’s effectiveness in reducing
cardiovascular risk.
Symptomatic patients most
commonly present with either
intermittent claudication or critical
limb ischaemia. These symptoms are
often the focus of treatment strategies
to revascularise the limb. Unlike
patients with coronary artery disease,
how to reduce cardiovascular risk in
patients with symptomatic peripheral
artery disease (whether treated with
revascularisation or medical therapy) is
not well understood. Clinicians often
rely on data from subgroup analyses of
patients with peripheral artery disease in
antiplatelet and statin studies to guide
cardiovascular risk reduction strategies.
With limited proven medical
therapies to reduce symptoms in
patients with peripheral artery disease,
peripheral endovascular and surgical
revascularisation for the symptomatic
management of patients with
peripheral artery disease has increased
dramatically over the past two decades.
Compared with revascularisation for
coronary artery disease, little evidence
guides clinicians on the choice and use
of antiplatelet medications in patients
who have undergone a peripheral
revascularisation procedure. The
optimal antithrombotic regimen for
long-term management of patients
with peripheral artery disease after
revascularisation is poorly defined
and often extrapolated from trials of
patients undergoing a percutaneous
coronary intervention.
Two critical questions surround
long-term prognosis and management
of patients who have undergone prior
lower extremity revascularisation:
1. Are patients who have been
revascularised at heightened risk
for cardiovascular and limb events
vs those who have not undergone
prior revascularisation?
2. Are more intensive antiplatelet
medications more effective yet safe
in this population?
Ticagrelor is a potent P2Y12
receptor antagonist with evidence
of benefit in patients with acute
coronary syndromes and those with
prior myocardial infarction. The
EUCLID trial was designed to
evaluate treatment, specifically in
patients with peripheral artery disease.
EUCLID tested the hypothesis that
monotherapy with ticagrelor would be
superior to clopidogrel in preventing
cardiovascular endpoints in patients
with peripheral artery disease.
Dr Jones described findings in
the subgroup of patients who were
enrolled based on their history of a
prior lower extremity revascularisation.
EUCLID randomised 13,885
patients with peripheral artery disease
to ticagrelor 90 mg twice daily or
clopidogrel 75 mg daily. Patients were
enrolled based on an abnormal ankle-
brachial index ≤0.80 or a prior lower
extremity revascularisation.
The analysis focused on the 7875
(57%) patients enrolled based on prior
lower extremity revascularisation.
Patients could not be enrolled
within 30 days of their most recent
revascularisation, and patients with an
indication for dual antiplatelet therapy
were excluded.
The primary efficacy endpoint was
a composite of cardiovascular death,
myocardial infarction, or ischaemic
stroke. The primary safety endpoint
was major bleeding.
Patients who had undergone prior
revascularisation were a mean age of
66 years, 73% were male, and median
baseline ankle-brachial index was 0.78.
After adjustment for baseline
characteristics, patients enrolled based
on prior revascularisation experienced
similar rates of the primary composite
endpoint (hazard ratio 1.10, 95% CI
0.98–1.23) and statistically significantly
higher rates of myocardial infarction
(hazard ratio 1.29, 95% CI 1.08–1.55,
P = 0.005) and acute limb ischaemia
(hazard ratio 4.23, 95% CI 2.86–6.25,
P < 0.001) than patients enrolled based
on ankle-brachial index criteria.
No differences in ticagrelor- versus
clopidogrel-treated patients were
observed for the primary efficacy
endpoint (11.4% vs 11.3%, hazard
ratio 1.01, 95% CI 0.88–1.15); all-
cause mortality (9.2% vs 9.2%, hazard
ratio 0.99, 95% CI 0.86–1.15); acute
limb ischaemia (2.5% vs 2.5%; hazard
ratio 1.03, 95% CI 0.78–1.36); or
major bleeding (1.9% vs 1.8%; hazard
ratio 1.15, 95% CI 0.83–1.59). The
median duration of follow-up was
approximately 30 months.
Dr Jones said that after adjustment
for baseline characteristics,
patients enrolled based on prior
revascularisation for peripheral artery
disease experienced higher rates of
myocardial infarction and acute limb
ischaemia with similar composite rates
of cardiovascular death, myocardial
infarction, and stroke versus patients
enrolled based on the ankle-brachial
index criterion.
No significant differences between
ticagrelor and clopidogrel were
observed in reduction of cardiovascular
or acute limb events. The findings
suggest that patients with prior
revascularisation have a substantial
residual rate of cardiovascular and
acute limb events, despite high
adherence to antiplatelet and statin
medications, and require further study.
The findings not only add context
to knowledge of antiplatelet
monotherapy after revascularisation
for peripheral artery disease, but
they also highlight the need for more
trials of antithrombotic agents after
revascularisation.
Specifically, whether patients should
be treated with one or two antiplatelet
agents, which agents should be
used, the duration of antiplatelet
monotherapy or dual therapy, and
whether antithrombotics that utilise
different mechanistic pathways (for
example, P2Y12 receptor antagonists,
factor Xa inhibitors) should be used in
isolation or in combination for these
complex patients to reduce their long-
term rates of cardiovascular events and
acute limb ischaemia have not been
determined.
Finally, while the optimal anti-
platelet medication regimen is being
studied and developed, the impact of
disease presentation, anatomic burden
of disease, and type of revascularisa-
tion procedures need to be understood.
“While ticagrelor was no more effec-
tive in reducing risk than clopidogrel,”
Dr Schuyler Jones said, “we learned
valuable information about this popu-
lation, specifically, that patients with a
history of lower extremity revasculari-
sation are at higher risk of acute limb
events and cardiovascular events.”
The findings not only add context to knowledge of antiplatelet
monotherapy after revascularisation for peripheral artery
disease, but they also highlight the need for more trials of
antithrombotic agents after revascularisation.
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