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EXPERT OPINION
Dr Joerg Herrmann on the FUTURE, EUCLID, ART and PRECISION trials
Written by Joerg Herrmann
MD
The FUTURE trial
The FUTURE trial set out to randomise
over 1,700 patients with multivessel CAD
that had to include the LAD to either FFR
or angiography alone in order to test if FFR
helps guide treatment strategy and thereby
improves outcome. The study was powered to
detect a 30% relative reduction in the risk of
MACE. However, at just over 900 patients, the
data safety monitoring and steering committee
advised to stop the trial in view of an >2-fold
increase in overall mortality in the FFR group.
One-year outcome data available for nearly
800 patients does not show a significant
difference in overall MACE and only a trend
towards higher overall and CV mortality in the
FFR group.
In summary, this trial may cast some
uncertainty on the future of the use of FFR
in clinical practice. Further data are needed
on the impact on decision making and how
this could be linked to adverse outcomes. By
itself the FFR procedure does not increase the
risk and nothing else is evident and intuitive.
However, the trial is a good reminder that one
of the greatest benefit in all previous FFR trials
was the reduction of stent implantations when
haemodynamically not required, and thereby a
reduction of costs and related risks.
The EUCLID trial
Encouraged by the results of the PLATO
trial of superior outcomes of ticagrelor
compared with clopidogrel in ACS patients
and the PEGASUS trial on the benefits of
ticagrelor over aspirin in patients with PAD,
the EUCLID trial was pursued. This was a
trial assessing the incidence of cardiovascular
death, MI, and stroke in nearly 14,000
patients with symptomatic PAD randomised
to ticagrelor or clopidogrel. No difference in
the primary composite endpoint was found,
even though there was a significant, 20% lower
rate of ischaemic stroke in the ticagrelor group.
There was no difference in bleeding events.
Even though contrary to the study hypothesis,
one important point is that poor metabolisers
of clopidogrel were excluded from this trial.
Thus, in essence this trial then shows that
clopidogrel is as effective as ticagrelor in this
population when effectively metabolised.
The observation of the difference of a lower
rate of strokes with ticagrelor needs further
exploration. These findings are opposite to the
PLATO trial results.
The ART trial
The ART trial randomised >3000 patients
scheduled for coronary artery bypass grafting
(CABG) to either left or bilateral internal
mammary (IMA) bypass grafting (of note, over
three quarters of patients had two or three
additional grafts). No significant differences in
major cardiovascular outcomes were found over
5 years of follow-up. However, the incidence of
sternal wound complication and reconstruction
was 2 and 3-fold higher, respectively, with
bilateral IMA bypass grafting, and all of these
events occurred in the first year and mainly in
diabetics and those with high BMI.
Of further note, 14% of patients assigned
to bilateral IMA underwent single IMA only
versus 2.4% of patients assigned to single
IMA undergoing bilateral IMA bypass surgery.
In summary, adding one more IMA graft to
patients undergoing CABG with LIMA
grafting does not add further clinical benefit
but may increase the risk of sternal wound
complication especially in at risk populations.
The PRECISION trial
This mega trial involved nearly 1,000
centres worldwide that enrolled 24,000
osteoathritis or RA patients with CV disease
or risk requiring NSAID therapy for at least 6
months. Patients were randomly assigned to
celecoxib 100 mg bid, ibuprofen 600 mg tid,
or naproxen 375 mg bid in conjunction with
esomeprazole. Celecoxib was not inferior to
naproxen and ibuprofen with regards to major
adverse cardiovascular events in the intention-
to-treat analyses. In fact, in the on treatment
analyses it was associated with a lower risk of
cardiovascular events and mortality compared
with ibuprofen. Celecoxib was associated with
a lower risk of major GI events compared with
both naproxen and ibuprofen and a lower risk
of serious renal events than ibuprofen and
even naproxen in the on-treatment analyses.
In the post-hoc analyses of any CV, GI, or
renal event, celecoxib had the lowest risk,
naproxen had intermediate risk and ibuprofen
the highest risk. These findings are striking as
they grant absolution to a drug condemned in
the cardiovascular community.
These charges date back to COX-2 inhibitor
story, which made headlines just over a
decade ago, pointing out the increased risk of
cardiovascular events with these drugs. Vioxx
was the prime contender and eventually left
the market in 2004; Bextra followed in 2005.
This has left Celebrex as the sole COX-2
inhibitor on the US market with stern black
box warnings. Other NSAIDs have also
been confronted with heightened levels of
concern eg, ibuprofen, whereas Naproxen has
prevailed in current opinion as one of the safer
representatives in his class. PRECISION
would attest that it is safer than ibuprofen,
but even so, the winner is, this time: celecoxib,
but against NSAIDS that also carry a risk.
Dr Herrmann is Associate
Professor of Medicine
at Mayo Graduate
School of Medicine,
Rochester, Minnesota.
Extended-duration betrixaban reduces stroke risk vs standard-dose
enoxaparin in hospitalised medically ill patients
Among hospitalised
medically ill patients,
extended-duration
betrixaban has been
shown to significantly
reduce all-cause and
ischaemic stroke
versus standard-of-care
enoxaparin through
77 days.
T
his outcome of a substudy
of the Acute Medically Ill
Venous Thromboembolism
Prevention with Extended
Duration Betrixaban (APEX) trial
was reported at the AHA Scientific
Sessions 2016.
Michael Gibson, MS, MD, of
Beth Israel Deaconess Medical
Center, Boston, Massachusetts,
explained that stroke is a leading
cause of morbidity and mortality
worldwide. In-hospital stroke
complicates 0.04% to 0.06% of all
hospitalisations and constitutes
2.2% to 15.2% of all strokes.
Stroke among patients hospi-
talised for acute medical illness
portends a less favourable outcome
than community-onset stroke.
Little is known, however, about the
effectiveness of novel oral anticoag-
ulants for stroke prevention in this
context. APEX evaluated extended-
duration thromboprophylaxis with
the oral anticoagulation betrixa-
ban in the prevention of venous
thromboembolism.
In this retrospective substudy,
Dr Gibson and colleagues compared
extended-duration betrixaban versus
standard thromboprophylactic
enoxaparin in the reduction of
stroke among hospitalised medically
ill patients.
Hospitalised acutely medically ill
subjects (n=7513) were randomised
in a double- dummy, double-blind
fashion to either extended-duration
oral betrixaban (80 mg once daily
for 35 to 42 days) or standard-dose
subcutaneous enoxaparin (40 mg
once daily for 10 ± 4 days) for
venous thromboprophylaxis.
Mean participant age was 76
years, 45% were male, 13% had
a stroke, and 45% had congestive
heart failure.
Fewer all-cause strokes (0.54%
vs 0.97%; relative risk 0.56 [0.32–
0.96], P = 0.032, absolute risk
reduction 0.43%; number needed
to treat 233) and ischaemic strokes
(0.48% vs 0.91%, relative risk 0.53
[0.30–0.94], P = 0.026; absolute
risk reduction 0.43%, number
needed to treat 233) were observed
among patients treated with
betrixabanthan with enoxaparin
through 77 days offollow-up.
Among high-risk subjects (those
with congestive heart failure or
ischemic stroke as their index
event) betrixaban reduced the risk
of all-cause stroke (0.72% vs 1.48%,
relative risk 0.49 [0.26–0.90],
P = 0.019; absolute risk reduction
0.76%, number needed to treat
132); and ischaemic stroke (0.63%
vs 1.38%, relative risk 0.45 [0.24–
0.87], P = 0.014, absolute risk
reduction 0.75%, number needed
to treat 134) vs enoxaparin.
Dr Gibson concluded that among
hospitalised medically ill patients,
extended-duration betrixaban
significantly reduced all-cause
stroke and ischaemic stroke through
77 days of follow-up.
Extended-duration thrombo-
prophylaxis with an experimental
oral factor Xa inhibitor may reduce
the risk of stroke among hospital-
ised medically ill patients.
In the post-hoc analyses of any CV, GI, or renal event, celecoxib had the lowest
risk, naproxen had intermediate risk and ibuprofen the highest risk.
These findings are striking as they grant absolution to a drug condemned in the
cardiovascular community.
© 2016 AHA
AHA 2016
VOL. 1 • No. 3 • 2016
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