good afternoon my name is Zac Stacy I'm
an associate professor of pharmacy
practice analyst college of pharmacy and
an alum in the 2002-2003 year I have a
practice cited the same at Mercy
Hospital where I practice in cardiology
and specialize in anticoagulation and
today I am going to talk about new heart
failure therapies and the presentation
entitled a paradigm shift in the heart
failure and those two terms will come up
later when we discuss some of the
primary literature involved in the new
heart failure regimens the learning
objectives for today are to take a look
at the traditional agents commonly used
in the management of stable heart
failure and that acronym HRF our EF is
now the new term for systolic heart
failure and then evaluating the role of
the new novel agents in the management
of heart failure traditional therapies
have been recommended according to the
American College of Cardiology American
Heart Association staging system with a
four tier system stage a through stage d
and stage a we have risk factors for
heart failure where the guidelines would
recommend an ACE inhibitor stage be
where there's structural damage to the
heart where we would have an ace
inhibitor and a beta blocker recommended
stage see where a patient will have had
symptoms or currently have symptoms and
in this stage we can see that there's a
number of different therapeutic options
including an ACE inhibitor and beta
blocker but also furosemide for the
symptoms digoxin for the symptoms for a
lactone hydralazine and nitrate
combination and then stage D is really more
of a late stage heart failure what we
sometimes refer to as a refractory heart
failure where the only additional
therapy that would be considered is the
use of oxygen this four tiered system
the way I like to think
about it is staged a is a speed
beta-blocker and c is a combination of
therapies and this is a traditional view
of some of our medications that we would
be recommending and a heart failure
patient the new therapies that we'll
talk about today are the brand names
entrust 0 & quarrelin are and what we
can see from this first slide is the net
rate of peptide sequence that has been
come a very important target for heart
failure medications so in the slide we
see the the angiotensin 2 which if
impeded and not inhibited can have
effects on the body including
vasoconstriction leading the increases
in blood pressure sympathetic tone and
increasing other natural peptides such
as aldosterone so traditionally our
therapies and targeted angiotensin 2 and
we've used things like ace inhibitors in
valsartan to to inhibit the activity of
angiotensin 2 well in what we also have
to consider it's the balance of the net
of these neural hormones and that's
where pro-bnp which is then broken down
into bnp can have a beneficial
effect on heart failure which leads to
vasodilation a reduction in blood
pressure reduction in sympathetic tone
and a reduction in other neurohormones
like aldosterone and so balancing the
the inhibition of the bad neural
hormones and promoting the good neural
hormones such as BMP has long been an
approach that we've tried to use in
heart failure and now we have an agent
which comes as a combination of the Q
betrayal and Bell fartin which can
prevent the breakdown of BNP there for
prolonging its effect it's good
potential in the body but also the valve
fartin which can inhibit the angio
tension too bad effects and so now we
have a balanced approach to our
therapeutic community
heart failure patients so this new agent
Entresto outcomes a fixed combination and
the starting dose that is 49 50 won't
flash 51 milligrams by mouth twice a day
and this can be taken with or without
food and we can use reduced starting
doses which we'll talk about here in
just a moment the approach starts with
us 49 and 51 milligram dose and we
double the dose every two to four weeks
to achieve a target dose of 97 / 10 3
milligrams twice a day and you can see
the dosage strengths come in a smaller
dose 24 / 20 26 all the way up to the
target dose 97 / 10 3 milligrams
Entresto dosing can be used as an
initial dose of this 24 / 26 milligram
twice daily in those patients who are
not currently taking an ACE inhibitor
when Entresto is considered or those
who are on low doses of ACE inhibitors
at the time address those initiated if a
patient would have severe renal
impairment which is defined as a GF are
of less than 30 or they have moderate
and a daq impairment again we can start
with this lower dose of 24 / 26
milligrams twice day and then if they
have severe panic impairment interested
would not be recommended in a heart
failure patient the trial that provides
some evidence as to the benefits of
interest though is the paradigm HF trial
and in this trial they took class two
three and four systolic heart failure
patients defined as an ejection fraction
of what's than forty percent randomized
them in this double-blind superiority
trial so that they would receive either
interest 0 100 milligrams twice a day or
enalapril 10 milligrams twice a day and
they look for the primary efficacy
endpoint which included a combination of
either cardiovascular death or heart
failure hospitalizations and the
paradigm trial found that this
combination or composite
primary endpoint was significantly
reduced with the use of interest though
which on this slide is indicated by the
red line LCD 696 which was a scientific
name as it was going through some of the
earlier trials and this significant
reduction didn't come against placebo
but rather came across enalapril which
is one of our standards of standards of
care so the benefit was seen not against
a generic placebo tablet but rather our
best other option which would be an hour
all we saw this reduced combination
reduced Menace benefit in this primary
composite endpoint now usually on a
primary composite endpoint a lot of the
reduction comes in hospitalization for
heart failure which we saw in this trial
so again entrust Oprah vining a benefit
compared to the traditional therapy
enalapril but what was unique about the
paradigm hf trial was that we didn't
even that would not only do we see the
benefit in hospitalizations but we also
saw the benefit in deaths from
cardiovascular causes and this this
curve you can see from the capital myers
you can is starting to separate at about
180 to 240 days and so patients who have
heart failure who are given in trust o
could see a reduction in death from
cardiovascular causes within a year when
they use in tres though compared to
enalapril so if we talk about the
efficacy of the agent it's fair to talk
about the potential safety concerns and
with the combination products the cubit
role valsartan which is interesti-- we
saw an increased rate of symptomatic
hypotension and an increased rate of
symptomatic hypotension with a systolic
blood pressure of less than 90
millimeters of mercury however this came
with a reduced rate of GFR reductions
and you can see elevated cracking
Clarence was elevated in
three-point-three percent of the
resco patients compared to four point
five percent of those receiving
traditional therapy of enalapril and so
we saw a fewer rates of renal
dysfunction with the new product
interest though also saw fewer rates of
very high levels of serum potassium so
four point three percent for Cuba
coralville Sartain vs five point six
percent and saw a reduction in the
number of people who experienced a cough
11.3 percent versus 14.3 percent with an
avril similar rates of NGO edema which
is probably one of our more serious side
effects that we consider with a mallet
realm the summary with interest oh is
that we have reduced cardiovascular
deaths and heart failure hospitalization
however this trial was a very short term
trial compared to the normal life
expectancy of a heart failure patient
and so long-term safety did it remains
somewhat unknown and the important
takeaway point from this bullet is that
both her failure hospitalization and
cardiovascular death benefits we're
seeing not just in the composite and so
this is an important point to remember
when we take a look at the new
guidelines that recommend entrust oh we
also saw that what we also think that
clinical experience is going to be used
to to decide what's the appropriate
starting dose the appropriate blood
pressure lowering effects and making
sure we realize those and it's important
as a practitioner to remember that we
need to discontinue ACE inhibitors ARVs
and renin inhibitors before we start and
tres though and when we just continue
them have a 36-hour washout period when
switching from the ACE inhibitor over to
interest though the 2006 accha heart
failure Society of America guidelines
now recommend as a class one
recommendation ACE inhibitors ARVs
and our knees which in our use a new
term for a lot of pharmacists which is
an NGO which angiotensin receptor nipple
is an inhibitor and they now recommend
this as a class one recommendation for
all heart failure patients who have
solid heart failure in addition to this
ace inhibitors continue to have a class
1 a recommendation to reduce morbidity
and mortality a arbys continue to have a
1 a recommendation to reduce morbidity
and mortality somewhat surprisingly a 1
B recommendation with seen and patients
who are now tolerant who could now
tolerate an ACE inhibitor or ARB the
recommendations from the guidelines are
to consider replacing that ace inhibitor
narb with this new class of drugs called
an arnie so this isn't the traditional
approach where we would swap out an ACE
inhibitor for someone who didn't
tolerate it for an ARV this is a
language that suggests that even if you
tolerate nice inhibitor or ARB you can
still consider switching that to an army
to help further reduce morbidity and
mortality in systolic heart failure
patients and then the last
recommendation is a class 3 which is in
other words saying you know caution or
don't do this on so our knees need to be
discontinued and not code need to be not
co-administered with an ace inhibitor
and that 36-hour washout period is
necessary for ace inhibitors the other
new medication that we have which is
goes under the brand name core lenoir
works on file atrial node and helping
with final atrial node depolarization
ivabradine the generic name enters the
cell and inhibits the sodium channels
the sodium potassium channels from the
intracellular side delaying sinoatrial
node depolarization so in this picture
the first receptor here you see sodium
entering cell from the extracellular
side
I've aberdeen entering it from the
intracellular side and then when the
action when the electrophysiological
potentials change across the membrane
potassium then tries to leave that same
membrane poor and it forces I've
aberdeen into its active site within the
channel and this is what delays
depolarization and file atrial node the
dosing of ivabradine is to initiate it
five milligrams twice daily with meals
and after two weeks you can adjust the
dose space on a goal heart rate of 50 to
60 beats per minute what the maximum
does here being seven point five
milligrams twice a day and both dosage
strengths are available in the United
States so in considerations here with
regards to the heart rate is that if the
heart rate is above 60 and you are on
the 2.5 or the 5 milligram twice daily
dose you could increase the dose up to
five or seven point five milligrams
twice a day if you had a heart rate
which was between 1560 beats per minute
you could maintain the current dose and
if you had a patient who had a heart
rate of less than 50 beats per minute or
signs or symptoms of bradycardia you
could reduce the dose or you could
discontinue it all together to prevent
these symptoms of bradycardia the
contraindications for I've aberdeen is
and it wouldn't want we wouldn't want to
initiate it in someone who is acutely
decompensated if they had a blood
pressure of less than 90 over 50 if they
had some other form of final atrial note
noble movies like sick sinus syndrome or
third-degree heart block if they had a
resting heart rate of already less than
60 beats per minute the bureau patek
impairment or if they were dependent on
a pacemaker so the evidence for
ivabradine comes from a trial called the
shift trial in which they randomized
patients and a double-blind superiority
trial with symptomatic heart failure
with an EF of less than thirty five
percent and heart rate of greater than
he beats per minute and this was in the
background of patients who are already
receiving ace inhibitors beta blockers
and diuretics these patients were
randomized to receive Aberdeen 5
milligrams twice a day or placebo which
again meant traditional therapy in these
patients and they looked at a primary
efficacy endpoint of cardiovascular
death and heart failure hospitalization
which was similar to the trust o
paradigm trial the first outcome that
I'll show here is heart rate which in
the surrogate endpoint means patients
but because it works on the sinoatrial
node it was it was hypothesized that we
were going to see a reduction in heart
rate and that's exactly what we saw with
the blue curves demonstrating the effect
of ivabradine on heart rate and we see a
heart rate that was achieved somewhere
in the mid-sixties versus placebo where
the heart rate was maintained or right
around 75 beats per minute and this was
throughout the course of the trial the
primary outcome which again was the
composite of cardiovascular deaths and
heart failure hospitalizations we saw a
significant reduction with I've aberdeen
compared to placebo and this was seen as
early as around four to six months with
the separation of the kaplan-meier
curves and maintained throughout the
course of the trial when we take a look
at those individual endpoints within the
composite this is first hospitalized
first hospitalization we see a reduction
in ninth aberdeen compared to placebo
again that corporation occurring
somewhere in that four to six month
period with the kaplan-meier curves but
unlike the interest though paradigm
trowel where we saw reductions both in
the shift trial of ivabradine we did not
see a reduction in cardiovascular death
which will will help us understand the
recommendations for I've Aberdeen we
take a look at the guideline
recommendations a moment so I've
aberdeen compared to placebo did not
provide a significant reduction
immortality however it did provide one
in overall hospitalizations for our
chair and so that's an important
take-home point again if we think if we
consider the potential benefits we also
have to consider the potential harm and
I've highlighted a couple important ones
here as they were as this drug works on
the sinoatrial node we saw an increased
number of patients with symptomatic
bradycardia five percent versus one
percent a significant difference in
asymptomatic bradycardia and an
increased risk for atrial fibrillation
nine vs eight percent with I've averaged
one outcome year or one side effect that
we don't commonly see which is
phosphenes and that is the the of the
presence of light during vision when
light isn't really present and that's
called a phosphine reaction this was
actually increased with ivabradine
compared to placebo in the summary will
summary with ivabradine is that it's a
selective inhibitor on the sinoatrial
node and it does reduce cardiovascular
death and heart failure hospitalizations
with a composite endpoint but that was
really driven by a reduction in heart
failure hospitalizations and this should
be initiated in patients with stable
chronic heart failure those receiving a
background therapy of ACE inhibitors and
beta blockers with a resting heart rate
of greater than 70 beats per minute and
so we saw a reduction in heart rate
without the reduction in contractility
which is a unique combination of
mechanisms for hearthfire so the
guideline recommendations here is that
it's a to a recommendation to consider
the use of I've Aberdeen and heart
failure patients with a new york art
class 233 grew are already unstable
chronic therapy and able to tolerate
reductions in their heart rate so i
started off the presentation with a
traditional look at what our therapies
were for stage a through d and as you
can see with the addition of the last
row here we can see that we can initiate
qubit roll valsartan which isn't resto
and stage a patient's
continue that through stage be an
through C and then consider the addition
of ivabradine and stage c as well and
this is going to be used ivabradine
would be used to reduce further or
future hospitalizations do a heart
failure and so our number of therapies
here continue to grow for the management
of heart failure patients and our number
of options we can continue to grow as
well I like to thank you for your time
today for for this webinar and if there
are any questions I can stay on the
webinar for a few more minutes here and
look to see if anyone has submitted a
question if you want to submit a
question you can type it out and they'll
come across on the on the webinar here
and I can I can see it
