all right so again my name is chindan
Mehta and I'm talking about
anticoagulation reversal strategies and
who's flipping my slides I don't okay
all right so what
starting off starting off after lunch
great here so why do we care we've we
spend so much time these days talking
about door to TPA time door to needle
time but we also need to care about door
to reversal time because time is
ultimately brain and you know if we're
not killing it off by ischemia then
we're also doing damage by not reversing
anticoagulation so what drugs do we care
about obviously this is a very lofty
topic to discuss just over a few minutes
so we're just going to concentrate
talking about the old drugs that we're
used to seeing in day to day practice
those include warfarin the
unfractionated heparin
low molecular weight heparin as well as
the new drugs which are most people's
concerns these days which are the dough
acts or no acts the direct oral
anticoagulation agents and these include
the direct thrombin
inhibitors dabigatran Pradaxa and 10a
inhibitors the apixaban to dock simians
rivaroxaban and this is the old
regulation cascade that we all learned
back in school and you can see in the
gray where the traditional
anticoagulation agents work and in the
pink where they direct oral
anticoagulation to work agent agents
work and I just wanted to kind of tie
this all together with a case and we
recently had a case of a 74 year old
gentleman with an aortic valve
replacement which was done over a decade
ago and this gentleman was on warfarin
for afib and he came in to the ER and
his INR was four point seven eight and
he arrived with a headache he had seen
this pcp ten days prior he had had a
fall in a hotel and she just reported
feeling off-balance subjectively
when he was examined he was noted to
have a normal neuro exam and so they
gave him two point five milligrams oral
vitamin K and they transferred him to
our er for evaluation and you can see on
the image there he's got a
moderate-sized
hemorrhage in the left cerebellar
hemisphere with some surrounding edema
fast forward to ten hours later this
gentleman became at unded he required
intubation and we sent a burst CT scan
and as you can see that hemorrhage
expanded rapidly and expanded to a very
very large size his INR at that time was
five point one six
and the decision was made at that time
to give him four factor PCC 35 units per
kg and his INR 37 minutes later was 1.51
and he ended up requiring operative
intervention going to the Oh r4
decompressive craniectomy and EBD
placement so what are our fears with
anticoagulation reversal we have the
fear of the gnome and that's that
somebody has a hemorrhage and we don't
know if it's going to expand the fears
of the unknown so what FC oh you know
this guy is a fib are we gonna make him
have a thrombotic event he's got a valve
are we gonna thrombosed his valve are we
gonna make him stroke out because of
that and what should be very
black-and-white and very clear take away
from this talk is that you need to treat
the known first you need to reverse
these patients this guy had a hemorrhage
he's a ticking time bomb when we're
waiting for something to happen
so his watchful waiting an option for
some patients the answer is in very very
few circumstances and we'll kind of get
to that so our common concerns again
that we said you know about mechanical
valves erratic mitral afib and the
thromboembolic events related to
reversal and you know going through lots
of retro sputter retrospective studies
the number of thromboembolic events in
reversing these patients has
significantly decreased as compared to
what we normally expect them to be so
study review showed within like a
three-week period post these patients
being reversed the number of percentage
of events was 0.6 to 0.7% so the risk is
significantly lower than you know what
we've been taught in medical school and
what we've been taught in pharmacy
schools so the answer is to reverse
these patients so your your standardized
approach should be getting a history
from a reliable historian a lot of our
patients come in through the ER they've
a obtunded or you know they're at an
LTAC or nursing facility so gotta get a
history from nursing staff when they
were lasting normal or from you know
family member you need to get stabbed la
stat labs including obviously a
coagulation profile you need to know
their creatinine you need to know their
liver function you need a timeline of
events medications the time administered
is very important especially for the DOE
apps and no X you need to know the last
dose and if a patient comes in and
they've recently ingested obviously one
of the oral medications
activated to our
call 50 grams is indicated for
administration with if they've taken
their mad within two hours so looking at
the trends in the community between 2013
and 2016 what are other people doing
what are their hospitals doing and this
was looking at a Phase two outcome
registry for a better informed treatment
of afib and they screened over thirteen
thousand patients ninety nine sixty
seven were included and there were only
two hundred seventy three events of
hemorrhage and no acts and 71 events and
warfarin and small amounts of
intracranial bleeds as well as GI bleeds
but what was commonly seen is that blood
products and correction agents were less
often used in Noack patients compared
with warfarin treated patients and that
was fifty three versus seventy six
percent for blood products and 0
actually versus 1.5% for recombinant
factor pcc products so what should you
do who needs reversal so any patient
that comes in to the ER and if they're
on a vitamin k antagonist agent so
obviously warfarin if they've got an INR
greater than two if they've got a
neurologic deficit and a hemorrhage on
the skin they should be reversed again
what time was the last dose so this is
obviously relevant for patients on
coumadin but most mostly applying to the
DOE acts where you might not have the
ability to determine you know by
regulation profile when their last
medication was get given where is the
hemorrhage posterior fossa like the case
I showed you any small amount of blood
there is very very relevant and should
not you should not pause and think and
wait and see kind of what happens
because you don't have space there to be
making decisions later if they bleed
they can easily herniate and die and
initially do these patients have any
overlapping renal or hepatic disease or
comorbidities which could prolong
anticoagulation effects we've seen cases
prior where we've got patients coming in
who were undertaking very minor surgical
interventions but they had renal
dysfunction and surgeons didn't
necessarily or maybe they were unaware
or they didn't consider the fact that
the the 10a effect could have been
prolonged in the patient system and they
ended up bleeding because of renal
dysfunction so quick drug review so
we've got too big a Tran and this is a
selective reversible direct thrombin
inhibitor and
peak concentration in the bloodstream
within two to three hours post ingestion
and half lave is 7 to 17 hours as you
can see when your creatinine clearance
drops you have a significantly prolonged
effect so reversal so since 2015
practice bind is a humanized monoclonal
antibody fragment that binds to Dybbuk
at ran and it's administered and 2.5
graham doses for a dose of 5 grams total
IV and the full cohort analysis which
just recently came out this past August
demonstrated that in 503 patients the
medium maximum percentage of reversal
time was 100% these patients all were
reversed it took about two and a half
hours for the bleeding to essentially
stop and many hospitals still don't have
access to this so because it's not very
highly protein bound you can actually
dialyze the bigoted ran out if I'm
urgently needed so in regards to 10a
inhibitors the rivaroxaban apixaban in a
doc Seban these are again selectively
reversible 10a inhibitors the half-life
of rivaroxaban is three to nine hours
and a half life of apixaban is eight to
fifteen hours and these are almost all
always protein bound so you cannot dial
use these out so the current trial that
we are running at Henry Ford and I know
a few hospitals in the area are also
participating in is the annex a for
phase three trial and this is looking at
competitively binding 10-8 inhibitors
with high affinity this drugs high
affinity for it and this stops bleeding
essentially within five minutes and the
study is being run on patients with GI
bleeds or life-threatening bleeds
including intracranial hemorrhage with
blasters some medication within 18 hours
and it's a bolus and infusion the bolus
takes a very short period of time and
you can have effect for up to two hours
post Bullis of anticoagulation reversal
and then you've got a one to two hour
infusion with two hours of effect post
infusion and if this is unavailable and
not a running study at your institution
for fact or PCC can be administered to
temporize bleeding effects so in terms
of the most common thing that we drug
that we see patients still coming in on
warfarin this obviously
inhibits vitamin K dependent
carboxylation of multiple blood factors
and so we we advised that vitamin K 10
milligrams should be administered along
with four factor PCC and four Pachter
PCC is preferred over FFP due to short
time of administration very low volume
in terms of the the drug administration
vs FFP FFP requires many units and
requires many hours to deliver the same
effect and four factor PCC can work in
fifteen to thirty minutes so failure to
correct INR within two hours and
comparing patients who had had FFP
versus PCC was found to be an
independent predictor of death or severe
disability in one retrospective cohort
so if patients are noted to still have
INR elevations greater than 1.4 1.5 six
to eight hours after dosing of FFP can
be given dependent on the urgency of the
situation that you're dealing with with
the patient or readmission of
four-vector pcc may be considered so in
regards to heparin and low molecular
weight heparin reversals you're going to
administer protamine sulfate and then
this is obviously dose dependent
depending on when the last dose was
given if it was given greater or less
than eight hours so adjunctive
medications which can be administered
recombinant factor 7a and this initiates
rapid hemostasis this can be given in
emergent operative settings when you're
unable to stop bleeding for factor PCC
when it's not the solution I mean in the
past for the big a trend reversal for
factor PCC was administered if you don't
have the reversal at your hospital then
you should consider PCC and patients on
dialysis desmopressin has been indicated
to stop bleeding
chanak stomach acid and amino caproic
acid as well as other blood products may
also be administered so your takeaway
from this should be that when in doubt
reverse patients don't wait for things
to happen because you know they may not
the patient may not bleed you know the
patient subdural may not progress in
size or inter-cranial hemorrhage may not
grow but the chance of taking that
upward to
that risk to to allow them to progress
to that is very a very dangerous
situation and not very justifiable when
we have appropriate reversal agents and
the risk of thromboembolic events is
very low so again it's a case-by-case
analysis and you need to discuss the
risks and benefits with care givers and
if a patient's got an LVAD that's a
completely different situation and
cardiology needs to be involved in that
decision-making process because those
patients usually should not be