Anticoagulation after acute stroke – when/ how to start

thank you very much miss Opoku it's a

great pleasure to be here and I'm very

happy that you just pointed to the very

important question I'm trying to answer

to you now because I only started

talking on heparin so my task was to say

something about the when and how first

of all here my disclosures so the most

important here of course that I'm a

neurologist first thing I asked myself

and I would quickly go through it so

when talking about the how and when what

is the evidence at all you all know that

we're talking about acute ischemic

stroke patients now that most of the

studies were done in patients with a sin

not necessary in patients with stroke so

what is the evidence it's it's

tremendous because we go back to 1993

just very quickly maybe a time point

when some of you weren't born yet or

haven't been have not been in school yet

and although that time the AF sorry

there was a tremendous effect of of

warfarin and perceiver was this great

reduction in new Ambala strokes of

recurrence in these stroke patients we

are talking about in the subgroup

patients so what's the evidence from the

dog trials all of these child included

patients who already he also had a

stroke and there sounded to suggest that

all the dogs also reduce the risk of

recurrence impacted had a stroke so what

is all the discussion about then the

when and how well it appears very

interesting or it's very interesting

that most of these trials on the dogs

did not exclude include that had very

recent stroke the rely study did not

include patient was in 14 days

rocket AF trial did not include patients

that had a stroke within the last 30

days the era's tosyl study did not

include patients who had a stroke was in

lost seven days and so on and even the

ef-2 study had the majority of the

patients included within 14 days but

were allowed to include patients up to

90 days

second row shelf is a number of patients

with jokes that were included in the

trials so for some reasons they were

very worried about including patients at

a very early phase in the very early

phase of acute stroke so this concern of

course is as mentioned before because

early initiation may accept or

exacerbate or cause have a

transformation or even parenchymal

hemorrhage something we are very afraid

of but what do we know about early

initiation is this a relevant concern we

have it's always two sides of the coin

isn't it one side of the coin earlier

which is assumed to be very high data

dating back to the 80s suggesting that a

patient had a stroke has a very high

risk to have a recurrence in the early

days up to 1% per day and on the other

side the fear to cause regular

hemorrhage or hemorrhagic transformation

and we know that this would very much

impair the prognosis of our stroke

patients there's only one randomized

controlled trial which gives the stage

of on very early initiation only this

very small study on not not yet two

hundred strokes patients was a very

small stroke you all know the NHS S

which is the score for stroke severity

too is very little not very much

impaired just a very small stroke and

the in fact volumes are very small to

they started in the media on day two and

their goal was to see how many new

events there would be on MRIs so no

clinical outcome just circuit marker

they compared rivaroxaban and warfarin

and did not find difference between

these two neither a new DWI lesion so

it's a good market for new stroke nor

for new bleeding on t to store images of

the MRI so in this cohort of patients

with stroke small straw

not severely impaired it seemed to be

safe from the part of you that there was

no difference between rivaroxaban and

warfarin or other data we have is data

of cohorts of prospective follow-up

studies and we do have and this actually

point to the question which we just had

we do have data on parental articulation

or Hedren and this data from this media

analysis which does not include of

course those concepts from 2007 did they

tell us that there was not really a lot

of data suggestions at which that we

should give heparins rather it tended

that there was no advantage at all to

start with heparins and when we look at

the Y we see again there's a mm yes

there heparins the parental interference

did reduce recurrence was a significant

odds ratio are not nearly nearly

significant or three with a number

needed to treat about 50 but on the

other ha on the other side it did cause

bleeding with a significant odds ratio

and a nominee division harm of 55 so

that was reason you know the the benefit

you bought was paid by the disadvantage

of the bleeding's so nearly all the

guidance a early administration of

parental or intercalation in the DOS

calling relevant blood-thinning not the

dose of preventing deep vein thrombosis

is not supported because the net

clinical benefit will be set off by the

bleeding sea cause in relation to the

reduction in recurrence you gain so this

data was about heparin and warfarin what

we know was a direct oral integrant so

this is again data on the subgroup of

the post stroke patients we all fear

bleeding of course this is a slider

always get a Oh from the audience when

it shows this little small

thank you okay I will fear of course

intracranial bleeding so so what did the

data show the data showed the New

Orleans are nearly all safe or all the

doses less severe bleeding less via

intracranial bleeding so this would be

an argument and that we are better off

as a direct oral anticoagulants and

might start earlier so this would be an

argument that those as opposed to

heparin and this assumption is always

also supported by some observational

studies we have like this notice this

array from Japan or the ref no work

study which also low inter Canyon

bleeding risk with door works including

hemorrhagic transformation if you start


this again is registered data supporting

the fact that we should not give low

molecular weight heparin and the data

now includes also darts the paper or the

the draft was on patients that did not

receive torques because they were not on

the market so basically supporting the

Assumption if the start was low hi Jose

this is not good for the patient as you

see that low weight heparins those cause

more ischemic events or do not prevent

more ischemic events as a yellow bar is

higher than the green bar and do not and

also cause more hemorrhages so again

early administration of habits not

supported bridging is not supported so

wide of timing measure the question was

about the wind so what do we know about

the timing then okay we know that in the

large Charles there were very few

patients that were included before day

14 does a few be day 14 will see a big

smart study so why is that obviously


early start of orientation is a

predictor of pure ankara hemorrhage

although the data could be questioned

because most analysis do not reach

statistical significance and because we

already mentioned that before parental

hemorrhage is a very strong predictor

for male outcome so what do we know

about the right time point is this

analysis from stroke 2015 again registry

data no control data where they try to

pick the best time span with both the

lowest return rate and the lowest energy

age and in this analysis just in multi

regression analysis it was between days

5 and 13 that the patients were best off

so this is an argument just from

registry data to start earlier than day

14 but not only the day four to three

again this is mainly patients with

warfarin just to stress that of course

we have a heterogeneous group of

different drugs and this is the analysis

supporting or suggestion that early


but not too early it would be the best

timing to go on with a regulation what

does the guidelines say we do have

guidelines and the guidelines actually

give us hints so ever answer

neurologists of course first stroke

minds and they say start at a four in

March job it's more in fact started day

seven and moderate stroke was medium in

fact and started a fourteen and severe

stroke with lot in force they also say

bottom line based on observational study

results reading therapy that was the

data I just showed you is not supported

prior to our integration must not be

used in patients AF and ischemic stroke

strong evidence or strong

sentence so here they make the point

it's not only time it's also about the

size or was a very interesting question

to talk about size and they say small

medium large they do not tell us what

small medium and large actually means

that just says small medium and large

but they do not give us any finished I'm

a bit remote control I'm sorry so what

does the ecological unsafe see

cardiology guidelines basically say the

same thing they start straightaway on

the left if you have a mild neurological

deficit small strokes or other few days

if you have a moderate or if you have a

moderate deficit Scott after six to

eight days with the severe deficit start

after twelve to fourteen eight but they

somehow introduce an extra point to be

here and to have more data to to build


they tell us if you have a moderate or

severe deficit better make a second

imaging and look at the second image and

look whether there's any change to the

in fact so same recommendation as the

neurology stroke recommendations more or

less one three six twelve so you double

the number so to say but very

interesting this recommendation made in

the 2018 you accommodations based on the

2013 recommendations they are basically

the same nearly the same and those based

on the warfarin data so that did not

somehow tell us that now they recommend

something on dogs which was basically

derived from it from a friend or

although we know that the drugs are

different again the given that it was

not a very good definition on what minor

moderate or severe means so they

emphasize and this is the only guideline

that recommends repeat imaging so the

size matter

yes size does matter

large reasons do predict prank or

hemorrhage and large

also do predict parenteral hemorrhage

and stroke patients with AF and yes it

does we do not want that this happens a

patient was a lot right in sixth row

which has a Frank remembered

so what will the future bring of the

future will bring us for more trials one

European one British one Swedish and one

Texan trial that all started with

different assumptions and different sets

to compare early and late initiation so

we will have more data to answer this

question but I cannot give any

information on these Charles apart from

that they are actually happening at this

moment so what the when difficult

question is there is only few data

regarding the timing of course very

simple answer it's a risk-benefit ratio

there's two fighters point and we have

to weigh benefits and risks as far as

the works are concerned it seems

reasonable safe to start within 14 days

and not later

although the trials did not include

patients for most of the charts include

patients earlier than 14 days stroke

size may help but it is it's a very

individual judgement we do not have a

definition in terms of milliliters or in

terms of what actually large means the

trials actually have so the Elantra has

a suggestion where to find the cut-offs

and we might just stick to the

guidelines and choose our one three six

twelve algorithm although they did not

differentiate between warfarin and dogs

and how well there's strong evidence not

to bridge actually you're going for dogs

because they have a very similar

half-life anyway so there's no advantage

in terms of pharmacodynamics to first

start with heparin and then start to


um neurologists actually start with

aspirin even if you have atrial

fibrillation and then switch to dogs

because there's all this data about the

bad-bad heparin and I hope that very

much in the future we will have new data

to answer this very interesting question

one early initiation thank you very much

for your attention