ANTITHROMBOTIC DILEMMAS IN

STROKE MEDICINE:NEW
DATA ,UNSOLVED CHALLENGES

Dr SREEDEVE SHAMRITHA
• Antithrombotic therapy remains the cornerstone of secondary
prevention after ischemic stroke or Transient ischemic attack.

• Both antiplatelet and anticoagulant are indicated for ischemic stroke

and in proportion of patients with ICH due to prior indication which
undoubtedly carries risk of bleeding.

• Despite new evidence,uncertainities remain regarding when to start

atithrombotics,here will discuss following situations and indication of
anti thrombotic in those
• 1.ANTITHROMBOTIC MEDICATION IN PATIENTS WITH ICH.

• 2.ANTITHROMBOTIC MEDICATION IN PATIENTS WITH CEREBRAL

MICROBLEEDS.

• 3.ANTITHROMBOTIC STRATEGIES IN PATIENTS WITH INDICATIONS FOR

BOTH ANTICOAGULANT AND ANTITHROMBOTIC TREATMENT.

• 4.ANTICOAGULATION INITIATION AFTER ACUTE AF ASSOCIATED ISCHEMIC

STROKE.

• 5.ANTITHROMBOTIC FAILURE.

• 6.SILENT STROKE AND ASYMPTOMATIC SMALL VESSEL DISEASE.

1.ANTITHROMBOTIC MEDICATION IN
PATIENTS WITH ICH:

• IN general one third of patients with ICH USE ANTI THROMBOTICS,

• Antiplatelets in 15-40%.
• Anticoagulants in 15-25%
• Case fatality in ICH is 40% at 1 month which is substantially higher in
patients on antithrombotic treatment.
• Non vitamin k oral anticoagulants have comparatively lesser incidence
of OAC associated ICH.
• CURRENT EVIDENCE:
• Patients with ICH are prone for DVT and pulmonary embolism.
• Optimal time to initiate anticoagulants prophylactically remains
uncertain.
• Based on cochraine review,based on two small randomised controlled
trails,there was no difference between the treatment groups in
occurrence of DVT or pulmonary embolism between patients who
were started LMWH after 2 days or heparin on day 4 and control
group.

• Datas suggest LMWH started within 48 hours after ICH is safe and did
not cause hematoma expansion
• 1.RESTART TRIAL:
• Antiplatelet therapy after ICH is safe.
• Out of 536 participants with ich on antithrombotics,who were
followed for 3 years-268 patients allotted to antiplatelet theraphy
had similar risk of recurrent ICH as the other 268 who were deferred
antiplatelets.
• Both groups had similar risk of major vascular events.

• 2.SoSTART(START OR STOP ANTICOAGULANTS RANDOMISED TRIAL)

• 203 PARTICIPANTS WHO HAD PREVIOUS SPONTANEOUS
INTRACRANIAL haemorrhage were randomised to start or to avoid
OAC.
• Patients were randomised in 115 days,people were followed up for
1.2 years
• Patients received NOAC
• Participants who were started on OAC had more intracranial
haemorrhage recurrences than those who were stopped.
• In terms of secondary outcomes,OAC are superior than avoiding it.
• Trial lacked stastical significance.
• 3.APACHE-AF(Apixaban after anticoagulation associated ICH IN
PATIENTS WITH AF)
• IN THIS STUDY ,participants allocated to APIXABAN had recurrent ICH
than the group who were not on anticoagulants but had lower risk of
ischemic stroke.
• Based on few other observational studies,survivors of ICH who are
started on OAC had lower risk of ischemic stroke ,but recurrence of
ICH was comparable and was associated with decreased risk of death
and ischemic stroke

• No randomised trials regarding commencing antithrombotics after

ICH .

• Based on Swedish stroke registry,optimal timing of initiation of OAC is

7-8 weeks afterICH for the prevention of stroke or vascular death and
to minimise the risk of severe haemorrhage.
• Of the ongoing trials,A3ich three arm trial which includes LEFT ATRIAL
APPENDAGE OCCLUSION(Advantage of LAAO is that long term anti
thrombotic medication can be avoided.

• But after implantation ,initially dual antiplatelet therapy is needed

which can then be switched to monotheraphy for 6 months.

• In STROKECLOSE (NCT 02830152),LAAO followed by aspirin for 6

months with or without clopidogrel in first 45 days is compared with
OAC,antiplatelet theraphy or no antithrombotic theraphy.
• RECOMMENDATIONS:
• 1.RESTARTING ANTIPLATELETS in patients who have had an ICH is safe
• 2.no clear preference for starting or avoiding OAC IN PATIENTS WITH
AF and previous ICH or IVH
• 3.Ideal to start NOAC than VKA,can be started 7-8 weeks for avoiding
early hemorrhagic events AND PREVENTION OF ISCHEMIC
COMPLICATIONS.
• 4.Role of LAAO remains uncertain in ICH SURVIVORS WITH AF.
• 5.Recruitment to ongoing RCT OF OAC and LAAO is recommended
2.ANTITHROMBOTIC MEDICATIONS IN PATIENTS
WITH CEREBRAL MICROBLEEDS:

• Cerebral microbleeds are small,black rounded lesions seen on MRI scans

sensitive to paramagnetic material

• Microbleeds correspond to small areas of bleeding related to cerebral

small vessels.
• Lobar location has diagnostic accuracy for cerebral amyloid angiopathy.

• Microbleeds are hypothesized to be marker of fragile,bleeding prone

small vessels and associated with increased intracranial bleeding risk
• Recent study have indicated thatmicrobleed improve prediction of
intracranial hemorrhagein patients with previous ischemic stroke or
TIA and MICON-ICH microbleed based score has better accuracy than
other scores.
• Pooled analysis from 38 studies indicated that risk of ischemic stroke
exceeded that of ICH even in patients with 10 or more microbleeds

• Annual rates ICH 2.7%,ISCHEMIC STROKE 6.4%.

• Based on the secondary analyses of PERFORM and NAVIGATE ESUS

TRIAL showed no interaction of microbleeds at baseline with the
treatment results.so therefore microbleed do not benefit or modify
the antithrombotic therapy.
• PICASSO TRIAL(PREVENTION OF CARDIOVASCULAR EVENTS IN
PATIENTS WITH ISCHEMIC STROKE at high risk of cerebral
haemorrhage ) enrolled patients with previous ischemic stroke and
high intracranial bleeding risk(symptomatic ICH,radiological evidence
of previous ICH OR 2 OR MORE CEREBRAL MICROBLEEDS)

• Patients with only microbleeds at baseline,CILOSTAZOLE was

associated with lower risk of ICH than aspirin.
• RESEARCH PRIORITIES:
• With microbleeds newer intervention that lower intracranial bleeding
risk can be made,
• AF using cerebral microbleed,the benefit of using LAAO can be
established.

• NON AF patients –identify patients for trial of antithrombotic agents

like cilostazol.

• Cortical superficial siderosis(CSS) associated with CAA;has high risk of

ICH in patients meeting modified boston criteria.
• RECOMMENDATIONS:

• mIcrobleeds should not precludeuse of antithrombotic agent for

secondary prevention.

• Other coexisting risk factots should be addressed

3.ANTITHROMBOTIC STRATEGIES IN PATIENTS
WITH INDICATIONS FOR BOTH ANTICOAGULANT
AND ANTI THROMBOTIC TREATMENT

• IN AF PATIENTs with associated coronary artery disease,anti

thrombotic management varies between acute and stable clinical
situations.

• AF related stroke PREVENTION requires OAC ,anti platelets to reduce

cardiac ischemia,need to minimise risk of stent thrombosis after
PCI,to reduce bleeding risk of combining anticoagulant and
antiplatelet
• AFIRE TRIAL(atrial fibrillation and ischemic events with RIVAROXABAN
in patients with stable coronary artery disease) compared single
antiplatelet with rivaroxiban to rivaroxiban alone in patients with AF
and stable coronary artery disease.
• Trial was stopped early due to mortality in combined treatment group

• But trial showed non inferiority of rivaroxiban for primary outcome of

stroke,MI,revascularisation and death.

• There is also increased prevalence of carotid stenosis in AF patients

was 12.4% and vice versa(prevalence 4.4-24.3%)
• 1in 10 patients with AF have carotid stenosis has AF and vice versa
• In cases where there is absence of evidence that concomitant antiplatelet
theraphy reduces risk of stroke or major cardiovascual events,EUROPEAN
GUIDELINES RECOMMEND AGAINST ITS USE IN PATIENTS WITH PVD
WITHOUT VASCULAR EVENTS IN LAST TWELVE MONTHS.

• 1.HIGH RISH STABLE ATHEROSCLEROTIC VASCULAR DISEASE without

AF,COMPASS TRIAL,
• 27935 patients were randomised to receive rivaroxiban 2.5 mg bd plus
aspirin 100 mg od,rivaroxiban/aspirin-
• Primary outcome cvs death,stroke or death lower in the combination group
than in single antiplatelet alone
• But combination group had occurrence of major bleeding
• Secondary outcomes-occurrenceof ischemic stroke was lower in combination
group
• Combination therapy also reduced major cardiovascular and
peripheral arterial events as well as stroke

• RESEARCH PRIORITIES:
• Ceratinity of Combination therapy as in COMPASS trial in patients with
vascular disease and AF IS UNCERTAIN.

• EMERGING TECHNIQUES SUCH AS PERCUTANEOUS PERMANENT

CAROTID FILTER(being investigated in CAPTURE TRIAL) are being
carried on.
• RECOMMENDATIONS:
• 1.In patients after an ACS with AF-initial one month period of triple
therapy with OAC,ASPIRIN AND P2Y12 INHIBITOR(clopidogrel)
• After which patient patient is managed with OAC and clopidogrel
• In patients with low risk of thromboembolism and high risk of
bleeding HASBLED score of 3 or more,previous ich with high
recurrence,initial triple therapy can be omitted.

• After the patient is stable,(12 months onwards) with anticoagulant

preferably NOAC
4.ANTICOAGULANT INITIATION AFTER
ACUTE AF ASSOCIATED ISCHEMIC STROKE:
• In the first 2 -4 weeks after AF associated ischemic stroke ,daily risk of
recurrence is 0.5% if untreated

• Should be balanced aginst risk of clinically significant hemorrhagic

transformation 0.4% per day in the first week after stroke which will
be aggrevated by anticoagulation.
• RCT SUGGEST non superiority of anticoagulation started within 48
hours over delayed initiation,with weak evidence of reduction in
ischemic stroke but increased risk of ICH.
• Current guidelines suggest delaying anti coagulation by 2 weeks

• CURRENT EVIDENCE:
• Only study till date on when to initiate anticoagulation with NOAC
after AF ASSOCIATED ISCHEMIC STROKE,TIMING STUDY-888
Participants were randomised to anticoagulation initiation 0-5,5-10
days from stroke and followed up for 90 days,early anticoagulation
was statistically non inferior to delayed anti coagulation.

• In the study,primary outcome of ischemic stroke,ich and mortality

was lower in early anticoagulation but superiority was not
demonstrated.
• No clear data on timing of initiation in patients with mild,moderate
and severe stroke
• Three RCT S are currently recruiting (OPTIMAS,ELAN AND START).

• SEVERAL OBSERVATIONAL STUDIES COMPILED-early anticoagulation

with an NOAC,NOT ASSOCIATED WITH INCREASED RISK OF ICH than
the recurrent ischemic stroke.
• RAF-NOAC study suggested optimal timing of anticoagulation might
lie between 4 and 14 days of onset.

• RESEARCH PRIORITIES:
• 1.CURRENTLY stroke severity and presence of hemorrhagic
transformation on initial imaging-major determinants of
anticoagulation influeneced by European society of cardiology s 1-3-6-
12 rule”

• 2.hemorrhagic transformation on initial imaging delays

anticoagulation-but minor hemorrhagic transformation by ECASS
classification is common after cardioembolic stroke
• Hemorrhagic transformation indicates DIFFUSE LOW PRESSURE BlEEDING
FROM NECROTIC BRAIN TISSUE rather than high pressure bleeding
triggered by reperfusion-which forms parenchymal hematoma (ECASS
PARENCHYMAL HEMATOMA TYPE 2).

• Early anticoagulation initiation insufficient to convert hemorrhagic

infarction to parenchymal hematoma.

• study=-96 pts with baseline hemorrhagic transformation ,started on early

anticoagulation none experienced symptomatic ICH.

• IN raf-noac study,in pts with hemorrhagic transformation delaying

anticoagulation mean of 12 days did not lead to additional ischemic
stroke compared with patients without hemorrhagic transformatio
• RECOMMENDATIONS:
• In centre not participating in RCT,it has been advised tostart
anticoagulation within 5 days for minor stroke with later initiation for
moderate or severe stroke.

• In absence of symptomatic ICH,ANTICOAGULATION CAN BE INITIATED

WITHIN 14 DAYS-PREFERABLY NOAC
5.ANTITHROMBOTIC FAILURE:

• BREAKTHROUGH STROKES(TREATMENT FAILURE)

• Antiplatelet therapy with Aspirin modest risk reduction for recurrent
stroke not related to AF(HOWEVER 20-35% OF PATIENTS WITH
STROKE WERE ON ANTIPLATELETS AT ONSET)
• REASONS FOR STROKE DESPITE ANTIPLATELET THERAPY:
• Insufficient reduction of platelet aggregation by aspirin/antiplatelets
• Underlying etiology –antiplatelets ineffective(AF,ipsilateral high grade
carotid stenosis)
• Assay of platelet functioning-invivo platelet functioning testing
• Testing for genetic polymorphism predisposing for reduced efficacy

• Role of these in guiding treatment is not clear.

• Dual antiplatelet effective in patients with minor stroke or high risk

TIA,recurrence of stroke despite dual antiplatelet found to be
associated with cyp2c19 loss of function allele.

• Anticoagulation is effective in preventing ischemic stroke and systemic

embolism in patients with AF,but despite incidence of stroke 1;1.5%
per year
• STROKE DESPITE ANTICOAGULANT THERAPY:
• 1.STROKE ETIOLOGY(due to large artery arteriosclerosis,small vessel
disease,cervical artery dissection,endocarditis,active malignancy or
other determined origin)

• 2.MEDICATION ERROR(also includes drugs which reduce NOAC plasma

levels-
rifampicin,carbamazepine,phenytoin,phenobarbitone,primidone)

• 3.CARDIOEMBOLISM DESPITE ANTICOAGULATION.

• Stroke despite anticoagulant therapy are at risk of having another
stroke,rate 0f 8.9%per year,neither changing the anticoagualation or
continuing the same reduced the risk.
• RESEARCH PRIORITIES:

• Optimal secondary prevention after stroke despite anti coagulation

remains unclear.

• Further studies should focus on other treatment option-LAAO,LAOS-III

TRIAL-found that LAAO with anticoagulation reduced ischemic
• Recommendations:
• Recurrence despite treatment-evaluvation of underlying cause

• Short term dual antiplatelet therapy.

• Platelet functioning assayfeentic function assays

6.SILENT STROKE AND ASYMPTOMATIC
SMALL VESSEL DISEASE:
• Evidence shows that presence of brain infarcts,high white mater
intensities and microbleeds-associated with higher risk of future
stroke independent of other risk factors.

• Pathophysiology of silent cva is less certain than for symptomatic

stroke
• Elderly-most common cause are lacunes,pathophysiology of silent
lacunes are different from symptomatic lacunar infarction
• Pathophysiology of WMH are not clear,few evidences pointing to
elevated brain permeability

• Two trials of warfarin and aspirin found that antithrombotic treatment

increased risk of ich in patients with WMH(HIGH wmh BURDEN MAY
HAVE AN UNDERLYING VASCULOPATHY)

• WMH are associated with higher risks of future ICH as well as ischemic
stroke.

• Guidelines do not recommend use of aspirin for primary

prevention,only recommended in higher risk patients based on cardiac
profile ,age grearter than 70
• RECOMMENDATIONS:

• ACC TO AMERICAN HEART ASSOCIATION,patients with silent brain

infarcts and high WMH should be considered high risk for stroke
without specific recommendation on Aspirin.

• Canadian dementia guidelines-against aspirin for high WMH without

brain infarction,but weakly recommends aspirin in patients with CI
and silent brain infarcts

• EUROPEAN STROKE ORGANISATION-recommends use of aspirin with

silent cerebral small vessel disease
• Generally aspirin not recommended to be used in patients with silent
cva,unless h/o TIA/ischemic stroke or MI

• In non embolic patern of infarction ,aspirin can be used if there is an

embolic pattern of infarction or evidence if atherosclerosis is the
cause