Anticoagulation in stroke

Acute stroke treatment

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Background

Anticoagulation is the controlled therapeutic inhibition of
blood coagulation by means of appropriate drugs (ie,
anticoagulants).

The role of anticoagulants in the treatment of cerebral

ischemia still is evolving.

No single treatment has proved effective against all

forms of brain ischemia,

including heparin, heparin analogues, and warfarin.

In the past decade, RCT have helped to define patients

who would potentially benefit from anticoagulation
therapy, despite the possible hemorrhagic complications.

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Early anticoagulation after stroke

Unfractionated heparin

In the past decade, no randomized studies have been performed
to evaluate early intravenous (IV) anticoagulation with
unfractionated heparin (UFH).

Authors disagree about:

The best level of anticoagulation

Route of administration

Timing and duration of treatment

Use of bolus dose

Dependency on severity of neurological deficits, or

Size of infarction on baseline computed tomography (CT)

Influence of either vascular distribution or presumed cause of
stroke.

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Indications currently proposed by many experts for
early full-dose IV heparin (UFH) after stroke or
transient ischemic attack (TIA) are as follows

High risk of cardiogenic re-embolization

 Atrial fibrillation with proven intracardiac thrombus on
echocardiography
 Artificial valves
 Left atrial or ventricular thrombi
 Myocardial infarction during the last 4 weeks

Symptomatic dissection of arteries supplying the brain

(after exclusion of subarachnoid hemorrhage on CT
scan)

Symptomatic stenosis of the extracranial internal carotid

artery prior to short-term operation (otherwise, a platelet
antiaggregant should be given)
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Symptomatic extracranial or intracranial arteriosclerotic
stenosis with crescendo-TIAs or early progressive stroke

Thrombosis of basilar artery: IV heparin usually is started

before intra-arterial fibrinolytic therapy.

Coagulopathies with hypercoagulability

 Protein C and S deficiencies,
 Activated protein C [APC] resistance
 Antithrombin deficiency
 Relevant titer of antiphospholipid antibodies

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Venous sinus thrombosis, even if associated with
cerebral hemorrhage

Patients with acute cerebral ischemia who received

systemic fibrinolytic therapy with recombinant tissue
plasminogen activator (rt-PA) IV should not be started on
anticoagulation therapy for at least 24 hours.

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Heparin analogues

Several randomized controlled trials that used

 Heparinoids, IV
 Subcutaneous low-molecular-weight heparin (LMWH),
 Subcutaneous heparin early after ischemic stroke

Failed to show a significant overall benefit of treatment.

 An exception might be early IV administration of the

LMWH danaparoid to patients with acute ischemic stroke
ipsilateral to a severe stenosis or occlusion of the internal
carotid artery in the TOAST trial

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On the basis of the current evidence, LMWH should not
be used routinely in stroke management.
 LMWH (in a body-weight–adapted dose) could be

used because of lower bleeding risk (not evidence

based).

 If early anticoagulation after ischemic stroke is

indicated but UFH is contraindicated because of
 Large brain infarctions,
 Hemorrhagic infarctions,
 Pronounced microangiopathic changes in the brain

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In patients with acute IS and AF, a controlled
randomized study (Heparin in Acute Embolic Stroke Trial
[HAEST]) failed to show
 The superiority of LMWH (dalteparin 100 IU/kg subcut. bid)
to aspirin (160 mg/d).

On the basis of current evidence, patients with acute IS

& AF should be treated with aspirin in the acute phase
(and then placed on anticoagulation).

A small pilot study found bridging LMWH (Enoxaparin 1

mg/kg subcutaneously bid) to be safer than bridging IV
application of UFH while awaiting therapeutic oral
anticoagulant levels in patients with acute or subacute
cerebral ischemia.

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Anticoagulation for stroke prevention
Atrial fibrillation

Maintaining rate verses sinus rhythm

Patients with atrial fibrillation (AF) have a stroke risk of 4.5% per
year,

Which is reduced by anticoagulation to 1.4% per year (70% relative
risk reduction with warfarin therapy).

Patients with additional risk factors: have an increased stroke risk of

at least 8% per year.

Age >75 years

Recent stroke or TIA

Systemic embolism

Hypertension

Congestive heart failure

Diabetes)

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Oral anticoagulation (ie, target INR 2.5, range
2-3) is the therapy of choice for primary and
secondary stroke prevention in patients with
AF and any of the additional risk factors
already described.

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 Asymptomatic patients with AF and none of the other risk factors

Age younger than 65 years with AF are at a low risk and should be
either treated with aspirin or not treated.

Aged 65-74 years are at moderate risk and could be treated with
warfarin (target INR 2.5, range 2-3) or aspirin 300 mg/day (not
evidence based).

Older than 75 years, a lower target INR of 2 (range 1.6-2.5) may be

accepted to decrease the risk of hemorrhage.

However, this lower INR level has not been established and some
authorities disregard age and accept a higher INR target of 2.5.

Patients older than 80 years with AF , aspirin (325 mg/d) might be

preferable to long-term anticoagulation because it carries less risk of
bleeding (not evidence based).

An individual decision based on the pts. risk profile should be made

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Long-term anticoagulation should not be used in patients with
an increased risk of bleeding, such as those:

With poor compliance,
Rretinopathy with bleeding

Uncontrollable hypertension

Aortic dissection,

Bacterial endocarditis,

Alcohol dependency,

Lliver disease,

Bleeding lesions,

Malignant tumor,
risk,

Advanced microvascular
changes in the brain

Known aneurysm of a
cerebral artery,

Previous spontaneous
cerebral hemorrhage,

Or tendency to bleeding
(eg, coagulopathies,
thrombocytopenia).

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In these cases, aspirin (325 mg/d) may be favorable as a long-
term treatment.

In the near future,direct thrombin inhibitors may become an

alternative to warfarin.

Pilot studies indicate higher safety and efficacy of the oral direct
thrombin inhibitor Ximelagatran when compared to warfarin for
prevention of thromboembolism in AF patients

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 Acute myocardial infarction

Patients with acute myocardial infarction (MI) have a general
cardioembolic stroke risk of approximately 2% during the first 4 weeks.

This risk is increased to 15% in patients with acute MI and LV thrombus.

Anticoagulation (target INR 2.5, range 2-3) for primary stroke prevention
is recommended in the following situations:

Patients who have had an MI with persistent AF

Patients with left ventricular thrombus

Patients with left ventricular aneurysm

Patients who have had MI with extensive wall motion abnormalities

resulting in decreased left ventricular ejection fraction of less than 25%

The optimal duration of anticoagulation in these patients is debatable..

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Other heart diseases
Absolute indications for oral anticoagulation (primary and secondary
stroke prevention) include the following:

Mechanical heart valve ( INR depending on type and location of

valve, mostly 3.5, range 3-4.5)

Mitral valve stenosis with any prior embolic event ( INR 2.5, R- 2-3)

Left atrial myxoma (INR 2.5, range 2-3)

Intraventricular thrombus (INR 2.5, range 2-3)

Dilated cardiomyopathy ( INR 2.5, range 2-3)

Ventricular aneurysm with thrombus ( INR 2.5, range 2-3)

Mobile thrombus in the ascending aorta (INR 2.5, range 2-3)

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Indications for oral anticoagulation after stroke only (ie, secondary
stroke prevention) include the following:

Large PFO with spontaneous right-to-left shunting, especially when

associated with atrial septal aneurysm (target INR 2.5, range 2-3)

As an alternative, operative or transcatheter occlusion may be

considered [not evidence based].

In case of small PFO, Aspirin 300 mg/d is sufficient.

Mitral valve prolapse with myxomatous leaflets (target INR 2.5,

range 2-3) - Not evidence based

Rupture of chordae tendineae (target INR 2.5, range 2-3)

Dyskinetic ventricular wall segment (target INR 2.5, range 2-3)

Mitral ring calcifications (target INR 2.5, range 2-3)

The etiology of the ischemic stroke should be confirmed as cardiogenic; other
possible causes should be excluded
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Dissections of internal carotid and vertebral arteries

The majority (85-95%) of ischemic symptoms are caused
by emboli from the site of the dissection

While 5-15% are due to vessel narrowing with

hemodynamic insufficiency.

Heparin IV in the acute phase and subsequent oral

anticoagulation for 3-24 months (target INR 2.5, range 2-
3) followed by antiplatelet agents for at least 2 years.
[Expert recommendation]

Only in rare cases an operation or stenting may be

considered.[ eg, with persistent high-grade proximal
stenosis of the internal carotid artery or with severe
hemodynamic impairment]

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No evidence of a higher embolic activity of pseudo-
aneurysms due to dissection exists.

Only in selected cases, continuation of anticoagulation or

interventional therapy may be preferable.

Anticoagulation is contraindicated in intracranial

dissections complicated by subarachnoid hemorrhage.

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Symptomatic stenoses of extracranial and
intracranial arteries

No current evidence-based guidelines address

anticoagulation in these patients.

Oral anticoagulation (target INR 3-4.5) was

compared with aspirin (30 mg/d) in patients with TIA
or minor ischemic stroke of presumed arterial origin
in the Stroke Prevention in Reversible Ischemia Trial
(SPIRIT).

 The trial was stopped after the first interim analysis

because of increased major bleeding complications in the
anticoagulant group.
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The Warfarin-Antiplatelet Recurrent Stroke Study
(WARSS) compared oral anticoagulation (target INR 1.4-
2.8) with ASS (325 mg/d).

 Failed to show any superiority of warfarin over aspirin;

 In fact, trends toward aspirin's superior efficacy were seen
in all but the "cryptogenic" stroke group.

Whether oral anticoagulation with an INR target range of

2-3 is superior to aspirin in treating patients after
nondisabling cerebral ischemia of arterial origin is being
assessed in the European/Australian Stroke Prevention
in Reversible Ischaemia Trial (ESPRIT).

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The Warfarin-Aspirin Symptomatic Intracranial Disease (WASID)
trial compared the efficacy of warfarin with an INR target range of
2-3 and aspirin (1300 mg/d) in patients with symptomatic
stenosis (50-99%) of a major intracranial artery. [NEJM, March
2005.]

Enrollment was stopped because of concerns about the safety of

the patients who had been assigned to receive warfarin.

Whereas there was no difference in the primary end point

(ischemic stroke, brain hemorrhage, or death from vascular
causes other than stroke)

Warfarin was associated with significantly higher rates of adverse

events (death, major hemorrhage, and myocardial infarction or
sudden death).

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As a consequence of this study, warfarin can not be
recommended for first-line use in patients with
intracranial arterial stenosis.

Aspirin (or other antithrombotic drugs) should be

preferred.

However, a few retrospective studies suggest that

anticoagulation might be efficacious in the following
specific situations:
1. Mobile aortic atheroma
2. Basilar artery dolichoectasia

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Venous sinus thrombosis

Those treated with full-dose heparin had better outcomes than those
treated with placebo. [Small trials]

After improvement under heparin therapy, patients usually are

switched to oral anticoagulation (target INR 2.5, (2-3).

The optimal duration has not been determined in randomized

studies.[ Oral anticoagulation is recommended for at least 6 months.]

It is unclear whether the decision to stop anticoagulation should be

based on the result of control (MRA or conventional angiography)
after 6 months.

In a recent study of 33 patients placed on anticoagulation,

recanalization occurred only within the first 4 months, but not
thereafter.

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Thrombophilia

In patients younger than 40 years of age with cerebral ischemia of

unknown origin, a search for hereditary thrombophilia is generally
recommended.

Oral anticoagulation after cerebral ischemia is usually recommended in

the following cases:

Antithrombin III deficiency (target INR 2.5, range 2-3) (Antithrombin III
concentrates for acute intervention or LMWH)

Protein C deficiency (target INR 3, range 3-3.5); alternatively fixed, low-

dose SC UFH or LMWH

Protein S deficiency (target INR 2.5, range 2-3); alternatively fixed, low-
dose SC UFH or LMWH

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APC resistance (target INR 2.5, range 2-3); alternatively fixed,
low-dose SC UFH or LMWH

Plasminogen deficiency/inhibition (target INR 2.5, range 2-3);

alternatively fixed, low-dose SC UFH or LMWH

Dysfibrinogenemia (target INR 2.5, range 2-3); alternatively fixed,

low-dose SC UFH or LMWH

High titers of anticardiolipin antibodies (target INR 3, range 2.5-
3.5)

After a single event of thrombosis or thromboembolism,
anticoagulation should be continued for at least 6 months.

After recurrent or life-threatening thrombosis or in case of
combination of different thrombophilias, lifelong anticoagulation is
usually recommended.

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