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Acute stroke treatment
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.
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.
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)
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
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.
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
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
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.
Anticoagulation for stroke prevention
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)
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.
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
Long-term anticoagulation should not be used in patients with an increased risk of bleeding, such as those:
With poor compliance, Uncontrollable hypertension Aortic dissection, Bacterial endocarditis, Alcohol dependency, Lliver disease, Bleeding lesions, Malignant tumor, Rretinopathy with bleeding risk, Advanced microvascular changes in the brain Known aneurysm of a cerebral artery, Previous spontaneous cerebral hemorrhage, Or tendency to bleeding (eg, coagulopathies, thrombocytopenia).
In these cases, aspirin (325 mg/d) may be favorable as a longterm 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
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..
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)
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
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 23) 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]
No evidence of a higher embolic activity of pseudoaneurysms 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.
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.
The Warfarin-Antiplatelet Recurrent Stroke Study (WARSS) compared oral anticoagulation (target INR 1.42.8) 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).
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).
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: Mobile aortic atheroma Basilar artery dolichoectasia
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.
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, lowdose SC UFH or LMWH Protein S deficiency (target INR 2.5, range 2-3); alternatively fixed, lowdose SC UFH or LMWH
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 2.53.5) 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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