Online newspaper of professor Yasser Metwally

The author: Professor Yasser Metwally

http://yassermetwally.com

INTRODUCTION

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, randomized, controlled studies have helped to define patients who would potentially benefit from anticoagulation therapy, despite the possible hemorrhagic complications.

Several new oral anticoagulant medications, including ximelagatran, are in the final stages of clinical trials for use in the prophylaxis of ischemic thromboembolic stroke. Once approved for use, the potential of such drugs in the arena of stroke treatment is significant.

TREATMENT

Medical Care:

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), and 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 (eg, atrial fibrillation with proven intracardial 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. Alternatively, anticoagulation could be started afterwards if intra-arterial thrombolysis or balloon angioplasty can be performed quickly after admission of the patient.

• Coagulopathies with hypercoagulability (eg, 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: Several small studies have demonstrated that patients treated with full-dose heparin have better outcomes than those treated with placebo.

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.

Conclusive data are lacking about the management of anticoagulation in patients with hemorrhagic conversion of ischemic brain infarction or with primary cerebral hemorrhage under oral anticoagulation. Small retrospective studies of patients with urgent need of anticoagulation (eg, with artificial heart valves) showed a better outcome of those treated with full-dose IV heparin (only after normalization of international normalized ratio [INR] values by administration of prothrombin complex and/or other warfarin antagonists) than in those treated with low-dose subcutaneous heparin.

In cases without such an urgent need for anticoagulation, full-dose heparin is often switched to subcutaneous heparin in a body-weight adapted dose after hemorrhagic conversion of a primary ischemic stroke (not evidence-based).

• Heparin analogues

Several randomized controlled trials that used IV heparinoids, subcutaneous low-molecular-weight heparin (LMWH), or 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, who appeared to benefit, but patient numbers in this analysis were small, and further research is needed to test this finding. On the basis of the current evidence, LMWH should not be used routinely in stroke management.

If early anticoagulation after ischemic stroke is indicated but UFH is contraindicated because of large brain infarctions, hemorrhagic infarctions, or pronounced microangiopathic changes in the brain, LMWH (in a body-weight–adapted dose) could be used because of lower bleeding risk (not evidence based).

In patients with acute ischemic stroke and atrial fibrillation, a controlled randomized study (Heparin in Acute Embolic Stroke Trial [HAEST]) failed to show the superiority of LMWH (dalteparin 100 IU/kg subcutaneously bid) to aspirin (160 mg/d). On the basis of current evidence, patients with acute ischemic stroke and atrial fibrillation 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. Further studies are needed to test this finding before this approach can be recommended generally.

Anticoagulation for stroke prevention

• Atrial fibrillation

Two randomized controlled trials have demonstrated that a strategy aimed at restoring (and maintaining) sinus rhythm neither improves the survival rate nor reduces the risk of stroke. In the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study, 4060 patients aged 65 years or older whose atrial fibrillation was likely to be recurrent, and who were at risk for stroke, were randomized to a strategy of rhythm control (cardioversion to sinus rhythm, plus one or more drugs to maintain sinus rhythm) versus a strategy of rate control (in which no attempt was made to restore or maintain normal sinus rhythm).

An insignificant trend toward increased mortality was noted in the rate-control group, and, importantly, no evidence suggested that the rhythm-control strategy protected patients from stroke. The AFFIRM study (and similar findings from the smaller Rate Control Versus Electrical Cardioversion [RACE] trial) has led to the development of consensus guidelines advocating a rate-control strategy for most atrial fibrillation patients.

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 (eg, age 75 years, recent stroke or TIA, systemic embolism, hypertension, congestive heart failure, or diabetes) have an increased stroke risk of at least 8% per year.

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 younger than 65 years with AF and none of the other risk factors are at a low risk and should be either treated with aspirin or not treated. Asymptomatic patients aged 65-74 years with AF and none of the other risk factors 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).

For asymptomatic patients older than 75 years with AF and none of the other risk factors, 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.

For asymptomatic patients older than 80 years with AF and none of the other risk factors, 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 patients 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, liver disease, bleeding lesions, malignant tumor, retinopathy 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 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.

Stroke Prevention Using Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) III and V trials were trials performed in Europe (SPORTIF III) and in North America (SPORTIF V). Both were noninferiority trials. By definition, noninferiority trials intend to show that an experimental treatment (ximelagatran) does not produce worse results than those of a known active control (warfarin) by a specified margin (2% per year).

SPORTIF III was reported in the Lancet in November 2003. It was a phase 3, multicenter, randomized, controlled clinical trial that compared warfarin to ximelagatran in the treatment of 3410 patients with AF and one or more stroke factors. The primary endpoint was stroke or systemic embolism. The primary event rate by intention to treat was 2.3% per year for warfarin and 1.6% for ximelagatran (absolute risk reduction, 0.7%; relative risk reduction, 29%). Rates of disabling or fatal stroke, mortality, and major bleeding were similar, but the rate of combined minor and major hemorrhages was 29.8% per year for warfarin and 25.8% for ximelagatran (relative risk reduction, 14%; P = .007). Raised serum alanine transferase levels were more commonly observed in the ximelagatran group.

SPORTIF V was reported in the American Heart Journal in September 2003 and at the American Heart Association Scientific Sessions in November 2003. This study included a double-blind treatment allocation with 3922 patients. Again, the primary endpoints were strokes and systemic embolic events with a noninferiority treatment objective compared to warfarin. The study commenced in July 2000 and enrollment ended in December 2001. Data analysis was extensive and included safety monitoring. The primary event rate by intention to treat was 1.2% per year for warfarin and 1.6% for ximelagatran. The ximelagatran rate was identical in the two studies, whereas the rate for warfarin in SPORTIF V was half that noted in SPORTIF III. The reasons for this difference in the warfarin groups continue to be evaluated.

In both studies, the rates of intracranial and/or other major bleeding events were insignificant. However, when the event rates for major and minor bleeding are combined, ximelagatran was significantly better than warfarin

Therapeutic alternatives to oral long-term anticoagulation include the following:

• Pharmacologic or nonpharmacologic restoration and maintenance of sinus rhythm (AF patients should receive oral anticoagulation 3 wks prior to electrical or chemical conversion and at least 4 weeks thereafter; when AF duration

• In selected cases, left atrial appendectomy or transcatheter occlusion (Studies on long-term safety and efficacy are warranted.)

• 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 left ventricular 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 (Usefulness is less well established for anticoagulation in post-MI patients with paroxysmal AF, but opinion is in favor of it.)

• 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. A meta-analysis of studies published between 1960 and July 1999 showed that two thirds of patients with coronary artery disease were treated with oral anticoagulation for longer than 2 years. Usually, administering oral anticoagulation according to the indications already listed is recommended as long as the causing condition persists and no contraindications emerge.

• Other heart diseases

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

• Mechanical heart valve (target INR depending on type and location of valve, mostly 3.5, range 3-4.5)

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

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

• Intraventricular thrombus (target INR 2.5, range 2-3)

• Dilated cardiomyopathy (target INR 2.5, range 2-3)

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

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

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

• Large patent foramen ovale (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 after dissection of brain-supplying arteries are caused by emboli from the site of the dissection, while the remaining ones are due to vessel narrowing with hemodynamic insufficiency. Many experts recommend anticoagulation with IV heparin 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. No randomized trials have been performed to determine optimal treatment, but the practice of anticoagulation is supported by several published case series demonstrating good outcome with low complication rates in patients undergoing anticoagulation.

Only in rare cases (eg, with persistent high-grade proximal stenosis of the internal carotid artery or with severe hemodynamic impairment), an operation or stenting may be considered. No evidence of a higher embolic activity of pseudo-aneurysms due to dissection exists; after oral anticoagulation for 3-6 months, a platelet antiaggregant is sufficient in most cases. 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 1.4-2.8) with ASS (325 mg/d) and 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 compares 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. This trial was recently stopped. The data are being analyzed, and results will be presented in February 2004.

Until the results of ongoing studies are available, no evidence from randomized studies supports oral anticoagulation after ischemic stroke of arterial origin; 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

Several smaller studies demonstrated that, of patients with venous sinus thrombosis, those treated with full-dose heparin had better outcomes than those treated with placebo. After improvement under heparin therapy, patients usually are switched to oral anticoagulation (target INR 2.5, range 2-3).

Although 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 angiography (magnetic resonance 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. Patients with thrombophilia should receive lifelong anticoagulation.

• 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

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

  • Prospective studies are ongoing to determine the optimal intensity of anticoagulation.

  • Retrospective studies showed superiority of INR greater than 2 over INR less than 2, and superiority of INR greater than 3 over INR less than 3, with or without aspirin; but it is unclear whether the benefit of higher INR exceeds the higher bleeding risk.

  • Because the Lupus-anticoagulans may interfere with INR determination, monitoring these patients using the prothrombin-proconvertin time and the chromogenic factor-X assay would be preferable, but these tests are expensive and not widely available. Therefore, some experts prefer long-term therapy with 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

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.

• Anticoagulation prior to the occurrence of stroke

Indications for anticoagulation for primary prevention of cardioembolic stroke (ie, prior to the occurrence of stroke) are summarized below.

• Atrial fibrillation (AF) if one or more of the following high risk factors is present: Age greater than 75 years, prior systemic embolism, arterial hypertension, diabetes mellitus, or congestive heart failure/heart disease with decreased left ventricular ejection fraction (EF) of 25% or less (target INR 2.5, range 2-3).

• Acute myocardial infarction if one or more of the following high risk situations is present: Persistent AF, left ventricular thrombus, left ventricular aneurysm, extensive wall motion abnormalities resulting in decreased left ventricular EF or 25% or less (target INR 2.5, range 2-3).

• Mechanical heart valve (target INR depending on type and location of valve, mostly 3.5, range 3-4.5)

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

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

• Intraventricular thrombus (target INR 2.5, range 2-3)

• Dilated cardiomyopathy (target INR 2.5, range 2-3)

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

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

MEDICATION

Anticoagulants used as treatment after ischemic stroke are heparin, heparin analogues, and vitamin K antagonists (eg, warfarin). They prevent intracardial and intravascular thrombogenesis and reduce the frequency of thromboemboli. Dose-adjusted warfarin significantly reduces levels of fibrin D-dimer and fibrinogen. Anticoagulation additionally supports restoration of arterial intima and decreases intimal thickening.

Drug Category: Anticoagulants — Conventional UFH and LMWHs are used. Conventional UFH activates antithrombin III, thereby inhibiting thrombin and, to a lesser extent, activated factor X (factor Xa).

LMWHs are derived enzymatically or chemically from UFH. LMWHs preferentially inhibit factor Xa rather than thrombin. Compared to UFH, LMWHs have a higher bioavailability, longer half-life, and reduced protein binding; they also have dose-independent clearance. LMWHs have less antiplatelet activity and cause less bleeding than UFH. LMWHs also cause less heparin-induced thrombocytopenia and osteoporosis.

For anticoagulation, UFH is given IV with monitoring of activated partial thromboplastin time (aPTT). aPTT of 1.5-2 times control value is therapeutic. Contraindications include large brain infarctions, uncontrollable arterial hypertension, and pronounced microangiopathic changes in the brain. LMWHs are given subcutaneously in a body-weight–adapted dose once or twice daily without monitoring.

Vitamin K antagonists interfere with hepatic vitamin K-dependent carboxylation, thereby inhibiting synthesis of coagulation factors II, VII, IX, and X. Vitamin K antagonists are administered orally with monitoring, preferably of the INR or, if the INR is unavailable, prothrombin time (PT), which normally increases in 2-3 days. An INR of 1.5-4 is therapeutic, the exact target range depending on the indication.

Protein C and, to a lesser extent, protein S, 2 major inhibitors of the procoagulant system, are also vitamin-K–dependent proteins. The half-life of protein C is considerably shorter (approximately 6-7 h) than those of factors II, IX, and X; therefore, warfarin therapy carries the potential for procoagulant activity in the first 24-48 h. Therefore, giving heparin simultaneously during the initial days of oral anticoagulation often is recommended in any patient in whom protein C or protein S deficiency is known or suspected.

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