eMedicine Specialties > Neurology > Neuro-vascular Diseases

Stroke Anticoagulation and Prophylaxis

Uwe Walter, MD, PhD, Associate Professor, Department of Neurology, University Hospital of Rostock, Germany; Director Neurological Intensive Care Unit and Stroke Unit, Head of Neurosonological Lab

Updated: Sep 6, 2009

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 is still 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 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.

Differential Diagnoses

Other Problems to Be Considered

Atrial fibrillation
Carotid disease and stroke

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 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 patients 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; this practice is not, however, 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.¹ 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).² 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.³ 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).⁴

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] trial⁵ ) has led to the development of consensus guidelines advocating a rate-control strategy for most atrial fibrillation patients.⁶

Patients with atrial fibrillation (AF) have a stroke risk of 4.5% per year, which anticoagulation reduces 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, according to guidelines from the American College of Cardiology, American Heart Association, European Society of Cardiology.⁶

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.

The choice of warfarin versus aspirin for prophylaxis in older patients was addressed in the Birmingham Atrial Fibrillation Treatment of the Aged Study (BAFTA). In this study, 973 patients 75 years of age or older (mean age, 81.5 years) were randomized to receive warfarin to an INR of 2–3 or aspirin, 75 mg/d; follow-up was for a mean of 2.7 years. Compared with aspirin, warfarin reduced the risk of major stroke, arterial embolism, or other intracranial hemorrhage  (yearly risk 1.8% vs 3.8%, relative risk 0.48, 95% CI 0.28-0.80, p=0.003; absolute yearly risk reduction 2%, 95% CI 0.7-3.2).⁷

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.

Other agents 

In the near future, direct thrombin inhibitors may become an alternative to warfarin. The first agent in this category, the oral direct thrombin inhibitor ximelagatran, was compared with warfarin for prevention of thromboembolism in AF patients in the 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).^8,9 Pooled analysis of SPORTIF III and V trials showed that ximelagatran was at least as effective as warfarin for the secondary and primary prevention of stroke, with significantly lower rates of bleeding events.

Ximelagatran is in use in several European countries; however, it has not been approved for stroke prevention in AF by the US Food and Drug Administration (FDA) due to the risk of severe liver toxicity. The FDA identified 3 patients whose death from liver failure was associated with ximelagatran use in the studies and estimated a 0.5% rate of severe hepatic injury among long-time users and a 0.05% rate of liver failure, need for liver transplantation, or death.

Proposed risk minimization plans need to be assessed in further studies. If the issue of hepatic injury can be resolved, ximelagatran will be a promising treatment option, especially for patients at high risk for intracranial hemorrhage or for those with a low quality of life with warfarin. Other direct thrombin inhibitors are under study, as well.¹⁰

The prospective, randomized Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W) trial compared oral anticoagulation therapy (INR target range 2-3; n = 3371) with clopidogrel (75 mg/d) plus aspirin (75-100 mg/d recommended; n = 3335) in patients with atrial fibrillation who had 1 or more risk factors for stroke. Primary outcome was first occurrence of stroke, non-CNS systemic embolus, myocardial infarction, or vascular death. The ACTIVE W study was stopped early because of clear evidence of superiority of oral anticoagulation therapy.¹¹

Other antithrombotic agents are under development as alternatives to warfarin, but sufficient data are not yet available to justify their clinical use in patients with AF.

Alternatives to long-term anticoagulation 

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 <48 hours or intracardial thrombus excluded on echocardiography, conversion can be performed immediately after placing the patient on IV heparin.)
• 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.¹² 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 3.0, range 2.5-3.5)
  • 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) in case of (1) recurrent cerebral ischemia while the patient was receiving aspirin 300 mg/d, (2) co-occurrence with atrial septal aneurysm, or (3) co-occurrence with deep venous thrombosis of the leg or abdomen (target INR 2.5, range 2-3, duration usually 2 years or longer) (As an alternative, operative or transcatheter occlusion may be considered [not evidence based]. In case of PFO without atrial septal aneurysm, 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.
• In patients with aortic atheromas identified on echocardiography, the ideal strategy for stroke prevention remains uncertain. Mixed outcomes have been reported for anticoagulation therapy; plaque stabilization with statins appears promising; neither approach has been tested in randomized controlled trials.¹³

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.¹⁴

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.¹⁵

The European/Australian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) assessed 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.¹⁶ This trial was prematurely ended because ESPRIT had previously reported that the combination of aspirin and dipyridamole was more effective than aspirin alone. Mean follow-up was 4.6 years, and the mean achieved INR in the patients on anticoagulants was 2.57. While no difference was reported in the primary end point (composite of death from all vascular causes, nonfatal stroke, nonfatal myocardial infarction, or major bleeding complication, whichever occurred first), the rate of major bleeding complications was significantly higher in the anticoagulation group.

As a conclusion from this study, oral anticoagulants (target INR 2.5, range 2-3) are not more effective than aspirin (or aspirin in combination with dipyridamole) for secondary prevention after TIA or minor stroke of arterial origin.

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.¹⁷ After 569 patients had been randomized, 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) between the warfarin group and the aspirin group, 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 cannot be recommended for first-line use in patients with intracranial arterial stenosis. Aspirin (or other antithrombotic drugs) should be preferred.

A systematic review of controlled studies found no evidence of benefit from prolonged anticoagulation therapy in patients who have experienced presumed non-cardioembolic ischemic stroke or TIA; rather, anticoagulation increased the risk of fatal intracranial hemorrhage (odds ratio [OR] 2.54, 95% confidence index [CI] 1.19 to 5.45) and of major extracranial hemorrhage (OR 3.43, 95% CI 1.94 to 6.08).¹¹ The reviewers noted that this is equivalent to anticoagulation causing about 11 additional fatal intracranial hemorrhages and 25 additional major extracranial hemorrhages per year for every 1000 patients treated.

Nevertheless, a few retrospective studies suggest that anticoagulation might be effective in patients with basilar artery dolichoectasia.

Guidelines for secondary prevention 

Current recommendations from the American Heart Association/American Stroke Association (AHA/ASA) for prevention of stroke in patients who have experienced noncardioembolic ischemic stroke or TIA are as follows¹⁸ :

• Class I recommendations:
  • Antiplatelet agents rather than oral anticoagulation are recommended to reduce the risk of recurrent stroke and other cardiovascular events (Class I, level of Evidence A).
    • Aspirin (50 to 325 mg/d) monotherapy, the combination of aspirin and extended-release dipyridamole, and clopidogrel monotherapy are all acceptable options for initial therapy (IA).*
    • The combination of aspirin and extended-release dipyridamole is recommended over aspirin alone (IB).
• Class II Recommendations
  • Clopidogrel may be considered over aspirin alone (IIbB).
  • Clopidogrel is reasonable for patients allergic to aspirin (IIaB).
• Class III Recommendation
  • The addition of aspirin to clopidogrel increases the risk of hemorrhage; therefore, combination therapy with aspirin and clopidogrel is not routinely recommended unless patients have a specific indication for this therapy (ie, coronary stent or acute coronary syndrome)(I).

*For patients who have an ischemic cerebrovascular event while taking aspirin, there is no evidence that increasing the dose of aspirin provides additional benefit.

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 in the following situations: (1) recurrent thrombosis, (2) combination of different inherited causes of thrombophilia, or (3) life-threatening thrombosis.

Thrombophilia

In patients with cerebral ischemia of unknown origin who are younger than 40 years, a search for hereditary thrombophilia is generally recommended. Oral anticoagulation after cerebral ischemia is usually 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
• 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 3.0, range 2.5-3.5)
• 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.

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.

Substances used are warfarin (Coumadin) and in some countries other than the United States, phenprocoumon (Marcumar, Falithrom). Contraindications include large brain infarctions, uncontrollable arterial hypertension, pronounced microangiopathic changes in the brain, known aneurysm of a cerebral artery, previous spontaneous cerebral bleeding, retinopathy with bleeding risk, active bleedings, hemophilia, aortic dissection, bacterial endocarditis, and malignant tumor.

Heparin sodium

Potentiates antithrombin III activity. Does not actively lyse but is able to inhibit further thrombogenesis. Prevents reaccumulation of clot after spontaneous fibrinolysis. aPTT of 1.5-2 times control value (50-80 s) is therapeutic.
Some experts do not use loading dose, beginning with continuous infusion. This policy derives from an anecdotal case of intracerebral hemorrhage in a patient given bolus heparin for embolic stroke.

Dosing

Adult

80 U/kg IV loading dose; follow with infusion of 25,000 U in 250 mL D5W (100 U/mL) and start at 18 U/kg/h; adjust dose based on aPTT results; some ED, especially those with many older patients, use regimen of 70 U/kg loading dose and 15 U/kg/h continuous infusion

Pediatric

50 U/kg/h IV loading dose; follow with 25 U/kg/h infusion

Interactions

Digoxin, tetracycline, nicotine, and antihistamines may decrease effects; NSAIDs, aspirin, dipyridamole, dextran, and hydroxychloroquine may increase toxicity

Contraindications

Documented hypersensitivity; subacute bacterial endocarditis; active bleeding; history of heparin-induced thrombocytopenia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Perform head CT scan to exclude hemorrhage; use with caution in trauma patients; increased risk of cerebral hemorrhage in patients with very large brain infarction, severe leukoencephalopathy from microangiopathy, or uncontrolled hypertension
Some preparations contain benzyl alcohol as preservative; benzyl alcohol used in large amounts has been associated with fetal toxicity (ie, gasping syndrome); use of preservative-free heparin recommended in neonates; use caution in shock or severe hypotension

Warfarin sodium (Coumadin)

Interferes with hepatic vitamin K–dependent carboxylation; used for prophylaxis and treatment of thromboembolic disorders; PT usually increases in 48 h.

Dosing

Adult

5-15 mg/d loading dose PO for 2-5 d; adjust daily dosage to desired INR or PT
In general, loading doses have lost popularity; probably safer to begin with maintenance dose and wait for INR to increase into therapeutic range

Pediatric

0.05-0.34 mg/kg/d PO; adjust dose according to desired INR; infants may require doses at or near high end of this range

Interactions

Barbiturates, carbamazepine, glutethimide, griseofulvin, nafcillin, phenytoin, rifampin, estrogens, oral contraceptives, vitamin K, cholestyramine, colestipol, spironolactone, and sucralfate decrease anticoagulant effects
Oral antibiotics, chloral hydrate, clofibrate, diazoxide, ethacrynic acid, ketoconazole, miconazole, nalidixic acid, phenylbutazone, salicylates, sulfonamides, sulfonylureas, allopurinol, chloramphenicol, cimetidine, disulfiram, metronidazole, phenytoin, propoxyphene, acetaminophen, anabolic steroids, gemfibrozil, and sulindac increase anticoagulant effects

Contraindications

Documented hypersensitivity; open wounds or GI ulcers; severe liver or kidney disease

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Perform head CT scan to exclude hemorrhage; use with caution in trauma patients; increased risk of cerebral hemorrhage in patients with very large brain infarction, severe leukoencephalopathy from microangiopathy, or uncontrolled hypertension; do not switch brands after achieving therapeutic response; use with caution in active tuberculosis or diabetes; patients with protein C or S deficiency are at risk of developing skin necrosis

Enoxaparin (Lovenox)

Enhances inhibition of Factor Xa and thrombin by increasing antithrombin III activity. In addition, preferentially increases inhibition of Factor Xa.
Average duration of treatment is 7-14 d.

Dosing

Adult

Prophylaxis of DVT in critically ill patients: 40 mg/d SC
Anticoagulation in DVT (and as alternative anticoagulant in selected indications after stroke, not evidence based): 1 mg/kg SC bid

Pediatric

Not established

Interactions

Platelet inhibitors or oral anticoagulants such as dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, and ticlopidine may increase risk of bleeding

Contraindications

Documented hypersensitivity; major bleeding; thrombocytopenia

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

If thromboembolic event occurs despite LMWH prophylaxis, discontinue drug and initiate alternate therapy; elevation of hepatic transaminases may occur but is reversible; heparin-associated thrombocytopenia may occur with fractionated LMWHs; 1 mg of protamine sulfate will reverse effect of approximately 1 mg of enoxaparin if significant bleeding complications develop

Dalteparin (Fragmin)

Enhances inhibition of Factor Xa and thrombin by increasing antithrombin III activity. In addition, preferentially increases inhibition of Factor Xa.
Average duration of treatment is 7-14 d.

Dosing

Adult

For prophylaxis of DVT in critically ill patients: 5000 IU/d SC
Anticoagulation in DVT (and as alternative anticoagulant in selected indications after stroke, not evidence based): 100 IU/kg SC bid

Pediatric

Not established

Interactions

Platelet inhibitors or oral anticoagulants such as dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, and ticlopidine may increase risk of bleeding

Contraindications

Documented hypersensitivity; major bleeding; thrombocytopenia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

If thromboembolic event occurs despite LMWH prophylaxis, discontinue drug and initiate alternate therapy; elevation of hepatic transaminases may occur but is reversible; heparin-associated thrombocytopenia may occur with fractionated LMWHs; 1 mg of protamine sulfate will reverse effect of approximately 1 mg of dalteparin if significant bleeding complications develop

Ardeparin (Normiflo)

Enhances inhibition of Factor Xa and thrombin by increasing antithrombin III activity. In addition, preferentially increases inhibition of Factor Xa.
Average duration of treatment is 7-14 d.

Dosing

Adult

100 IU/kg/d SC

Pediatric

Not established

Interactions

Platelet inhibitors or oral anticoagulants such as dipyridamole, salicylates, aspirin, NSAIDs, sulfinpyrazone, and ticlopidine may increase risk of bleeding

Contraindications

Documented hypersensitivity; major bleeding; thrombocytopenia

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

If thromboembolic event occurs despite LMWH prophylaxis, discontinue drug and initiate alternative therapy; elevation of hepatic transaminases may occur but is reversible; heparin-associated thrombocytopenia may occur with fractionated LMWHs; 1 mg of protamine sulfate will reverse effect of approximately 1 mg of ardeparin if significant bleeding complications develop

Follow-up

Patient Education

• For excellent patient education resources, visit eMedicine's Stroke Center. Also, see eMedicine's patient education article Stroke.

References

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Keywords

cerebral ischemia, ischemic thromboembolic stroke, anticoagulants, anticoagulation therapy, anticoagulant, anticoagulant therapy, blood coagulation, heparin, heparin analogues, warfarin

Contributor Information and Disclosures

Author

Uwe Walter, MD, PhD, Associate Professor, Department of Neurology, University Hospital of Rostock, Germany; Director Neurological Intensive Care Unit and Stroke Unit, Head of Neurosonological Lab
Disclosure: Nothing to disclose.

Medical Editor

Draga Jichici, MD, FRCP, Associate Clinical Professor, Department of Medicine, Division of Neurology and Critical Care Medicine, McMaster University, Canada
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Howard S Kirshner, MD, Professor of Neurology, Psychiatry and Hearing and Speech Sciences, Vice Chairman, Department of Neurology, Vanderbilt University School of Medicine; Director, Vanderbilt Stroke Center; Program Director, Stroke Service, Vanderbilt Stallworth Rehabilitation Hospital; Consulting Staff, Department of Neurology, Nashville Veterans Affairs Medical Center
Howard S Kirshner, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, American Heart Association, American Medical Association, American Neurological Association, American Society of Neurorehabilitation, National Stroke Association, Phi Beta Kappa, and Tennessee Medical Association
Disclosure: Boehringer Ingelheim Honoraria Speaking and teaching; BMS/Sanofi Honoraria Speaking and teaching; Novartis Honoraria Speaking and teaching

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Helmi L Lutsep, MD, Professor, Department of Neurology, Oregon Health & Science University; Associate Director, Oregon Stroke Center
Helmi L Lutsep, MD is a member of the following medical societies: American Academy of Neurology and American Stroke Association
Disclosure: Co-Axia Consulting fee Review panel membership; Talecris Consulting fee Review panel membership; AGA Medical Consulting fee Review panel membership; Boehringer Ingelheim Honoraria Speaking and teaching; Concentric Medical Consulting fee Review panel membership; Abbott Consulting fee Consulting; Sanofi  Consulting

We thank C. Geller, MD, Associate Professor, Department of Cardiology, University Hospitals, Otto-von-Guericke University of Magdeburg, Germany, and J.C. Kroger, MD, Assistant Professor, Institute of Diagnostic and Interventional Radiology, University of Rostock, Germany, for helpful discussion.

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