Stroke Anticoagulation and Prophylaxis 

Anticoagulation is the controlled therapeutic inhibition of blood clotting by means of appropriate drugs (ie, anticoagulants). The role of anticoagulants in the treatment of cerebral ischemia has changed. For many years, anticoagulation was used routinely in acute ischemic stroke. However, in the past 2 decades, randomized, controlled studies have helped to better define the role of anticoagulants in the acute treatment and prevention of stroke. In addition, several new oral and parenteral anticoagulants are in different stages of clinical trials for use in the prophylaxis of ischemic thromboembolic stroke.

For more information, see the topics Hemorrhagic Stroke and Ischemic Stroke.

See also Acute Stroke Management and Mechanical Thrombolysis in Acute Stroke.

Current data do not support the routine use of anticoagulation for acute ischemic stroke. Several randomized, controlled trials that used IV heparinoids, subcutaneous low-molecular-weight heparin (LMWH), or subcutaneous unfractionated heparin (UFH) early after ischemic stroke failed to show a significant overall benefit of treatment over controls.

The International Stroke Study (IST) compared aspirin with subcutaneous UFH at 2 different doses (5000 units or 12,500 units bid); no difference in morbidity and mortality from stroke was shown between the group treated with aspirin and the group treated with UFH. In addition, although UFH seemed to decrease the risk of pulmonary embolism and deep venous thrombosis (DVT), it increased the risk of hemorrhagic complications.

A systematic review by the Cochrane collaboration demonstrated that anticoagulation (with UFH, LMWH, heparinoids, oral anticoagulants, or thrombin inhibitors) did not decrease the odds of death or development of dependency from stroke.^[1] Although anticoagulants prevented pulmonary embolism, they also increased the risk of hemorrhage, leading to the conclusion that anticoagulation cannot be recommended for the treatment of acute ischemic stroke.

The last trial evaluating early intravenous anticoagulation with UFH was published in 1986. It showed no benefit in the treatment arm compared with the control arm.

An exception to the lack of benefit from anticoagulation might be in patients with acute ischemic stroke ipsilateral to a severe stenosis or occlusion of the internal carotid artery. In the TOAST (Trial of Org 10172 in Acute Stroke Treatment) trial, this group appeared to benefit from early IV administration of the LMWH danaparoid. However, this was a post hoc analysis with a small number of individuals, so the effect of chance cannot be excluded. Therefore, further research is needed to confirm the findings.^[2]

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, although this recommendation is not based on solid evidence.

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).^[3] On the basis of this evidence, patients with acute ischemic stroke and atrial fibrillation should be treated with aspirin in the acute phase (and then placed on anticoagulation).

When long-term anticoagulation is indicated, the use of UFH or LMWH has been advocated to serve as a bridge while a therapeutic international normalized ratio (INR) is achieved with warfarin. A small pilot study found that LMWH (enoxaparin 1 mg/kg subcutaneously bid) was safer than IV UFH for this purpose in patients with subacute cerebral ischemia.^[4] However, further studies are needed to confirm this finding before this approach can be recommended generally.

Despite evidence from the randomized clinical trials discussed above, anticoagulation continues to be recommended for some specific clinical situations. These recommendations are based on uncontrolled studies and expert opinion.

Even among experts there is disagreement about the best level of anticoagulation, route of administration, timing and duration of treatment, use of a bolus dose, and safety of the therapy, given the severity of neurologic deficits, size of infarction on baseline computed tomography (CT), vascular distribution, or presumed cause of stroke.

Some of the indications currently proposed by many experts for early full-dose IV heparin after stroke or transient ischemic attack (TIA) include the following:

• Conditions with potential high risk of early cardiogenic reembolization, such as atrial fibrillation with proven intracardial thrombus on echocardiography, artificial valves, left atrial or ventricular thrombi, or myocardial infarction during the last 4 weeks
• Symptomatic dissection of the 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
• Basilar artery occlusion before or after intra-arterial pharmacological or mechanical thrombolysis.
• Known hypercoagulable states (eg, protein C and S deficiencies, activated protein C [APC] resistance, antithrombin deficiency, relevant titer of antiphospholipid antibodies)
• Cerebral venous sinus thrombosis

The use of anticoagulation in cerebral venous sinus thrombosis is based on open case series with no controls. Anticoagulation has been used even in the presence of hemorrhagic infarctions typical of this condition. Authors have reported good outcomes compared with historical controls.

Conclusive data are lacking about the management of anticoagulation in patients with hemorrhagic conversion of ischemic brain infarction or primary cerebral hemorrhage who have an absolute indication for anticoagulation for the prevention of embolism (ie, atrial fibrillation or mechanical heart valves). Small retrospective case series of patients with urgent need for anticoagulation (eg, with artificial heart valves) showed a better outcome for those treated with full-dose IV heparin (only after normalization of INR values by administration of prothrombin complex and/or other warfarin antagonists) than for those treated with low-dose subcutaneous heparin; however, these studies lack concomitant control subjects, thus making any conclusions about true efficacy and safety difficult.

At the present time, patients with acute ischemic stroke treated with intravenous recombinant tissue plasminogen activator (rtPA) clearly should not be treated with anticoagulation for at least 24 hours post thrombolysis.

Two randomized, controlled trials have demonstrated that a strategy aimed at restoring (and maintaining) sinus rhythm in patients with atrial fibrillation 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).^[5]

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^[6] ) has led to the development of consensus guidelines advocating a rate-control strategy for most atrial fibrillation patients.^[7]

Patients with atrial fibrillation 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 transient ischemic attack [TIA], systemic embolism, hypertension, heart failure, or diabetes) have an increased stroke risk of at least 8% per year.

Several risk stratification schemes have been created for primary and secondary prevention of ischemic stroke in patients with atrial fibrillation. The table below summarizes the risk stratification according to 4 widely used schemes.

Table 1. Risk stratification according to the most widely used schemes (Open Table in a new window)

Of these schemes, the CHADS₂ score is most widely used. The score has 5 components: recent heart failure, hypertension, age ≥75 years, and diabetes (each of which accounts for 1 point) and prior stroke/TIA (which accounts for 2 points). The total score ranges from 0-6. The table below shows how the CHADS₂ score quantifies the risk of stroke for patients with atrial fibrillation.

Table 2. Quantifying the risk of stroke in patients with atrial fibrillation using CHADS₂ score (Open Table in a new window)

A prospective study of patients with atrial fibrillation who were treated with long-term oral anticoagulation was conducted by Poli et al to evaluate the agreement of predictive ability and correlation with adverse events among the 4 widely used schemes (AFI, ACCP, CHADS₂, and NICE), and the results showed that for primary stroke prevention, the CHADS₂ and NICE scores had the best predictive accuracy.^[12] However, for secondary stroke prevention, the risk stratification is not needed, and oral anticoagulant should be the treatment of choice.

In a cohort of 796 patients with atrial fibrillation with a mean follow-up of 2.4 years, 70% were treated with warfarin. Among subjects not anticoagulated, the rate of embolic events increased significantly with increasing CHADS₂ score. Event rates by CHADS₂ score among those receiving warfarin versus those not anticoagulated were as follows:

• CHADS₂ score of 0: 1% versus 4.1%
• CHADS₂ score of 1: 0.6% versus 7.1%
• CHADS₂ score of 2: 0.5% versus 5.1%
• CHADS₂ score of 3: 2.4% versus 12.5%
• CHADS₂ score of 4 or greater: 2.9% versus 20%

These results support long-term anticoagulation with warfarin in subjects with a CHADS₂ score of 2 or higher.^[13]

Oral anticoagulation (ie, target INR 2.5, range 2-3) is the therapy of choice for primary and secondary stroke prevention in patients with atrial fibrillation and any of the additional risk factors described above, according to guidelines from the American College of Cardiology, American Heart Association, and European Society of Cardiology.^[7]

Prophylaxis in asymptomatic patients

Asymptomatic patients younger than 65 years with atrial fibrillation and none of the other risk factors are at a low risk and either should be treated with aspirin or should not be treated at all. Asymptomatic patients aged 65-74 years with atrial fibrillation 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 atrial fibrillation 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 atrial fibrillation 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 patient's risk profile should be made.

Dabigatran

The RE-LY study evaluated the efficacy and safety of 2 different doses of dabigatran relative to warfarin in more than 18,000 patients with atrial fibrillation. Patients were randomized to 1 of 3 arms: (1) adjusted dose warfarin, (2) dabigatran 110 mg bid, or (3) dabigatran 150 mg bid. Dabigatran 110 mg was noninferior to warfarin for the primary efficacy endpoint of stroke or systemic embolization, while dabigatran 150 mg was significantly more effective than warfarin or dabigatran 110 mg. Major bleeding occurred significantly less often with dabigatran 110 mg than warfarin; dabigatran 150 mg had similar bleeding to warfarin.^[14]

Dabigatran, a competitive, direct thrombin inhibitor, was approved by the US Food and Drug Administration in 2010 for prevention of stroke and thromboembolism associated with nonvalvular atrial fibrillation. The dose is 150 mg PO bid (decrease to 75 mg PO bid with renal impairment). When converting from warfarin, discontinue warfarin and initiate dabigatran when INR < 2.0.

Guidelines from the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA)/Heart Rhythm Society (HRS) on atrial fibrillation have been updated to include the use of oral direct thrombin inhibitors (ie, dabigatran).^[15] The guidelines include a class Ib recommendation (ie, treatment is useful/effective based on a single randomized trial) for dabigatran. The guidelines recommend dabigatran may be used as an alternative to warfarin for the prevention of stroke and systemic thromboembolism in patients with paroxysmal-to-permanent atrial fibrillation and risk factors for stroke or systemic embolization. Patients with atrial fibrillation who are not candidates include those with prosthetic heart valves or hemodynamically significant valve disease, severe renal failure (creatinine clearance ≤ 15 mL/min), or advanced liver disease.

Prophylaxis in older patients

The choice of warfarin versus aspirin for prophylaxis in older patients was addressed in the Birmingham Atrial Fibrillation Treatment of the Aged Study (BAFTA), and compared with aspirin, warfarin reduced the risk of major stroke, arterial embolism, or other intracranial hemorrhage (yearly risk, 1.8% vs 3.8%). 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/day; follow-up was for a mean of 2.7 years.^[16]

Long-term anticoagulation should not be used in patients with an increased risk of bleeding due to factors such as the following:

• 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
• Bleeding diathesis (eg, coagulopathies, thrombocytopenia).

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

HEMORRHAGES

A bleeding risk stratification scheme called HEMORR₂ HAGES has been validated in at least a dataset of anticoagulated patients. The score is calculated as the sum of the following risk factors for bleeding:

• Hepatic or renal disease
• Ethanol abuse
• Malignancy
• Old age (>75 y)
• Rebleeding
• Reduced platelet counts or platelet dysfunction
• Hypertension that is uncontrolled
• Anemia
• Genetic factors
• Elevated fall risk
• Stroke

All of the above risk factors are assigned a value of 1 point, except for rebleeding, which counts for 2 points.

The table below shows the incidence of major bleeding stratified by the HEMORR₂ HAGES score (data from the National Registry of Atrial Fibrillation).^[17]

Table 3. Bleeding risk stratification scheme^[17] (Open Table in a new window)

Direct thrombin inhibitors may become an alternative to warfarin for prevention of thromboembolism in atrial fibrillation patients. The first agent in this category was the oral direct thrombin inhibitor ximelagatran.

Ximelagatran

Ximelagatran was compared with warfarin in the Stroke Prevention Using Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) III and V trials.^{[18, 19]} SPORTIF III was performed in Europe; SPORTIF V was performed in North America. Pooled analysis of these 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.^[20]

Ximelagatran is in use in several European countries; however, it has not been approved for stroke prevention in atrial fibrillation 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.^[21]

ACTIVE W trial

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, and the study was stopped early because of clear evidence of superiority of oral anticoagulation therapy. Primary outcome was first occurrence of stroke, non-CNS systemic embolus, myocardial infarction, or vascular death.^{[22, 23]}

Dabigatran

Dabigatran is another direct oral competitive inhibitor of thrombin. Dabigatran has a bioavailability of 6.5%, and 80% of the dose is excreted by the kidneys. It has a serum half-life of 12-17 hours and does not require regular monitoring.

A randomized non inferiority clinical trial in patients with atrial fibrillation found that dabigatran at 110 mg twice a day is comparable to warfarin for the prevention of stroke and systemic embolization while having a lower rate of hemorrhagic complications. In addition, dabigatran 150 mg twice a day was superior to warfarin for the prevention of stroke and systemic embolization while having a risk of hemorrhagic complications similar to that of warfarin.^[24] In a subgroup analysis of the RE-LY trial, patients with previous stroke or transient ischemic attack who were treated with either 110 mg or 150 mg of dabigatran showed no difference in effects than those treated with warfarin.^[25] The results of this study lead to the recent approval of dabigatran 150 mg orally twice a day for the prevention of stroke and embolization in patients with atrial fibrillation.^[26]

Other antithrombotic agents

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

Pharmacologic or nonpharmacologic restoration and maintenance of sinus rhythm renders anticoagulation unnecessary. Patients with atrial fibrillation should receive oral anticoagulation 3 weeks prior to electrical or chemical conversion and at least 4 weeks thereafter. However, if the duration of atrial fibrillation has been less than 48 hours or intracardial thrombus has been excluded on echocardiography, conversion can be performed immediately after placing the patient on IV heparin.

Left atrial appendage is the source of embolization in 90% of patients with atrial fibrillation. On this basis, closure of the left atrial appendage (LAA) intuitively makes sense as an alternative to anticoagulation for decreasing the risk of embolization or stroke. Closure of the LAA proved non inferior to warfarin therapy for preventing embolization among patients with atrial fibrillation in the PROTECT trial (percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomized non inferiority trial).^[27]

During the first 4 weeks after acute myocardial infarction (MI), the risk of cardioembolic stroke is approximately 2%. 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 after MI is recommended in patients with the following risk factors^[28] :

• Persistent or paroxysmal atrial fibrillation
• Left ventricular thrombus
• Left ventricular aneurysm
• Extensive wall motion abnormalities resulting in a left ventricular ejection fraction (LVEF) < 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.^[29] Usually, administering oral anticoagulation according to the indications already listed is recommended as long as the causing condition persists and no contraindications emerge.

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)
• Ventricular aneurysm with thrombus (target INR 2.5, range 2-3)
• Mobile thrombus in the ascending aorta (target INR 2.5, range 2-3)
• Dilated cardiomyopathy (target INR 2.5, range 2-3):

However, the use of anticoagulation in 2 of those conditions, left atrial myxoma and dilated cardiomyopathy, has only qualified support. Surgical resection is the treatment of choice for left atrial myxoma ; anticoagulation has been used in patients awaiting surgical resection, but this strategy is controversial at best.^{[30, 31]} )

Although dilated cardiomyopathy has been considered an indication for anticoagulation, currently no data from randomized clinical trials support this assertion. A European study, the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial, failed to show superiority of warfarin over aspirin. The American counterpart of WATCH, the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction study (WARCEF), is still ongoing.

Oral anticoagulation is indicated for patients with a large patent foramen ovale (PFO) under 3 circumstances:

• Recurrent cerebral ischemia while the patient was receiving aspirin, 300 mg/d
• Co-occurrence of PFO with atrial septal aneurysm
• Co-occurrence of PFO with deep venous thrombosis of the leg or abdomen

The target INR in such cases is 2.5 (range 2-3). The duration of anticoagulation is usually 2 years or longer.

As an alternative to anticoagulation, operative or transcatheter occlusion of the PFO may be considered; however, this strategy is not evidence based. In cases of PFO without atrial septal aneurysm, aspirin at a dosage of 300 mg/day is sufficient.

Other cardiac indications for oral anticoagulation for secondary stroke prevention include the following:

• 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)

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.^[32] 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 remainder 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, and the practice of anticoagulation is supported only by several published case series demonstrating good outcome with low complication rates in patients undergoing anticoagulation. However, these studies do not have a control or comparative group to establish efficacy.

Only in rare cases (eg, with persistent high-grade proximal stenosis of the internal carotid artery or with severe hemodynamic impairment) should an operation or stenting be considered. No evidence of a higher embolic activity of pseudoaneurysms 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, but this practice is not supported by randomized, controlled studies.

Anticoagulation is contraindicated in intracranial dissections complicated by subarachnoid hemorrhage.

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 transient ischemic attack (TIA) or minor ischemic stroke of presumed arterial origin in the Stroke Prevention in Reversible Ischemia Trial (SPIRIT), but the trial was stopped after the first interim analysis because of increased major bleeding complications in the anticoagulant group.^[33]

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.^[34]

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,^[35] but this trial was ended prematurely because ESPRIT had previously reported that the combination of aspirin and dipyridamole was more effective than aspirin alone.

Mean follow-up in ESPRIT 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 ESPRIT, 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,^[36] but 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 MI or sudden death).^[36]

As a consequence of WASID, warfarin cannot be recommended for first-line use in patients with intracranial arterial stenosis. Aspirin (or other antithrombotic drugs) should be preferred.^[36]

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 and of major extracranial hemorrhage.^[23] The reviewers noted that the study rates were equivalent to anticoagulation causing about 11 additional fatal intracranial hemorrhages and 25 additional major extracranial hemorrhages per year for every 1000 patients treated.

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

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 provided below.^[37]

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).

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

A study by Bushnell et al found that one fourth of patients who have experienced a stroke stop taking one or more of their prescribed secondary prevention medications within 3 months of hospitalization for acute stroke.^[38] Patients reported many reasons, but several were modifiable; because of this reason, improvement in long-term secondary stroke prevention is possible.

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 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.

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 for patients with the following disorders:

• Antithrombin III deficiency (target INR 2.5, range 2-3)
• Protein C deficiency (target INR 3, range 3-3.5)
• Protein S deficiency (target INR 2.5, range 2-3)
• Activated protein C (APC) resistance (factor V Leiden; target INR 2.5, range 2-3)
• Plasminogen deficiency/inhibition (target INR 2.5, range 2-3)
• Dysfibrinogenemia (target INR 2.5, range 2-3)

As an alternative to oral anticoagulants, patients with thrombophilia may be treated with fixed, low-dose subcutaneous unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). Patients with antithrombin III deficiency can receive antithrombin III concentrates for acute intervention 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 the case of a combination of different thrombophilias, lifelong anticoagulation is usually recommended.

Patients with recurrent thrombotic events despite warfarin pose a challenge for clinicians. The INR at the time of recurrence is important; an INR below the target therapeutic range represents inadequate anticoagulation as opposed to warfarin failure.

These patients may be treated in the same manner as a patient presenting with new thrombosis without warfarin.

Possible treatment options for recurrent thrombosis despite an INR in the target range include increasing the intensity of warfarin anticoagulation to achieve a higher target INR (target INR, 2.5-3.5 or 3.0-4.0), switching from warfarin to therapeutic doses of unfractionated heparin or low-molecular weight heparin, or adding an antiplatelet agent to warfarin.^[39]

Because the lupus anticoagulants may interfere with INR determination, monitoring these patients using the prothrombin-proconvertin time and the chromogenic factor-X assay would be preferable. However, these tests are expensive and are not widely available.

Several studies have addressed secondary prevention of stroke in patients with antiphospholipid antibodies. This group includes patients with medium or high-titer anticardiolipin antibodies or the presence of lupus anticoagulants.

In the Antiphospholipid Antibodies and Stroke Study (APASS), a prospective cohort study within the randomized double-blind WARSS that compared warfarin (INR 1.4-2.8) and aspirin (325 mg/d) for prevention of recurrent stroke or death, patients were classified into 2 groups based on the presence or absence of antiphospholipid antibodies. Among the 1770 patients included in APASS, no difference was reported in the risk of thrombotic events in patients treated with warfarin compared with aspirin and no difference was reported in the risk of bleeding.^[40]

Based on the APASS data, patients with first ischemic stroke and a single positive antiphospholipid antibody test result who do not have another indication for anticoagulation may be treated with aspirin (325 mg/d) or warfarin (INR 1.4-2.8). Aspirin is likely to be preferred because of its ease of use and lack of need for laboratory monitoring.

Patients with ischemic stroke due to cerebral arterial thrombosis and a positive antiphospholipid antibody test who have a history of venous thrombosis but were not receiving anticoagulant drugs when suffering the stroke should be treated with moderate-intensity warfarin (target INR 2.5, range 2-3).

In 2 prospective randomized studies, high-intensity warfarin (target INR 3.5, range 3-4) was not superior to moderate-intensity warfarin (target INR 2.5, range 2-3) in preventing recurrent thrombosis and was associated with an increased rate of minor hemorrhagic complications.^{[41, 42]}