Stroke Anticoagulation and Prophylaxis 

Updated: Oct 18, 2017
  • Author: Salvador Cruz-Flores, MD, MPH, FAHA, FCCM, FAAN, FACP, FANA; Chief Editor: Helmi L Lutsep, MD  more...
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Practice Essentials

The role of anticoagulation in the treatment of cerebral ischemia has changed. For many years, it was used routinely in acute ischemic stroke. However, more current studies are helping to refine its role 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.

Anticoagulation for acute ischemic stroke

Current data do not support routine use of anticoagulation for acute ischemic stroke. However, anticoagulation continues to be recommended for some specific clinical situations. 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
  • Symptomatic dissection of the arteries supplying the brain
  • 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
  • Cerebral venous sinus thrombosis

Stroke prevention in atrial fibrillation

Oral anticoagulation is the therapy of choice for primary and secondary stroke prevention in patients with atrial fibrillation and any of the known additional risk factors. [1, 2] 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.

Risk factors for bleeding

Risk factors for bleeding in anticoagulated patients include the following:

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

Stroke prevention after acute myocardial infarction

Anticoagulation for primary stroke prevention after myocardial infarction (MI) is recommended in patients with the following risk factors [3] :

  • Persistent or paroxysmal atrial fibrillation
  • Left ventricular thrombus
  • Left ventricular aneurysm

Stroke prevention in other heart diseases

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

  • Mechanical heart valve
  • Mitral valve stenosis with any prior embolic event
  • Left atrial myxoma (qualified support from the data)
  • Intraventricular thrombus
  • Ventricular aneurysm with thrombus
  • Mobile thrombus in the ascending
  • Dilated cardiomyopathy (qualified support from the data)

Oral anticoagulation may be considered for patients with a large patent foramen ovale (PFO) under 3 circumstances:

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

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

  • Mitral valve prolapse with myxomatous leaflets
  • Rupture of chordae tendineae
  • Dyskinetic ventricular wall segment
  • Mitral ring calcifications

No current evidence-based guidelines address anticoagulation in patients with symptomatic stenoses of extracranial arteries.  The WASID trial showed no benefit to warfarin compared to aspirin in symptomatic intracranial disease. [4]

Guidelines for secondary prevention

Class I 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 follows [5] :

  • Antiplatelet agents rather than oral anticoagulation are recommended to reduce the risk of recurrent stroke and other cardiovascular events ( IA); aspirin 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, increasing the dose of aspirin provides no additional benefit; the combination of aspirin and extended-release dipyridamole is recommended over aspirin alone ( IB)

Class II recommendations are as follows:

  • Clopidogrel may be considered over aspirin alone ( IIbB)
  • Clopidogrel is reasonable for patients allergic to aspirin ( IIaB)

Class III recommendations are as follows:

Because of an increased risk of hemorrhage, combination therapy with aspirin and clopidogrel is not routinely recommended unless there is a specific indication for this therapy (IIIA)

In May 2013, new consensus guidelines on the delivery of optimized inpatient anticoagulation therapy were published. [6, 7] These guidelines, which were endorsed by the Anticoagulation Forum, call for the increased use of technology (eg, computerized physician order entry, bar code scanning, and dose range checking) for decreasing medication errors and increasing multidisciplinary involvement in the anticoagulation management system. [7]

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 for patients with the following disorders:

  • Antithrombin III deficiency
  • Protein C deficiency
  • Protein S deficiency
  • Activated protein C resistance
  • Plasminogen deficiency/inhibition
  • Dysfibrinogenemia
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Role of Anticoagulants

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 Hemorrhagic Stroke, Ischemic Stroke, Acute Management of Stroke and Mechanical Thrombolysis in Acute Stroke.

See also Acute Stroke, a Critical Images slideshow, for more information on incidence, presentation, intervention, and additional resources.

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Anticoagulation for Acute Ischemic 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. [8] 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. [9]

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). [10] 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. [11] 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; see alteplase) clearly should not be treated with anticoagulation for at least 24 hours post thrombolysis.

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Stroke Prevention in Atrial Fibrillation

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). [12]

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 [13] ) has led to the development of consensus guidelines advocating a rate-control strategy for most atrial fibrillation patients. [14]

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). [15] 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)

Scheme Low risk Moderate risk High risk
AFI Age < 65 and no other risk factors Age >65 and no other risk factors -Previous stroke or TIA



-Diabetes



-Hypertension



ACCP Age < 65 and no risk factors Age 65-75 and no other risk factors -Age >75



-Previous stroke/TIA



-Diabetes



-Hypertension



-Moderate to severe LV systolic dysfunction



CHADS2 Score 0 Score 1-2 Score 3-6
NICE Age < 65 and no risk factors -Age ≥65 and no risk factors



-Age < 75 plus hypertension, diabetes, or vascular disease



-Previous stroke/TIA or thromboembolic event



-Age >75 and hypertension, diabetes, or vascular disease



-Heart failure or LV dysfunction or valvular heart disease



AFI: Atrial Fibrillation Investigators [16] ; ACCP: American College of Chest Physicians Conference on Antithrombotic and Thrombolytic Therapy [17] ; CHADS2: Congestive heart failure, Hypertension, Age ≥75, Diabetes, Stroke/TIA [18] ; NICE: National Institute for Health and Clinical Excellence [19]

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)

CHADS2 score No. of patients (n=1733) No. of stroke (n=94) NRAF crude stroke rate per 100 patient-years NRAF adjusted stroke rate (95% CI)
0 120 2 1.2 1.9 (1.2-3.0)
1 463 17 2.8 2.8 (2.0-3.8)
2 523 23 3.6 4.0 (3.1-5.1)
3 337 25 6.4 5.9 (4.6-7.3)
4 220 19 8.0 8.5 (6.3-11.1)
5 65 6 7.7 12.5 (8.2-17.5)
6 5 2 44.0 18.2 (10.5-27.4)
NRAF: National Registry of Atrial Fibrillation [18]

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. [20] 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:

  • CHADS 2 score of 0: 1% versus 4.1%
  • CHADS 2 score of 1: 0.6% versus 7.1%
  • CHADS 2 score of 2: 0.5% versus 5.1%
  • CHADS 2 score of 3: 2.4% versus 12.5%
  • CHADS 2 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. [21]

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. [14]

In a 2014 update of guidelines for stroke prevention by the American Academy of Neurology, the AAN recommended routinely offering anticoagulation to patients with nonvalvular atrial fibrillation and a history of transient ischemic attack or stroke. The American Heart Association and American Stroke Association expanded their list of recommended anticoagulants to include dabigatran, apixaban, and rivaroxaban, as well as warfarin, for patients with nonvalvular atrial fibrillation who are at acceptably low risk for hemorrhagic complications. [22, 23]

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.

Direct thrombin inhibitors and Factor Xa inhibitors

Novel oral anticoagulants (NOACs) include apixaban, dabigatran, rivaroxaban, and edoxaban. NOACs are alternatives to warfarin for high-risk patients (including those with a history of stroke) who have atrial fibrillation. [24, 25, 26, 27, 28, 29] Apixaban, edoxaban, and rivaroxaban inhibit Factor Xa, whereas dabigatran is a direct thrombin inhibitor. Apixaban and dabigatran were shown to be superior to warfarin for the prevention of stroke and systemic embolism, while rivaroxaban and edoxaban were shown to be equivalent. The rates of intracranial hemorrhage are lower for NOACs compared with warfarin. Dabigatran carries a higher risk of gastrointestinal bleeding compared with warfarin, and it appears to increase the risk of myocardial infarction. [24] These medications have not been compared against each other.

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. [30]

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.

The FDA approved a monoclonal antibody reversal agent (idarucizumab [Praxbind]) for patients treated with dabigatran when reversal of dabigatran’s anticoagulant effects are needed for emergency surgery or urgent procedures, or in the event of life-threatening or uncontrolled bleeding. Idarucizumab is specific for reversing dabigatran, although other NOAC reversal agents are currently in clinical trials or awaiting FDA approval (eg, andexanet alfa, PER977).

Accelerated approval for idarucizumab was based on interim analysis of the Re-VERSE AD trial. Investigators found that, among 39 patients who had been receiving dabigatran and required an urgent procedure were then given idarucizumab, 36 underwent their urgent procedure—with 33 (92%) having normal hemostasis during the event. Two of the remaining patients had mildly abnormal bleeding (with slight oozing), while just one had moderately abnormal yet controlled bleeding. Among 35 of 51 patients who had serious bleeding were able to be assessed, hemostasis, as determined by local investigators, was restored at a median of 11.4 hours. [31]

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). [32] 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.

Apixaban

Apixaban (Eliquis) was approved by the FDA in December 2012. Approval was based on 2 clinical trials. The ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial compared apixaban with warfarin for the prevention of stroke or systemic embolism in patients with atrial fibrillation and at least one additional risk factor for stroke. Results showed that apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality. [25]

Edoxaban

Edoxaban (Savaysa) was approved by the FDA in January 2015 to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. In the ENGAGE AF-TIMI 48 trial (n=21,105), edoxaban was noninferior to warfarin with respect to the prevention of stroke or systemic embolism. Edoxaban was associated with significantly lower rates of major bleeding (P < 0.001) and death from cardiovascular causes (P=0.01%) compared with warfarin. [29]

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. [33]

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). [34]

Table 3. Bleeding risk stratification scheme [34] (Open Table in a new window)

HEMORR2 HAGES score No. of patients No. of bleeding Bleeding per 100 patient-years warfarin (95% CI)
0 209 4 1.9 (0.6-4.4)
1 508 11 2.5 (1.3-4.3)
2 454 20 5.3 (3.4-8.1)
3 240 15 8.4 (4.9-13.6)
4 106 9 10.4 (5.1-18.9)
≥5 87 8 12.3 (5.8-23.1)
Any score 1604 67 4.9 (3.9-6.3)
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Stroke Prevention after Acute MI

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 [3] :

  • Persistent or paroxysmal atrial fibrillation
  • Left ventricular thrombus
  • Left ventricular aneurysm
  • Consider in extensive wall motion abnormalities resulting in a left ventricular ejection fraction (LVEF) < 25%. While the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial did not show benefit for warfarin compared to aspirin, a WARCEF exploratory analysis showed that prior stroke and EF <15% were risk factors recurrent for ischemic stroke. [35]  It is unknown whether warfarin reduces stroke risk in this population. 

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. [36] Usually, administering oral anticoagulation according to the indications already listed is recommended as long as the causing condition persists and no contraindications emerge.

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Alternatives to Long-term Anticoagulation

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). [37]

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Stroke Prevention in 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) (qualified evidence)
  • 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) (qualified evidence)

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. [38, 39] )

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), also showed no benefit to the use of warfarin.

Oral anticoagulation may be considered 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.

Operative or transcatheter occlusion of the PFO may be considered on the basis of recent trials, such as the final reported results of the RESPECT trial. In general in PFO, aspirin at a dosage of 300 mg/day is sufficient.

Other cardiac indications for oral anticoagulation for secondary stroke prevention may 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. [40]

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 large randomized trials have been performed to determine optimal treatment. 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. The CADISS trial was a randomized trial but was not powered sufficiently to show differences between treatments.

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.

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Symptomatic Stenoses of Extracranial and Intracranial Arteries

No current evidence-based guidelines address anticoagulation in these patients. Oral anticoagulation (target INR 3-4.5) was compared with aspirin (30 mg/d) in patients with 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. [41]

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. [42]

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, [43] 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, [4] 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). [4]

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. [4]

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. [44] 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.

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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 provided below. [5]

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. [45] Patients reported many reasons, but several were modifiable; because of this reason, improvement in long-term secondary stroke prevention is possible.

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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 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.

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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 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.

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Recurrent Thrombosis

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. [46]

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.

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Antiphospholipid Antibodies

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. [47]

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. [48, 49]

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