Stroke is one of the most common primary neurologic disorders in hospitalized patients. Stroke care maybe divided into (a) an immediate phase of stroke recognition to define ischemic or hemorrhagic stroke, with possible urgent therapeutic intervention in the emergency department, intensive care unit, or other hospital areas; and (b) an acute management phase with subsequent initiation of secondary stroke prevention therapies.

Stroke is defined as abrupt neurologic dysfunction due to disturbances in the brain supply of blood, oxygen, and glucose. Stroke occurs because of either ischemia or hemorrhage, resulting in damage manifested by persistent clinical deficits, or accompanied by characteristic abnormalities on brain imaging. In acute ischemic stroke (AIS), not all brain tissue is salvageable. The ischemic penumbra is the part of the brain tissue that is oligemic, but not infarcted, and can potentially recover without damage at the lowest threshold of cerebral blood flow (CBF).^1,2 When disturbances are self-limited, correlating with transient focal neurological deficits, and not accompanied by neuroimaging changes, the cerebrovascular event is called a transient ischemic attack (TIA).

On average, every 40 seconds someone in the United States has a stroke, and someone dies of stroke approximately every 4 minutes.³ About 87% of all strokes are ischemic strokes (IS), 10% are intracerebral hemorrhage (ICH), and 3% are subarachnoid hemorrhage (SAH). In the last decade, the relative rate of stroke deaths fell by 35.8%.³ Significant improvements in stroke outcomes have occurred concurrently with improved risk factor control. Despite gradual declines in overall stroke mortality, stroke remains a leading cause of death and disability. The aphorism “Time is Brain” highlights the degree to which brain tissue depends on an uninterrupted blood supply. Saver quantified the urgency of stroke treatment and calculated that the typical stroke patient loses 1.9 million neurons each minute following stroke onset: “Compared with the normal rate of neuronal loss in brain aging, the ischemic brain ages 3.6 years each hour without treatment”.⁴ By comparison, someone who suffers a myocardial infarction (MI) can lose 10% of myocardial tissue and still run a marathon but losing much less than 10% of certain brain tissue segments can result in devastating disability.⁴

A mechanistic approach is helpful in evaluating stroke patients and is the basis for the organization of this chapter. The main division is between ischemic (IS) and hemorrhagic stroke (HS). Determination of ischemic subtype is made after the immediate evaluation, and eligibility for thrombolysis does not depend on IS subtype. There are several IS classifications, but the TOAST classification is the most useful, with a mechanistic scheme consisting of five major categories: (1) large-vessel atherothromboembolic stroke; (2) cardioembolic stroke; (3) small-vessel stroke; (4) stroke of other determined etiology; and (5) stroke of undetermined etiology.⁵ The strength of the modified TOAST scheme is that it incorporates newer imaging modalities in the definition of IS subtypes.⁶ This mechanistic approach provides a framework for testing strategies in the diagnostic evaluation of IS and helps guide treatment strategies. The TOAST classification also helps clinicians guide patients and families as to prognosis.

Transient ischemic attack (TIA)

What is the next step in evaluating this patient?

• 
  

  The classical definition of TIA is a sudden focal neurologic deficit that lasts for less than 24 hours, is presumed to be of vascular origin, and is confined to an area of the brain or eye perfused by a specific artery.

  
  
  
  
  • 
    

    This definition has been modified: TIA is described as a brief episode of neurologic dysfunction caused by focal brain or retinal ischemia, with clinical symptoms typically lasting less than 1 hour, and without evidence of acute infarction by CT, or preferentially by MRI.⁷

    
    
  • 
    

    TIA should be considered as “unstable angina of the brain” as it frequently portends an ischemic stroke.

    
    
  • 
    

    After a first TIA, 10% to 20% of patients have a stroke in the following 90 days.

    
    
    
    
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      50% of those patients will have that stroke within the first 48 hours after TIA.

    
    
    
    
  • 
    

    Additionally, one-third of untreated TIA patients have a stroke within 5 years.

  
  
  
  
• 
  

  Factors associated with increased stroke risk after TIA included advanced age, diabetes mellitus, symptoms persisting for more than 10 minutes, weakness, and impaired speech.

  
  
  
  
  • 
    

    The ABCD₂ risk score stratifies IS risk after a TIA with ABCD₂ scores of 4 or greater indicating a moderate to high stroke risk (see Table 13-1).

    
    
  • 
    

    A recent modification, the ABCD₃ I score (see Table 13-1), takes into account data from neuroimaging to refine the predictive value of stroke recurrence.⁸

    
    
  • 
    

    The ABCD₂ score should not be used as a primary medical decision-making tool regarding urgency of evaluation or hospital admission.

    
    
    
    
    • 
      

      For example, a young patient with a TIA, in the context of possible vertebrobasilar arterial dissection, might have an ABCD₂ score of 1 and should still be admitted for stroke evaluation.

    
    

  
  
  
  
• 
  

  In all instances, patients with TIA should be managed similar to acute stroke patients with a rapid diagnostic evaluation, and managed by aggressive appropriate risk factor modification, with treatment intervention based on the underlying stroke/TIA mechanism.

Carotid artery disease

How you should manage this patient?

• 
  

  Patients with moderate or severe symptomatic carotid artery stenosis, without significant medical comorbidities, should always be evaluated for possible carotid artery intervention.⁹

  
  
• 
  

  In hospital, most stroke patients should undergo cervico-cerebral imaging, by either magnetic resonance angiography (MRA) or computerized tomography angiography (CTA), prior to consideration of carotid artery revascularization.

  
  
  
  
  • 
    

    Stroke patients should not undergo carotid artery revascularization on the basis of duplex scanning alone.

    
    
  • 
    

    Digital subtraction angiography (DSA) is not required for most patients, but may be indicated if there is discordance between 2 noninvasive studies, or if there are anatomic or other surgical concerns raised by the noninvasive studies (ie, vessel tortuosity, uncertainty about the degree or extent of stenosis, etc.).¹⁰

    
    
  • 
    

    The benefit of carotid artery revascularization for symptomatic patients is significant. Based on the data from the North American Symptomatic Carotid Endarterectomy Trial (NASCET):^{11 , 12}

    
    
  • 
    

    For patients with high-grade (70–99%) symptomatic carotid artery stenosis, the number needed to treat (NNT) was 8 patients who underwent carotid artery endarterectomy (CEA) to prevent one recurrent stroke at 2 years.

  
  
  
  
  • 
    

    For patients with moderate-grade (50–69%) symptomatic carotid stenosis, the NNT was 20 patients who underwent for CEA to prevent one recurrent stroke at 2 years.

  
  
  
  
• 
  

  Time from symptom onset to treatment is an important factor affecting the relative benefit of carotid artery revascularization.

  
  
  
  
  • 
    

    Preferentially, patients should be treated within 2 weeks post event (ideally, within a few days).

    
    
    
    
    • 
      

      Patients with large carotid artery territory strokes, who are severely disabled, may undergo delayed intervention after 4–6 weeks, depending on the patient’s clinical status and the degree of remaining tissue at risk.

      
      
      
      
      • 
        

        In those patients, theoretically, a delay may minimize reperfusion injury in the context of large cerebral infarcts.

      
      

    
    
    
    
  • 
    

    Hemorrhage, due to reperfusion post-carotid artery revascularization, is an uncommon but real concern, best managed by tight control of blood pressure, during and post procedure.⁹

  
  

How to determine if the patient would benefit from carotid artery stenting (CAS) versus carotid artery endarterectomy (CEA)?

• 
  

  The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) showed that, for patients with either symptomatic or asymptomatic carotid artery stenosis, the risk of stroke, MI, or death did not differ statistically between patients who underwent CEA or CAS.

  
  
  
  
  • 
    

    The 4-year rate was 7.2% for CAS and 6.8% for CEA.¹³

    
    
  • 
    

    A European study of symptomatic carotid artery patients found that the risk of CAS versus CEA was higher, with the 30-day risk of stroke or death being 8.5% after CAS, versus 4.7% after CEA.¹⁴

    
    
  • 
    

    In the CREST study, there were no differences by sex or symptomatic status, but older patients (age >70 years) fared better with CEA because of a lower stroke rate. Younger patients, by contrast, fared better with CAS as a result of a lower MI rate.

    
    
  • 
    

    Over age 80, the risk of CAS was such that these patients were excluded from the randomized study.

    
    
    
    
    • 
      

      The choice of CAS versus CEA should be made based on the experience of the proceduralists, taking into consideration patient preferences or other logistical issues.

      
      
      
      
      • 
        

        In a study of Medicare beneficiaries who underwent carotid artery stenting, 2-year mortality was high (32% for symptomatic and 27.7% for asymptomatic carotid artery stenosis).¹⁵

        
        
      • 
        

        Older age, symptomatic disease, and nonelective admissions were associated with a greater risk of poor outcomes.

        
        
      • 
        

        The conclusion was that the generalizability of the CREST study did not seem applicable to the “real-world” situation of these Medicare beneficiaries.

      
      

    
    

  
  
  
  
• 
  

  All other factors being equal, CEA is possibly the preferred option for most patients with symptomatic carotid artery stenosis.¹⁵

An initial decision was made to treat the patient with CEA but then the patient developed intermittent chest pain. What should be done now?

• 
  

  All patients with moderate or high-grade carotid artery stenosis should probably undergo a cardiac evaluation, including cardiac stress testing.¹⁶

  
  
• 
  

  Staged CEA, prior to coronary artery bypass graft (CABG), is reasonable for patients with stable severe coronary artery disease and symptomatic high-grade carotid artery disease.

  
  
  
  
  • 
    

    Stroke-related morbidity and mortality with simultaneous combined procedures appear to be in an acceptable 3% to 6% range, although overall mortality is slightly higher than for CABG alone.¹⁷

  
  
  
  
• 
  

  CAS for symptomatic severe carotid artery stenosis preceding CABG is a reasonable approach, but may necessitate delay in CABG because of the need for 4–6 weeks for dual antiplatelet therapy post-stent.

Intracranial atherosclerosis

• 
  

  The frequency of IS due to intracranial arterial stenosis is possibly equal to that of extracranial cervical arterial disease.¹⁸

  
  
• 
  

  Warfarin does not appear to be superior to aspirin for symptomatic intracranial stenosis, even for basilar artery stenosis or occlusion.

  
  
  
  
  • 
    

    In a study comparing warfarin (INR 2–3) to aspirin (1300 mg daily), there was a trend to stroke benefit for warfarin, but this was outweighed by statistically significant risks of bleeding and death in the warfarin group.¹⁸

    
    
  • 
    

    Theoretically, the novel oral anticoagulants (NOACs), with their lesser bleeding risk compared with warfarin, might be superior to antiplatelet agents for patients with intracranial arterial stenosis but, at the present time, this is purely conjecture.

  
  
  
  
• 
  

  Intracranial artery stenting remains an unproven therapy.^19–21 To date, the only currently available randomized trial showed that stenting was inferior to medical therapy.

  
  
  
  
  • 
    

    In the Stenting vs. Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial,²¹ 14% of patients in the angioplasty/stent arm experienced a stroke, or died within 30 days of enrollment, compared with 5.8% treated with medical therapy alone.

    
    
  • 
    

    Current guidelines suggest that, for either anterior or posterior circulation intracranial arterial stenosis, therapy with antiplatelet agents, statins, and risk factor modification is recommended.

    
    
    
    
    • 
      

      Endovascular therapy should only be considered if patients are having recurrent symptoms despite aggressive medical therapies.⁹

    
    

  
  

Aortic arch atheroma²²

• 
  

  Aortic arch atheroma is an uncommon but recognized source of artery-to-artery embolism, particularly during, or immediately after, cardiac surgery in the context of cannulation for cardiopulmonary bypass procedures.

  
  
• 
  

  There are no randomized clinical trials regarding the management of ulcerated aortic arch atheroma.

  
  
• 
  

  Antiplatelet and statin therapy for secondary stroke prevention is recommended.

  
  
  
  
  • 
    

    There is no evidence for preferential anticoagulation of IS patients with aortic arch atheroma.

  
  
  
  
• 
  

  Aortic endarterectomy for secondary stroke prevention is not recommended.

Medical therapy for small and large vessel cerebral atherosclerosis

What is the best medical management for this patient?

• 
  

  As described by C. Miller Fisher, the putative mechanism of most subcortical small vessel ischemic stroke is often due to lipohyalinosis.²³

  
  
  
  
  • 
    

    Subcortical strokes, with associated lacunar-type syndromes, may be due to other mechanisms such as cardiac or artery-to-artery embolism, however.²³

    
    
  • 
    

    The diagnosis of small vessel subcortical (“lacunar”) stroke is somewhat of an exclusionary diagnosis.²⁴

  
  
  
  
• 
  

  In the absence of other etiologies, small vessel strokes are managed with antiplatelet therapy and cardiovascular risk factor control.

  
  
  
  
  • 
    

    The SPS3 study suggested that targeting to arterial systolic blood pressure (SBP) <130 mmHg, for patients with recent lacunar-type stroke, might be beneficial.²⁵

  
  
  
  
• 
  

  In the AHA guidelines, clopidogrel was deemed likely as effective as aspirin, or extended-release dipyridamole plus low-dose aspirin, though because of the nature of the clinical trial evidence, clopidogrel was not recommended preferentially compared with the other two drugs.²⁶

  
  
• 
  

  The guidelines noted that agent selection should be based on relative effectiveness, safety, cost, patient characteristics, and patient preferences. The preferential choice of aspirin as the first-line drug is mainly based on its low cost.

  
  
  
  
  • 
    

    There are no data to support the choice of aspirin 300–325 mg or 75–81 mg preferentially.

  
  
  
  
• 
  

  The absolute benefit of all of the antiplatelet therapies is fairly small.

  
  
• 
  

  There are no clinical trials that indicate switching antiplatelet agents necessarily reduces the risk for subsequent events.

  
  
  
  
  • 
    

    Despite the concept of dose-related aspirin resistance, aggregate data do not support the premise that intermediate-dose aspirin (300–325 mg daily) is superior to low-dose aspirin (50–81 mg daily) for secondary stroke prevention.

    
    
    
    
    • 
      

      For patients already on aspirin at the time of first-ever or recurrent stroke, switching to another agent, rather than using an aspirin dose escalation strategy, seems reasonable.²⁶

    
    

  
  
  
  
• 
  

  Several studies have explored dual antiplatelet therapy versus antiplatelet monotherapy for secondary stroke prevention.

  
  
  
  
  • 
    

    The MATCH study showed that clopidogrel plus aspirin was not superior to clopidogrel monotherapy.²⁷

    
    
  • 
    

    The SPS3 study showed that clopidogrel plus aspirin was not superior to aspirin monotherapy.²⁸

    
    
  • 
    

    The PRoFESS study showed that extended-release dipyridamole plus low-dose aspirin was not superior to clopidogrel monotherapy.²⁹

    
    
  • 
    

    Dual antiplatelet therapy was associated with an increased risk of bleeding over time. A Chinese study suggested that clopidogrel plus aspirin was beneficial for minor stroke or TIA, when given within 24 hours, but when dual therapy was given beyond 21 days, the bleed risks outweighed long-term benefits.³⁰

  
  
  
  
• 
  

  At the present time, dual antiplatelet therapy should only be given long-term to stroke patients if there is another medical indication necessitating dual therapy (ie, presence of a coronary artery stent) or stroke recurrence despite use of several monotherapy regimens.

Cervical artery dissection (CAD)

What is the most likely diagnosis?

• 
  

  CADs comprise 2% of all ischemic strokes, but are important and under-recognized causes of stroke in younger patients.^9,26,31,32

  
  
• 
  

  CAD can be spontaneous, but can also result from trauma although minor in degree.

  
  
  
  
  • 
    

    Connective tissue disorders, such as Marfan syndrome, Loeys-Dietz syndrome, vascular type Ehlers-Danlos (type IV), and unspecified connective tissue disorders, have long been associated with CAD.

    
    
  • 
    

    Osteogenesis imperfecta and fibromuscular dysplasia (FMD) are other syndromes that should be considered.

    
    
  • 
    

    Patients with CAD may also be at risk for systemic large vessel dissection or intracranial aneurysm.

    
    
  • 
    

    An association, but not causality, has been suggested between cervical manipulative therapy and CAD.³²

  
  
  
  
• 
  

  The initial complaint may just be nonspecific headache or neck pain.

  
  
  
  
  • 
    

    Cervicalgia and Horner syndrome are the most common warning signs for cerebral or retinal ischemia in patients with carotid CAD.

    
    
  • 
    

    Patients with vertebral artery dissection may present with headache, neck pain, vertigo, nausea, or visual disturbance.

  
  
  
  
• 
  

  Artery-to-artery embolism from the dissected segment to distal vessel segments is the main cause of CAD-related stroke.

  
  
• 
  

  Strokes can occur immediately post-dissection, or in a delayed fashion.

  
  
  
  
  • 
    

    The Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) database did not find an increased risk of symptomatic bleeding or worse outcome in patients with AIS and CAD treated with thrombolytic therapy.³³

    
    
  • 
    

    Recurrent ischemic event rates ranged from 0% to 13% at 1 year; most recurrent events occurred within the first month of the initial event.

  
  
  
  
• 
  

  Antiplatelet or anticoagulant therapy for at least 3–6 months is recommended.

  
  
• 
  

  There are no clear randomized data to support anticoagulation as preferable to antiplatelet therapy.

  
  
  
  
  • 
    

    The Cervical Artery Dissection in Stroke Study (CADISS) showed that the stroke recurrence rate post dissection is very low and there was no clear benefit for anticoagulation versus antiplatelet therapy.³⁴

  
  
  
  
• 
  

  Endovascular stenting is not indicated but may be an option for those patients with recurrent events despite all medical therapies.

Cardioembolic stroke

At this stage in the evaluation what is the most appropriate management to prevent stroke recurrence?

• 
  

  Cardioembolic etiologies comprise about 25% of all ischemic strokes (IS).

  
  
• 
  

  Cardioembolic strokes are associated with high mortality rates, ranging up to 27% of all hospitalized IS patients.²⁶

  
  
  
  
  • 
    

    Cardioembolic strokes have an overall higher risk of disability, and stroke recurrence, compared with other stroke subtypes.

    
    
    
    
    • 
      

      Patients with mechanical prosthetic heart valves, rheumaticvalvular heart disease, infective endocarditis, some cardiomyopathies, and intra-atrial tumors are at particular high risk of cardiac embolism.

      
      
      
      
      • 
        

        Table 13-2 reviews the recommendations for primary and secondary stroke prevention for certain nonatrial fibrillation-related sources of cardiac embolism.

      
      

    
    

  
  
  
  
• 
  

  Half of cardioembolic strokes are secondary to nonvalvular AF.

  
  
  
  
  • 
    

    AF increases stroke risk by a factor of five.³⁵

    
    
  • 
    

    The overall risk of stroke secondary to AF is approximately 5%.^26,31,35

    
    
    
    
    • 
      

      Individual prediction of stroke risk is best estimated by taking into account various comorbidities.

      
      
      
      
      • 
        

        The CHA₂DS₂-VASc score should be used to stratify cardiac embolism risk in nonvalvular AF patients (see Table 13-3).

      
      
      
      
    • 
      

      Chronic kidney disease (CKD) increases stroke risk by 3.7 for AF patients

      
      
      
      
      • 
        

        For patients with AF and CKD, the stroke hazard ratio was 1.49, compared with those with AF without CKD. ³⁶

      
      

    
    

  
  
  
  
• 
  

  Rate versus rhythm control management for AF is beyond the scope of this chapter. See the AHA/ACC guidelines on atrial fibrillation for more on this topic.^26,37

  
  
• 
  

  Selection of antithrombotic therapy for AF patients should be made based on patient risk, regardless of whether AF is paroxysmal, persistent, or permanent.³⁵

  
  
  
  
  • 
    

    Anticoagulation therapy with warfarin, targeted to an INR goal of 2.0–3.0, reduces the risk of stroke up to 68% (95% CI 50% to 79%) with absolute annual risk reduction from 4.5% to 1.4%.

    
    
    
    
    • 
      

      Serial monitoring of the INR should occur at least weekly during initiation of therapy, and monthly when the INR is stable.³⁷

    
    
    
    
  • 
    

    Patients with a CHA₂DS₂-VASc score ≥2 should be prescribed an anticoagulant, unless there are specific contraindications to preclude such treatment.³⁸

    
    
    
    
    • 
      

      By definition, patients with TIA or stroke are assigned a score of at least 2.

    
    
    
    
  • 
    

    Patients with AF and mechanical heart valves should be anticoagulated with an international normalized ratio (INR) intensity based on the type and location of the mechanical heart valve prosthesis (2.0–3.0 or 2.5–3.5).

    
    
    
    
    • 
      

      Patients with AF and mechanical heart valves should be bridged with unfractionated heparin (UFH) or low-molecular-weight heparins (LMWH), if interruption of warfarin is necessary.

      
      
      
      
      • 
        

        The role of bridging therapy for patients with nonvalvular AF is not clear, but AF patients with a history of stroke or TIA, and a CHA₂DS₂-VASc score 5 or 6, should undergo bridging therapy.

      
      

    
    

  
  
  
  
• 
  

  For nonvalvular AF patients, at high risk of bleeding, or refusing anticoagulant therapy, clopidogrel plus aspirin provides additional efficacy when compared with aspirin, but clopidogrel plus aspirin actually conveys a risk of bleeding higher than warfarin.³⁹

  
  
  
  
  • 
    

    Antiplatelet monotherapy is therefore preferred.

  
  
  
  
• 
  

  Combination anticoagulant therapy with antiplatelet therapy should not be used routinely, but may be reasonable in patients with clinical coronary heart disease (ie, with acute coronary syndromes or coronary stents).

  
  
• 
  

  Immediate initiation of anticoagulants in acute ischemic stroke (AIS) is unproven, and bridging therapy is not indicated.

  
  
  
  
  • 
    

    Initiation of anticoagulation within 2–14 days of AIS onset is acceptable practice.

    
    
    
    
    • 
      

      Oral anticoagulation can be initiated immediately in patients with TIA or minor stroke.

      
      
    • 
      

      For AIS patients with hemorrhage, or at high risk for hemorrhagic conversion, delayed anticoagulation beyond 14 days is appropriate.

      
      
      
      
      • 
        

        Prior to anticoagulation of patients with medium to large infarctions, repeat brain imaging to exclude hemorrhagic stroke conversion should be considered.

        
        
        
        
        • 
          

          Brain imaging, preferably with MRI, might also be reasonable for older patients without history of stroke/TIA, who have cognitive impairment, prior to anticoagulation, so as to identify possible asymptomatic hemorrhage (ie, microbleeds, occult subdural hematoma, prior ICH) that could be a marker for the increase in the risk of subsequent intracranial bleeding.

        
        

      
      

    
    
    
    
  • 
    

    The HAS-BLED scale is one tool that can help estimate bleeding risk in AF patients being considered for anticoagulation (see Table 13-4).⁴⁰

  
  
  
  
• 
  

  All other risks being equal, the default decision should be for anticoagulation.

How you should advise this patient?

• 
  

  Novel oral anticoagulants (NOACs) were as effective, or noninferior, when compared with warfarin, for both primary and secondary stroke prevention, in nonvalvular AF patients.^37,41–44

  
  
  
  
  • 
    

    Agents currently prescribed in the United States include dabigatran etexilate (direct thrombin inhibitor), rivaroxaban, and apixaban (factor Xa inhibitors). Edoxaban (factor Xa inhibitor) has also been recently approved.⁴⁵

    
    
    
    
    • 
      

      There are no direct comparisons of these drugs with each other.

      
      
      
      
      • 
        

        Apixaban and dabigatran (at the dose of 150 mg twice daily) were possibly superior to warfarin. ^{41 , 43 , 44}

      
      

    
    
    
    
  • 
    

    Dose adjustment is required in patients with CKD. These drugs are contraindicated in patients with creatinine clearance <15 mL/min, or who require renal dialysis.

    
    
    
    
    • 
      

      NOACs are also contraindicated in patients with hepatic disease, or who are pregnant or lactating.

      
      
    • 
      

      NOACs are also relatively contraindicated in elderly patients who have a diminished creatinine clearance.

    
    

  
  
  
  
• 
  

  Compared to warfarin, NOACs offer the advantage of fewer drug–drug interactions, and no dietary limits (with vitamin K-containing food).

  
  
  
  
  • 
    

    NOACs pharmacologic profiles are also less variable compared with warfarin.

    
    
  • 
    

    Onset is more rapid than warfarin, making bridging possibly unnecessary.

    
    
  • 
    

    There is no need for regular monitoring of the INR or aPTT.

  
  
  
  
• 
  

  In the randomized clinical trials, the risk of intracranial hemorrhages with the NOACs was somewhat lower than warfarin.

  
  
  
  
  • 
    

    Dabigatran, rivaroxaban, and edoxaban were associated with a greater frequency of major gastrointestinal (GI) bleeding compared with warfarin.

    
    
  • 
    

    Other disadvantages of NOACs include cost, lack of well-studied reversibility protocols, and a risk of increased thromboembolism if even a single dose is missed.

  
  

Hypercoagulable state

What would be the next step in the management?

• 
  

  Evaluation of possible hypercoagulable states should be considered for stroke patients <55 years with no clear stroke etiology.²⁶

  
  
• 
  

  Other indications for hypercoagulable studies include:

  
  
  
  
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    History of multiple strokes with no other clear etiology.

    
    
  • 
    

    Prior history of systemic arterial embolism with no other defined etiology.

    
    
  • 
    

    Prior history of venous thromboembolism (VTE).

    
    
    
    
    • 
      

      There are a number of inherited thrombophilias particularly associated with VTE that should be considered.

    
    
    
    
  • 
    

    Family of history of hypercoagulability or marked abnormalities on routine screening coagulation studies (PT or aPTT).²⁶

    
    
  • 
    

    History of neoplasm may also be associated with hypercoaguable states.

    
    
    
    
    • 
      

      Occasionally, IS can be the first presentation of neoplasm.

    
    
    
    
  • 
    

    Patients with recurrent strokes previously exposed to UFH or LMWH should also be evaluated for heparin-induced thrombocytopenia.

  
  
  
  
• 
  

  SLE or other autoimmune collagen-vascular disorders may be associated with APAS.

  
  
  
  
  • 
    

    APAS-related strokes sometimes present as Sneddon syndrome, manifested clinically by livedo reticularis and cerebrovascular disease.

  
  
  
  
• 
  

  For patients with suspected thrombophilia, screening tests depend on whether a venous or arterial thromboembolism is suspected.

  
  
• 
  

  Current guidelines for management of IS patients with thrombophilias are as follows.²⁶

  
  
  
  
  • 
    

    Arterial cerebral ischemia (stroke or TIA), in the absence of VTE, with a proven inherited thrombophilia, may be managed with either anticoagulant or antiplatelet therapy.

    
    
    
    
    • 
      

      For first-ever arterial cerebral ischemia, antiplatelet therapy may suffice, but if stroke patients have an associated APAS, or if patients have recurrent strokes with no other explanation and positive antibodies, long-term warfarin is recommended with a target INR 2–3.

      
      
    • 
      

      For patients with arterial stroke or TIA, and associated VTE, anticoagulation is recommended with the duration of therapy dependent on the thrombophilia type.

    
    
    
    
  • 
    

    For patients with cerebral venous sinus thrombosis (CVST) and recurrent VTE, or inherited thrombophilia, long-term anticoagulation is recommended.

    
    
  • 
    

    Patients with hypercoagulable states related to neoplasm should be on long-term anticoagulation.

    
    
  • 
    

    There is no indication for any of the NOACs in patients with stroke and hypercoaguable states at this time.

    
    
  • 
    

    Warfarin or, in certain circumstances, long-term LMWH anticoagulation is recommended in pregnant women, with a history of ischemic stroke and thrombophilias.

    
    
  • 
    

    UFH should be started prior to warfarin for patients with suspected protein C or protein S deficiencies.

  
  

Embolic stroke of undetermined etiology (ESUS) or “cryptogenic” stroke