Stroke and Transient Ischemic Attack

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Chapter 59

Stroke and Transient Ischemic Attack

1. What is stroke? How common is stroke? How common is it in the setting of cardiac disease?

    Stroke is a focal disturbance of blood flow to the brain. Stroke is not a single disease but the end result of many different pathophysiologies leading to cerebrovascular occlusion or rupture. It can be classified as either primarily ischemic (80%) or hemorrhagic (20%). Ischemic strokes can develop a hemorrhagic component, termed hemorrhagic conversion, especially if the stroke is large. There are approximately 700,000 strokes per year in the United States, and it is the leading cause of disability. The biggest risk factor for stroke is prior stroke, and the second biggest risk factor is age. Risk factors common to both stroke and atherosclerotic cardiac disease include hypertension, diabetes, and smoking. In addition, cardiac diseases such as atrial fibrillation and valvular disease are risk factors for stroke. Strokes occur after cardiac procedures at a rate of 0.7% to 7%, depending on the procedure, and may be due to intrinsic disease or emboli or microemboli from the procedure itself.

2. What is a transient ischemic attack, and why is the clinical recognition of it important?

    Transient ischemic attack (TIA) is a neurologic deficit that, by definition, resolves within 24 hours, although most resolve within 5 to 15 minutes. It is important to identify TIAs because they represent an opportunity to intervene with appropriate strategies to prevent future strokes and permanent disability. Ninety-day stroke rates for patients with TIA are in excess of 10% in some series, with the greatest risk within the 48 hours to first week after the TIA. Longer duration, a lesion on diffusion-weighted magnetic resonance imaging (MRI), and the presence of large cerebral artery stenosis (seen on carotid duplex, computed tomographic [CT], or magnetic resonance [MR] angiography) are all associated with a higher risk of stroke following TIA.

3. What are the major causes of stroke and TIA?

    The major etiologies of ischemic stroke are cardioembolism, small vessel vasculopathy leading to lacunar stroke, and large vessel atherosclerosis (including intracranial atherosclerotic plaque rupture, as well as embolization from large arteries, such as the carotid, vertebral, and basilar arteries, to cerebral arteries [Fig. 59-1 and Table 59-1]). Hemorrhagic strokes include subarachnoid hemorrhage (usually due to aneurysm rupture) and intraparenchymal hemorrhage. Intraparenchymal hemorrhages are classified by their location: subcortical (associated with uncontrolled hypertension in 60% of cases) versus cortical (more concerning for underlying mass, arteriovenous malformation, or cerebral amyloid angiopathy; see Fig. 59-1). Figure 59-2 summarizes the major causes of stroke and their relative frequency.

    Among the other potential causes of stroke, dissection of the blood vessels needs to be considered, especially if there is face or neck pain or a history of trauma. Illicit drug use is a possible cause of either ischemic stroke (cocaine-, stimulants-, or “bath salts”–induced spasm) or hemorrhagic stroke (as a result of vascular injury or sudden massive increase in blood pressure). Patent foramen ovale (PFO) remains a controversial cause of stroke (see Question 18). Other, rarer, causes of stroke include hypercoagulable states (e.g., lupus and antiphospholipid antibody syndrome) and genetic disorders, such as homocystinuria and fibromuscular dysplasia.

4. How are stroke and TIA diagnosed?

    Stroke and TIA are diagnosed clinically, and no imaging correlation is usually required for the diagnosis, although imaging procedures are performed to rule out other causes, such as tumor. Focal neurologic deficits with sudden onset should be considered as a vascular event until proven otherwise because of the possibility of recurrence or progression of the deficit. Focal weakness, numbness, facial asymmetry, or speech difficulties are classic presentations. Altered level of consciousness, vertigo, and cranial nerve deficits are often seen with vertebrobasilar-brainstem strokes. See Table 59-1 for lists of the clinical signs and symptoms of the major subtypes of stroke: large vessel atherosclerosis and thrombosis, cardioembolic stroke, and small vessel stroke.

5. What should be done in cases of suspected stroke or TIA?

    A head CT must be performed immediately to distinguish ischemic from hemorrhagic strokes (see Fig. 59-1) because these are managed very differently. The CT itself does not diagnose stroke; it is primarily used to rule out causes other than ischemic stroke, including hemorrhagic infarction, tumor, subdural hematoma, and other causes. Figure 59-1 demonstrates the CT findings of strokes and stroke mimics.

    In cases of suspected stroke, one should page the stroke team (when one exists) or the service responsible to rapidly address stroke—every minute counts. Immediately check blood glucose because hypoglycemia or hyperglycemia can cause focal neurologic deficits mimicking stroke. Also obtain an electrocardiogram (ECG) and basic blood analysis (complete blood cell count, coagulation studies, and renal/electrolyte panel). The ECG and cardiac workup initially can reveal atrial fibrillation or the surprisingly common coexistence of various kinds of acute cardiac syndromes with stroke.

6. How are ischemic acute strokes treated?

    Three possible treatments are now suggested to improve outcomes after acute ischemic stroke: (1) intravenous tissue plasminogen activator (tPA); (2) aspirin; and, in the case of large strokes, (3) hemicraniectomy performed before clinical herniation.

tPA

The only medication approved by the U.S. Food and Drug Administration (FDA) for acute ischemic strokes is intravenous (IV) tPA, administered within 3 hours of symptom onset. Based on the European Cooperative Acute Stroke Study III (ECASS III), American Heart Association (AHA) guidelines recommend treatment with IV tPA in selected patients out to 4.5 hours after symptom onset, but this is not yet approved by the FDA. Note, however, that the earlier tPA is given, the better the clinical outcome. The greatest benefit of tPA occurs at earlier time points. It is critical to give tPA as soon as possible if head CT does not reveal signs of hemorrhage or hypodensity. Only tPA is approved for acute stroke thrombolysis. Only eight stroke patients need to be treated with IV tPA to result in one patient with complete or near-complete recovery, and this number needed to treat (NNT) takes into account the increased risk of hemorrhage after tPA administration. Patients of any age benefit from tPA. Contraindications to IV tPA for the treatment of stroke are given in Box 59-1. Although tPA administration is not contraindicated in the setting of moderately elevated international normalized ratios (INR of 1.3-1.7), recent studies suggest an increased risk of brain hemorrhage compared to tPA administraton with a normal INR. Importantly, patients who have their strokes after cardiac catheterization and who meet these criteria may still benefit from tPA, despite the recent administration of heparin and glycoprotein IIb/IIIa inhibitors, although this is outside the usual protocols and should be done only with expert help. In this situation, various treatments have been reported, including intraarterial therapy or IV abciximab, but these uses remain investigational.

BOX 59-1   CONTRAINDICATIONS TO INTRAVENOUS tPA FOR THE TREATMENT OF STROKE.

image Presentation more than 3 hours (4.5 hours in select cases) from the time the patient was last seen normal

image Any history of spontaneous intracerebral hemorrhage

image Intracranial neoplasm or arteriovenous malformation

image Minor or rapidly resolving deficits (including transient ischemic attack [TIA])

image Uncontrolled hypertension greater than 185/110 mm Hg despite antihypertensive treatment

image Major surgery in the previous 2 weeks

image Gastrointestinal (GI) or urinary hemorrhage in the previous 3 weeks

image Stroke, head trauma, intracranial/intraspinal surgery, or myocardial infarction within 3 months

image Current bacterial endocarditis

image International normalized ratio (INR) > 1.7

image Platelet count < 100,000

image Elevated partial thromboplastin time (PTT)

image Clinical picture concerning for subarachnoid hemorrhage or aortic dissection

After tPA administration, frequent clinical examinations are crucial and blood pressure must be controlled to less than 180/105 mm Hg. Subcutaneous heparin and antiplatelet agents are held for 24 hours, until follow-up imaging confirms absence of hemorrhagic conversion.

In patients with ischemic stroke who are not candidates for tPA, optimal blood pressure is not known but is often permitted to run high (up to 220/120 mm Hg), as long as there are no signs of hypertensive end-organ damage. This is theoretically designed to increase perfusion of brain tissue at continued risk for ischemia, but it is unknown if outcome is improved. Cautious control of blood pressure is recommended to avoid sudden drops or rises. Any hypotension or relative hypotension associated with neurologic worsening should be treated with intravenous fluids and, if necessary, pressors until clinical examination improves or upper limits specified earlier are reached.

Endovascular devices for cerebral clot disruption/retrieval are FDA approved, although their efficacy for improving outcome has yet to be demonstrated. The Interventional Management of Stroke 3 trial did not show a benefit of combined IV tPA plus endovascular treatment over IV tPA alone. At this time, endovascular treatment of acute stroke is often suggested in patients who present early but are ineligible for IV tPA because of anticoagulation or another condition posing an unacceptably high risk of systemic bleeding, but ongoing randomized trials may clarify their exact role.

Hemicraniectomy

Patients with malignant middle cerebral artery occlusion are at risk of death from cerebral edema and herniation. Removal of the overlying skull has been shown to improve mortality with an NNT of 2. It is also often suggested for strokes within the cerebellar hemisphere, but this is largely anecdotal. Early consultation with neurosurgery is suggested.

7. How are hemorrhagic strokes managed?

    Hemorrhagic strokes are managed by reversing any coagulopathy and withholding administration of subcutaneous heparin and antiplatelet agents. Controlling blood pressure is a focus of interest because high blood pressure is associated with hematoma expansion and rebleeding. It is considered safe to decrease blood pressure by up to 25% in the first 2 to 6 hours, as long as findings on neurologic examination do not worsen.

8. What other measures are important in the management of all strokes?

    In patients not treated with thrombolytic therapy, subcutaneous heparin or low-molecular-weight heparinoids for deep vein thrombosis (DVT) prophylaxis should be started as soon as possible in nonambulatory patients unless contraindicated. Keep patients nil per os (NPO) until safe swallowing can be confirmed, to prevent aspiration. Physiological variables are maintained as close to the patient’s normal as possible, but there is no evidence yet for aggressive management of blood sugar, in particular, although hyperglycemia is associated with a worse outcome.

9. Is the presence of atrial fibrillation in patients with stroke or TIA an important consideration for future management?

    Yes. Any patient with atrial fibrillation who has had a stroke or TIA is considered at high risk for future strokes without anticoagulation (see Question 11). As such, all patients should be monitored with telemetry to optimize identification of intermittent (paroxysmal) atrial fibrillation, because intermittent atrial fibrillation is as much of a risk factor for stroke as persistent atrial fibrillation. A single ECG (unless it reveals atrial fibrillation) is inadequate for detection of this important risk factor. Prolonged event monitors reveal subclinical atrial fibrillation in a substantial proportion of patients with cryptogenic stroke, and are warranted in cases where clinical suspicion is high.

10. What is the utility of echocardiogram for workup of acute stroke?

    In stroke patients with a suspected cardioembolic cause, echocardiogram is indicated (see also Chapter 5 on echocardiography). Transesophageal echocardiogram is often performed in patients with suspected embolic stroke and a nondiagnostic transthoracic echocardiogram. An echocardiogram is not needed to determine secondary stroke prevention strategies for stroke patients with known atrial fibrillation, because these patients should be anticoagulated; however, identification of a cardiac thrombus would affect timing of anticoagulation initiation and may have some prognostic value.

11. Which patients with atrial fibrillation merit anticoagulation therapy for the prevention of stroke?

    All patients with history of stroke and atrial fibrillation merit consideration for anticoagulation, because the risk of subsequent stroke in these patients is 2% to 15% per year and anticoagulation results in a greater than 60% reduction in ischemic strokes. Other high-risk groups include those over the age of 75 (especially women) and those with the following risk factors: poorly controlled hypertension, diabetes, and poor left ventricular function or recent heart failure. A number of risk stratification schemes can help determine which patients should be anticoagulated to prevent stroke. These include CHADS2 (see Fig. 34-1), Stroke Prevention in Atrial Fibrillation (SPAF), Atrial Fibrillation Investigators (AFI), and Framingham, among others. These schemes integrate risk factors to assist in the decision for anticoagulation therapy: The greater the number of risk factors, the higher the risk of stroke. It is important to note that these schemes relate to primary prevention in atrial fibrillation; a stroke or TIA automatically places a patient in the high-risk category for each of these schemes. As such, secondary prevention of stroke in patients with atrial fibrillation should involve anticoagulation unless there is a contraindication. The elderly also appear to benefit from anticoagulation for secondary stroke prevention; thus, age alone is not a contraindication, although elderly patients are at higher risk for bleeding.

    Contraindications to preventive anticoagulant therapy include history of severe gastrointestinal (GI) bleeding and history of falls or an extremely high fall risk. The HAS-BLED score is a simple method for assessing bleeding risk, although this score was validated in a group that had already been considered safe for anticoagulation, which is a serious limitation of its applicability. After stroke, many patients are at risk for falls. As they improve, their fall risk status may also improve, so it is important to reconsider anticoagulation at future visits. Goal INR for secondary stroke prevention is 2 to 3; studies have demonstrated that many stroke prevention failures are the result of subtherapeutic INRs. The most serious bleeding risk associated with anticoagulation is intraparenchymal hemorrhage. This risk is probably higher for patients with extensive small vessel disease or cortical microhemorrhages than for those with healthier brain parenchyma. Many centers will perform a susceptibility-sensitive MRI (e.g., gradient echo) to assess the presence of microhemorrhages, particularly in the cortex. The decision for anticoagulation in particular patients should be a collaborative one, with the risks, benefits, and monitoring schedule clearly explained so that the patient can make an informed decision.

12. What are the benefits and risks of the newer anticoagulants for stroke prevention in the setting of atrial fibrillation?

    New oral anticoagulants include the direct thrombin inhibitor dabigatran and the factor Xa inhibitors apixaban and rivaroxaban (Fig. 59-3). Dabigatran and apixaban were superior to warfarin in preventing vascular events and death in large randomized controlled trials of subjects with atrial fibrillation; rivaroxaban was noninferior to warfarin. The benefit of these agents over warfarin is due to better efficacy for stroke prevention, as well as lower overall bleeding risk (Table 59-2). The most serious complication of anticoagulation is intracerebral hemorrhage, which was reduced substantially with these agents. Subgroup analysis of the dabigatran trial found that concomitant aspirin use increased risk of intracerebral hemorrhage 1.6-fold. Dabigatran and rivaroxaban had a higher rate of GI bleeding relative to warfarin; apixaban showed no such trend. Dabigatran has shown a small but consistent increase in myocardial infarction (MI) compared to warfarin, although it decreases overall vascular events and mortality.

13. Are there options other than anticoagulation for secondary stroke prevention in the setting of atrial fibrillation?

    Treatments aimed at reducing stroke risk in atrial fibrillation (and thus the need for anticoagulation) include restoring sinus rhythm, resecting the left atrial appendage, and transcatheter closure of the left atrial appendage opening. Unfortunately, no studies have thus far demonstrated a sufficient reduction of stroke risk to warrant anticoagulation discontinuation. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study found that restoring sinus rhythm did not reduce stroke risk. The Watchman trial, which studied the efficacy of device closure of the left atrial appendage, similarly did not find a reduction in stroke risk; additional device trials are ongoing. The Left Atrial Appendage Occlusion Study II is an ongoing phase 3 trial comparing surgical excision of the left atrial appendage with best medical therapy. At this time, anticoagulation is the only intervention that has been demonstrated to reduce stroke in the setting of atrial fibrillation.

14. Which patients merit antiplatelet therapy for prevention of stroke? What is the benefit? What are the risks?

    All patients who do not meet criteria for anticoagulation after stroke should receive antiplatelet therapy with either (a) aspirin, (b) clopidogrel, or (c) aspirin plus extended release dipyridamole. These three agents are similarly efficacious for stroke prevention, decreasing risk of second stroke by 14% to 18%. Ensuring optimal compliance with antiplatelet therapy is more important than the individual agent used, so the choice of agent should be guided by comorbidities, tolerability, and cost. Clopidogrel may be preferred in patients with history of significant GI bleeding, peripheral vascular disease, or drug-eluting cardiac stents. Aspirin plus dipyridamole can cause headaches initially and so may be difficult to tolerate for patients with chronic headache. The Prevention Regimen for Effectively Avoiding Second Strokes (PROFESS) trial comparing clopidogrel with aspirin plus extended release dipyridamole found that neither regimen was superior; each regimen had a somewhat different side-effect profile. Aspirin alone may be a good choice when not contraindicated, particularly when cost of the alternative agents would hinder compliance.

    Aspirin should not be used in combination with clopidogrel for long-term secondary stroke prevention, as the combination showed an unacceptably high bleeding risk without additional protection from strokes, compared with either aspirin alone (in lacunar stroke patients) or clopidogrel alone (in all stroke patients), particularly after 90 days. However, the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial used aspirin plus clopidogrel for 90 days followed by aspirin alone in their management of high-risk intracranial stenosis patients with better-than-expected outcomes, although this regimen was not compared to a single-agent regimen. Patients may require both aspirin and clopidogrel for cardiac conditions such as drug-eluting stents, and such patients may be continued on this combination regimen after stroke, with an understanding that bleeding risk may be elevated.

15. How soon after a stroke or TIA should anticoagulation or antiplatelet therapy be initiated?

    In general, antiplatelet therapy can be initiated immediately in patients who are not candidates for tPA and do not have any indication of hemorrhagic component, and after 24 hours in patients who received tPA once lack of hemorrhage has been confirmed by imaging. Timing of anticoagulation is highly case-specific. Larger strokes are more likely to bleed than small strokes, especially early on. The risk of a second stroke in the 2 weeks after initial stroke in patients with atrial fibrillation is only 0.5% (in the absence of a known cardiac thrombus). The risk of bleeding from full dose heparinization of 1 week duration has been estimated at 5% based on the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) trial. Because of this, it is common practice to wait 1 month after a large stroke before initiating anticoagulation, although such a strategy has not been prospectively studied in a large trial. Patients with very small strokes may be started on anticoagulation within 1 or 2 days of stroke. The decision is much more difficult in patients with large strokes at higher risk for embolization, such as those with mechanical valves or demonstrated cardiac thrombus. In such cases, oral anticoagulation may be started cautiously after 5 to 15 days, depending on the individual situation. Retrospective data suggest bridging with heparin or low-molecular-weight heparin causes higher bleeding risk. In the absence of clinical or laboratory evidence of a hypercoagulable state, it is probably acceptable to start warfarin at low doses to achieve therapeutic anticoagulation slowly. Some clinicians suggest use of aspirin until an INR of 2 is achieved.

16. How should patients with carotid stenosis be managed?

    Patients with symptomatic carotid stenosis greater than 70% should be treated with carotid endarterectomy within 2 weeks of a TIA or non-disabling stroke because their risk of recurrent stroke is 15% per year over 5 years, and carotid endarterectomy CEA cuts this rate in half. Patients with symptomatic stenosis 50% to 69% benefit less from CEA but have the same up-front surgical risk, so good perioperative results are critical to their management. Asymptomatic patients, especially those with 60% stenosis or greater, have a 2% to 4% annual stroke rate, which is also cut in half after CEA. However, because up-front risk of death or stroke from the procedure is 3% to 6%, overall benefit is less than with symptomatic carotid stenosis, and a longer duration of survival is needed to benefit from the procedure.

    The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) comparing CEA with carotid stenting showed higher stroke and death rates in the carotid stenting group, but higher MI rates with CEA: overall rates of the combined endpoint were not different between groups. Older patients fared better with CEA than with carotid stenting and quality of life was better in those with MI than those with stroke.

17. How should patients with intracranial stenosis be managed?

    In the SAMMPRIS trial, subjects with a recent mild stroke or TIA in the territory of a major cerebral artery with 70% to 99% stenosis were randomized to receive stenting within 3 days plus protocol-guided aggressive medical management, versus medical management alone. All subjects received aspirin plus clopidogrel for 90 days, followed by aspirin alone. In addition to blood pressure and lipid goals, lifestyle coaches developed goals for weight loss, regular exercise, and smoking cessation with each participant. The trial was stopped early because 14.7% of subjects in the stenting arm had a stroke within 30 days (the majority within 1 day of stenting) compared with 5.8% in the medical management group; 1-year stroke rates were 20% and 12.2% respectively. Based on these data, stroke due to intracranial atherosclerosis is now managed with aggressive medical management.

18. How should patients with stroke and patent foramen ovale be managed?

    The CLOSURE I trial compared PFO closure to best medical management in subjects with cryptogenic stroke, and did not find a benefit of PFO closure after 2 years of follow up. More than 75% of subjects in each group with recurrent stroke had evidence of a mechanism other than paradoxical embolism.

Bibliography, Suggested Readings, and Websites

1. Adams, H.P., Jr., Bendixen, B.H., Kappelle, L.J., et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST: Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993;24:35–41.

2. Archives of Internal Medicine [No authors listed] . Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med. 1994;154:1449–1457.

3. Furie, K.L., Kasner, S.E., Adams, R.J., et al. American Heart Association Stroke Council, Council on Cardiovascular Nursing, Council on Clinical Cardiology, and Interdisciplinary Council on Quality of Care and Outcomes Research: Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42(1):227–276.

4. Giraldo, E.A. Stroke (CVA). Available at http://www.merckmanuals.com/professional/neurologic_disorders/stroke_cva/overview_of_stroke.html. Accessed March 26, 2013

5. Jauch, E.C., Kissela, B., Stettler, B. Acute Management of Stroke. Available at http://emedicine.medscape.com/article/1159752-overview. Accessed March 26, 2013

6. Jauch, E.C., Saver, J.L., Adams, H.P., Jr., et al. American Heart Association Stroke Council, Council on Cardiovascular Nursing, Council on Peripheral Vascular Disease, and Council on Clinical Cardiology: Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;4(3):870–947.

7. Morgenstern, L.B., Hemphill, J.C., 3rd., Anderson, C., et al. American Heart Association Stroke Council and Council on Cardiovascular Nursing: Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2010;41(9):2108–2129.

8. Khatri, P., Taylor, R.A., Palumbo, V., et al. The safety and efficacy of thrombolysis for strokes after cardiac catheterization. J Am Coll Cardiol. 2008;51:906–911.

9. National Heart, Lung and Blood Institute and Boston University. The Framingham Heart Study risk score profiles. Available at www.framinghamheartstudy.org/risk. Accessed March 26, 2013

10. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581–1587.

11. Schneck, M.J., Xu, L. Cardioembolic Stroke. Available at http://emedicine.medscape.com/article/1160370-overview. Accessed March 26, 2013

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