Stroke in Primary Care Patients: Part II: Imaging and Clinical Management
April 16, 2001 28 minutes read
Stroke in Primary Care Patients: Part II: Imaging and Clinical Management
Author: Alan Z. Segal, MD, Assistant Professor, Department of Neurology, Weill Medical College, Cornell University, Ithaca, NY.
Editor’s Note—As outlined in Part I of this series, brain imaging with CT scanning and MRI have revolutionized the assessment and management of stroke. In the emergency evaluation of a patient with acute stroke, there are 3 major goals: to exclude hemorrhage, assess for early infarct signs, and identify the vascular lesion. The first 2 goals may be accomplished with routine noncontrast cranial CT scan. Given the time urgency of acute stroke therapies, rapid acquisition of cranial CT is crucial. Adjunctive modalities listed below may also be helpful but should not delay the initiation of therapy.
Noncontrast cranial CT in the acute setting is sensitive for hemorrhage and may show subtle swelling, hypodensity, and loss of the distinction between gray and white matter consistent with early infarct. Identification of these changes is crucial to determine eligibility for thrombolysis.1 A hyperdensity indicating clot may rarely be visualized in the basilar artery or proximal middle cerebral artery (MCA).2
CT angiography (CTA) may be available in major centers. This technique requires an approximately 120 cc contrast injection with rapid image acquisition using a spiral (helical) scanner. CTA allows the rapid identification of occlusions in large blood vessels such as the basilar or proximal MCA. (See Figure 1.) Depending on when the passage of contrast is captured, visualization more proximally in the carotid artery or distally in MCA branches may be achieved. Disadvantages of CTA include a requirement for peripheral vascular access, possible anaphylactic reactions, and limited use in patients with renal failure.
MRI with DWI (diffusion weighted imaging) may allow visualization of infarcts in the "hyperacute" stage. Unlike CT or standard MRI, in which stroke is not identified for up to 24 hours after symptom onset, DWI will reveal tissue ischemia within minutes. DWI abnormalities will disappear within 10 days after an infarct and, therefore, may be helpful in distinguishing between acute and chronic lesions. DWI is also sensitive for the presence of multiple lesions outside of the symptomatic territory. Other useful MRI techniques include MR angiography (MRA), which may visualize narrowed or occluded blood vessels, and perfusion weighted imaging (PWI), which may differentiate between tissue that is infarcted and salvageable tissue at risk.3,4 (See Figure 2.)
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Ultrasound is an alternative method of gaining rapid information about blood flow in the large cerebral vessels. Carotid noninvasive studies may be performed to evaluate the carotid bifurcation while anterior and posterior transcranial doppler (TCD) can evaluate the distal carotid artery, vertebral-basilar system, and the proximal trunks of the anterior, middle, and posterior cerebral arteries.
With techniques such as CTA, MRA, or TCD to image occluded blood vessels, a "vascular diagnosis" can be made in the acute setting. With this information, the clinician is able to make more informed decisions about thrombolytic therapy, such as triage between IV and intra-arterial thrombolysis.5,6
Laboratory evaluation should include standard serum chemistries and hematology: SMA-20, complete blood count, and coagulation profile. Serum glucose is of particular importance as hypoglycemia may mimic stroke. Electrocardiography and chest radiography should also be considered. Additional tests that may be considered in specific circumstances include a hypercoagulability panel (proteins C and S, ATIII, factor V Leiden), D-dimers, fibrinogen, erythrocyte sedimentation rate (ESR), toxicology screen, and blood cultures.
Cardiac evaluation is necessary to isolate potential sources of emboli. Echocardiography with agitated saline contrast injection evaluates the presence of thrombus in any of the chambers, left ventricular size and function, left atrial size, mitral and aortic valvular disease, and the presence of a right-to-left shunt. Transesophageal echocardiography (TEE) studies are more sensitive to left atrial thrombus and atheromatous disease of the aortic arch. TEE is particularly important in a young patient with no other known cause of embolism. Injection of agitated saline may facilitate identification of intracardiac shunts. A 24-hour Holter monitor may identify arrhythmias such as atrial fibrillation (AF).7
Additional evaluation may be needed to identify more unusual causes of stroke, particularly in young patients. These disorders were outlined in Part I of this series.
Treatment of Acute Ischemic Stroke
Acute treatment of stroke is one of the most rapidly evolving fields in medicine. Because neurons tolerate ischemia more poorly than any other cell type in the body, time is critical. As cardiology practice has evolved with the slogan "time is muscle," the concept of "time is brain" should be promoted for 21st century stroke care. Multidisciplinary stroke teams and treatment protocols including emergency medicine, neurology, neurosurgery, internal medicine, radiology, and nursing should be assembled to facilitate this process.8
The process of acute stroke treatment should begin in the ambulance, and emphasis is now being placed on the prehospital care of the patient. Emergency dispatch service protocols should be designed to quickly recognize potential stroke victims and develop priority dispatch with appropriate response teams.9 Once the time of onset is clearly established to be less than 3 hours, and intracranial hemorrhage and early signs of stroke have been excluded with a cranial CT, all patients with the clinical diagnosis of ischemic stroke are candidates for IV rt-PA.
The most important study published in the field of stroke in the past 10 or more years is the National Intsitute of Neurological Disease and Stroke IV tPA Study (known as NINDS).10 The NINDS study demonstrated that among stroke patients treated within 3 hours of onset of their neurologic deficit, there was a significant increase in the percentage of patients with complete recovery or minimal deficit at 3 months. The NINDS trial was divided into 2 parts and enrolled a total of 624 patients in the combined study. The first part of the study was designed to assess whether patients receiving tPA achieved significant early improvement in neurologic deficits compared to those receiving placebo. Early improvement was defined as complete resolution of the neurologic deficit or an improvement from baseline of 4 or more points on the National Institutes of Health Stroke Scale (NIHSS) 24 hours after the onset of stroke. The NIHSS is available on the internet at http://www.stroke-site.org, the Brain Attack Coalition web site.
The second, pivotal part of the NINDS trial was an outcomes study that assessed whether treatment with tPA reduced the chance of disability in those receiving tPA compared with placebo measured at 3 months after stroke onset. Four outcome measures were used: the NIHSS, the Barthel index (BI), the modified Rankin scale (MRS), and the Glasgow Outcome Scale. Details of these scales are also available at the Brain Attack Coalition web site. A global statistic was used to determine whether the differences in these outcome measures were statistically significant between the tPA arm and the placebo arm before analysis of individual outcome measures. The magnitude of efficacy was impressive; there was an 11-13% absolute increase in the number of tPA-treated patients exhibiting minimal or no neurologic deficits or disabilities compared with placebo-treated patients. The relative efficacy was even greater. The study reported a 30-55% relative improvement in clinical outcome for tPA-treated patients compared with placebo-treated patients. This benefit was achieved despite an increased rate of hemorrhage of 6% in the tPA group compared to 0.6% in the placebo arm. Efficacy was observed for all types of stroke, including atherothrombotic large vessel disease, cardioembolic stroke, and lacunar (small-vessel) stroke.
The other important multicenter trial, performed in Europe, unfortunately did not completely confirm the NINDS results. In the European Cooperative Acute Stroke Study (ECASS),11 620 patients with acute ischemic hemispheric stroke who presented within 6 hours of symptom onset were randomized to receive either tPA (1.1 mg/kg, maximum dose 100 mg) or placebo. Primary end points were scored on the BI and the MRS 3 months after stroke. No significant benefit was seen with therapy in the intention-to-treat population as measured by the primary end points. Of the 620 patients enrolled, 109 (17.4%) were considered to have had major protocol violations. When these patients were excluded from analysis, a statistically significant benefit of treatment with tPA was seen on the MRS at 3 months in the remaining target population. The rate of symptomatic intracerebral hemorrhage (ICH) was significantly higher in the treated patients (19.8% vs 6.5% in the placebo group), but there was no significant difference in mortality at 1 month. The majority of protocol violations occurred in patients with early radiographic signs of major infarction or other CT abnormalities. These patients were over-represented in the tPA treated group and had higher rates of symptomatic ICH and death. Hacke and colleagues concluded that tPA was recommended only with optimisation of patient selection.
In comparison to NINDS, ECASS and other thrombolytic studies were less stringent in their eligibility requirements and in their enforcement of these criteria. Other flaws of these studies evaluated higher doses of tPA (closer to cardiac doses), other thrombolytic agents (eg, streptokinase or urokinase), longer time windows for treatment (4-6 hours), and the use of concomitant medications, such as aspirin and heparin. These agents should be withheld for 24 hours after tPA administration to minimize the risk of bleeding.12,13
The issue of efficacy has also been studied in a large meta-analysis that evaluated the combined benefits of various thrombolytic agents for acute ischemic stroke. Although fraught with flaws such as heterogeneity in study designs, differences in drugs studied, and concomitant medications, as well as varying inclusion and exclusion criteria, the meta-analysis supported the validity of the findings in the NINDS study. Although this analysis found an excessive number of cases of symptomatic ICH in all treatment groups, it found that thrombolytic therapy within 3 hours of stroke was beneficial overall.14 The best available evidence suggests that thrombolytic therapy for patients with acute ischemic stroke is of probable benefit but is associated with considerable risk. The American College of Emergency Physicians has recommended "with reservations" the use of tPA for acute stroke.15
Studies of the use of tPA in clinical practice have confirmed its safety when given according to the NINDS protocol. Complications are closely linked to protocol violations, such as errors in drug dosing. Because "time is brain," the sooner tPA can be given the better. Subgroup analysis of the NINDS trial has confirmed that if the drug is given in the first 90 minutes, it is more effective than at 90-180 minutes. Dosing beyond the 3-hour time window is clearly associated with an increased hemorrhage rate.16 Table 1 outlines in detail the inclusion and exclusion criteria for the use of tPA.
| Table 1. Criteria for the Use of tPA in Acute Ischemic Stroke |
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Inclusion Criteria
Absolute Exclusion Criteria
Relative Contra-Indications
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The only way to extend the therapeutic time window for thrombolysis is with intra-arterial (IA) therapy. IA thrombolysis should be considered if an interventional neuroradiology team is immediately available. IA urokinase may be used only in the setting of confirmed large-vessel occlusion. This requires transfemoral angiography. Techniques such as CTA or TCD may provide a noninvasive means of making this diagnosis. As shown by the Prolyse in Acute Cerebral Thromboembolism (PROACT) investigators, IA thrombolysis is beneficial up to 6 hours after onset of stroke. The primary outcome of the PROACT II trial was the ability to live independently at 3 months, an outcome that was attained by 40% of the patients treated with prourokinase and heparin as compared with 25% of those treated with heparin alone (P = .04). This represented a 60% relative benefit. Intracerebral hemorrhage with neurologic deterioration occurred in 10% of the patients in the prourokinase group and in 2% of those in the heparin-only group (P = .06). Contraindications to IA thrombolysis are the same as for intravenous thrombolysis.17
IA therapy has been used in the basilar artery territory up to 12 hours after the onset of symptoms.18 While this practice is not supported by randomized data, such heroic-type therapy may still be considered given the uniformly poor prognosis for complete brainstem infarction.
Alternative anticoagulant therapies have been under investigation to achieve acute revascularization. Ancrod is an agent similar to snake venom and functions by converting fibrinogen into soluble fibrin products, depleting fibrinogen as a substrate needed for thrombus formation. In a recent trial involving 500 patients treated within 3 hours of stroke onset, total or near-total recovery at 3 months was achieved in 42% of patients given ancrod, as compared with 34% placebo (P = .04).19 Ancrod is not yet FDA-approved, and it is currently not clear what role this agent will play as compared to tPA in the hyperacute (3-hour) time interval.
Antithrombotic Therapy
It is common practice to use heparin in the treatment of acute stroke, particularly in the setting of presumed cardioembolism. Despite its theoretical benefits, no data from clinical trials exist to support this practice. While surveys show that many neurologists use heparin for acute stroke, few believe that it offers a proven benefit to acute stroke patients.20,21 The use of heparin in acute stroke has recently undergone large-scale, randomized megatrials, though some consider the data from these to be flawed. The International Stroke Trial (IST) randomized 19,436 patients to 12,500 U of subcutaneous (SQ) heparin twice daily, compared with 5000 U SQ heparin or aspirin. Heparin was shown to reduce the rate of recurrent stroke, but this benefit was offset by a significant increase in intracerebral hemorrhage. The weaknesses of this study include a lack of requirement for screening CT (in one-third of cases) and no laboratory monitoring of the magnitude of anticoagulation.22
Three trials have evaluated the use of low molecular weight SQ heparin (LMWH). The only trial showing a positive effect involved 308 patients in Hong Kong, randomized to LMWH (nadroparin) or placebo. They were treated within 48 hours of stroke for a duration of 10 days. No difference was seen at 3 months, but there was a significant benefit at 6 months. Unfortunately, a larger European multicenter trial, FISS-bis, which included 750 patients, was unable to corroborate these benefits.23 In the United States, the Trial of ORG 10172 in Acute Stroke Treatment (TOAST), a placebo-controlled trial of another LMWH, danaparoid, evaluated 1281 patients treated within 24 hours after the onset of stroke. There was no difference in the rate of recurrence or progression of stroke in those who received danaparoid compared with placebo. Subgroup analysis did suggest a potential benefit of danaparoid in patients with occlusion or severe stenosis of the internal carotid artery or an intracranial large-artery narrowing.24 Of note, even in the setting of AF (a disease in which long-term anticoagulation is clearly indicated), acute treatment with LMWH has not shown benefit in patients when compared with aspirin. Finally, a recent Cochrane group meta-analysis of data from trials of early treatment with anticoagulant drugs for patients with acute ischemic stroke suggest no clinical benefit with such treatment.25
Despite this large body of data against heparin as an acute treatment for stroke, there are a number of clinical syndromes in which heparin might be considered. These include basilar thrombosis, cervical artery dissection, tight carotid stenosis in the setting of an incomplete MCA infarct, stroke patients with fluctuating deficits, and suspected cardioembolism with fresh clot within the myocardial chambers. (See Table 2.) Also, because none of the large trials evaluated intravenous adjusted unfractionated drip heparin, many continue to feel that under ideal conditions, heparin, administered properly, continues to be of potential benefit in a wide range of stroke patients. Clearly, the benefits of heparin are best achieved with compulsive attention to activated partial thromboplastin time (aPTT) monitoring, shifting the balance toward the most favorable possible risk-benefit profile. The aPTT should be monitored every 6 hours and the rate adjusted (see Table 3) until the aPTT is in the range of 60-80 seconds. The use of bolus heparin is not recommended, except in cases of acute basilar thrombosis. Close clinical attention to patients on heparin is also crucial.
| Table 2. Possible Indications for Heparin in Acute Ischemic Stroke |
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| Table 3. Blood Pressure Management After tPA |
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Antiplatelet Therapy
Aspirin in doses ranging from 160 mg to 1000 mg daily may benefit patients with acute stroke for whom thrombolysis or antithrombotics are not used. In the International Stroke trial, aspirin was found to be as equally efficacious as heparin. In the Chinese Acute Stroke Trial (CAST) in which 160 mg of aspirin or placebo was given daily for 4 weeks to 21,106 patients with acute ischemic stroke, the mortality rate at 1 month in the aspirin group was slightly but significantly lower than that in the placebo group (3.3% vs 3.9%). There was no difference between the groups in the overall rate of death or severe disability.26 Further discussion on the dosing of aspirin, alternate antiplatelet therapies, and their use in the prevention of TIA/recurrent stroke will be addressed below.
Acute Stroke Therapies— Neuroprotection/Promotion of Recovery
Despite promising data from animal models, no agent has demonstrated efficacy as a neuroprotective drug in humans with acute ischemic stroke. Several drugs have been tested including naloxone, gangliosides, nimodipine, N-methyl-d-aspartate-receptor antagonists, antibodies to adhesion molecules, and free-radical scavengers. All have proved ineffective in phase 3 trials. These failures may be due to delays in the initiation of treatment, inadequate doses, inadequate tissue penetration, or prohibitive occurrence of side effects. The design of these clinical trials has also been flawed in patient selection, treating all strokes equally (ie, failing to take stroke mechanism and severity into account).
Carotid endarterectomy (CEA) may be indicated acutely in cases of stroke in which there is a critical level of carotid stenosis causing recurrent emboli to the brain or a low flow state with poor intracranial collaterals. CEA may be indicated if the acute stroke is small with a large territory of threatened brain. CEA in cases of large completed strokes may be associated with reperfusion bleeding and should be delayed by weeks to months.27 CEA on an elective basis for secondary stroke prevention in the setting of TIA will be discussed below.
Hospital Management— Supportive Intensive Care
Patients treated with thrombolytic medications or those at risk for significant stroke associated with swelling or hemorrhagic conversion should be hospitalized in an intensive care unit (ICU). Patients with subacute or smaller strokes may be placed on a general medical ward. If available, patients should be admitted to an integrated stroke unit with a continuum of care beginning at or shortly after hospital admission and continuing beyond the period of acute medical care and through the initial stages of rehabilitation. Randomized trials and meta-analyses indicate that short-term and long-term mortality rates are lower, hospitalization shorter, and the likelihood of discharge to the home greater among patients treated in integrated stroke units than among those treated in general medical units.28
A large proportion of morbidity and mortality in the post-stroke setting is attributed to medical complications. Management should focus on prevention of fever, as elevated body temperatures may worsen ischemic damage. Regularly scheduled dosing of acetaminophen or other nonpharmacologic means such as cooling blankets may be required. Fluid titration should aim for the maintenance of normovolemia; therefore, volume depletion with diuretics should be avoided if possible.
Blood pressure (BP) should be carefully monitored in all patients. In patients with underlying chronic hypertension, autoregulation of cerebrovascular tone may have been altered so that a higher mean arterial pressure (MAP) is required to maintain cerebral perfusion pressure. Therefore, unnecessary reduction of MAP must be avoided. In fact, in some patients, pharmacologic elevation of BP is indicated (see below).
In patients who have received a thrombolytic agent within 24 hours, the protocol as shown in Table 3 should be followed. In patients who have not received thrombolytic therapy, hypertension is not generally a concern until SBP is greater than 220 or DBP is greater than 120. Labetalol or nitroprusside may be used (as shown in Table 3) to achieve a BP no lower than 160/90. Peripherally acting calcium channel blockers should be avoided because of the risk of excessive reduction in BP and consequent sacrifice of the ischemic penumbra.
In patients with multiple stenotic large vessels, pharmacologically induced hypertension with phenylephrine may be indicated. Some investigators have suggested that increased BP may put patients at risk for reperfusion injury, particularly in the post-thrombolysis setting. Such therapy has been shown to be safe and possibly efficacious in small series.29
Elevated intracranial pressure (ICP) may complicate strokes, with a maximum at 48-72 hours after stroke onset. Treatment of increased ICP may require mannitol or hyperventilation in an ICU setting. In severe hemispheric infarction and cerebellar infarction, decompressive surgery can be life-saving. Young patients with stroke may develop early edema; particularly, the infarct involves the complete MCA territory. This is considered to be a "malignant MCA" stroke syndrome. Surgery should be given consideration early, particularly if the stroke affects the nondominant hemisphere.30 Acute therapy with hypothermia as a neuroprotective mechanism has also been explored in cases of "malignant MCA" infarction, with promising early results.
Hemorrhage Complicating Ischemic Stroke
Hemorrhagic conversion may occur in up to 30% of strokes. Such conversion may be minor (petechial hemorrhage) and without symptoms. Larger regions of hemorrhage leading to clinical deterioration are most likely to occur in large MCA infarcts with deep gray matter structures, such as the putamen and globus pallidus. As noted previously, patients who have received thrombolytic medications or ongoing treatment with antithrombotic agents, such as heparin, are at an increased risk of hemorrhagic conversion.
When ICH is suspected in patients receiving thrombolysis, immediate cranial CT must be obtained along with emergent neurosurgical and hematologic consultation. STAT prothrombin time, aPTT, complete blood cell count, D-Dimer, and fibrinogen must be sent. Treatment includes 2 units of fresh frozen plasma to replete Factors V, VII, 20 bags of cryoprecipitate to replete fibrinogen, and 6 units of platelets. Patients treated with heparin should receive protamine IV 1 mg/100 U of unfractionated heparin given in the preceding 4 hours. Coagulation parameters should be repeated every hour until bleeding is controlled. If these measures fail to control bleeding, then E-aminocaproic acid 5 g IV over 1 hour is given as a last resort.
Prevention of Further Medical Complications
Early attention to mobility and nutrition are necessary to minimize complications such as deep-vein thrombosis, pulmonary embolism, pneumonia, urinary tract infection, and decubitus ulcers. Because abnormalities in swallowing are common, patients with abnormalities of speech or tongue and mouth movements should undergo a formal evaluation of swallowing. The use of intermittent pneumatic compression stockings and/or SQ heparin are recommended to prevent deep-vein thrombosis. While the use of heparin as a treatment for cerebral ischemia is controversial, there is widespread agreement that it is helpful in preventing this complication.
Rehabilitation
Early and intensive attention to rehabilitation is crucial in minimizing the disability associated with a major stroke. Rehabilitation, either in the inpatient or outpatient setting, should ideally involve a multidisciplinary team including physicians, physical and occupational therapists, and social workers.31 Significant gains in motor function may be achieved. Further, attention should be paid to the treatment of poststroke depression (eg, with an "activating" SSRI such as sertraline)—a mood disorder may have a major negative impact on the recovery process.
Prevention of Recurrent TIA/Secondary Stroke
Among patients who have suffered a TIA or stroke, long-term management is controversial. Among patients who have AF or who have severe extracranial carotid stenoses, antithrombotic therapy with warfarin and CEA are well-proven therapies (see below). For the remainder of patients, antiplatelet therapy or, in a minority, warfarin will be the management of choice. Figure 3 presents an algorithm for this management.
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Aspirin, the mainstay of antiplatelet therapy may be given in a wide range of doses, from 25 mg twice daily to up to 1300 mg/d in divided doses. Two randomized trials have directly compared aspirin doses: 30 mg vs. 283 mg in the Dutch TIA trial and 300 mg vs. 1200 mg in the UK-TIA trial.32,33 Both of these trials have demonstrated no difference in the incidence of stroke between the lowest and highest doses. Some studies in fact suggest that lower-dose aspirin may be more effective as an anticoagulant than high-dose. Low doses may preferentially affect platelet cyclooxygenase (TxA2), an antithrombotic effect, without affecting endothelial production of prostatcyclin, a prothrombotic phenomenon. The Aspirin CEA trial (ACE) compared different aspirin doses and stroke risk postendarterectomy. Patients assigned low-dose ASA (81 or 325 mg) had fewer recurrent strokes than those patients assigned to the higher doses (650 mg or 1300 mg).34 A recent meta-analysis combining 10 trials of ASA in patients with prior stroke or TIA showed that aspirin at varying dosages reduced the odds of recurrent events by 16%.35 Of note, ASA has not been shown to be beneficial in the primary prevention of first ischemic stroke and may be associated with an increased risk of hemorrhagic stroke (SAH) in women, particularly those without underlying vascular disease.36
Aspirin may not be tolerated by the gastrointestinal tract in many patients. Although gastric toxicity is dose-related, even low-dose aspirin may increase the risk of GI bleeding.
Ticlopidine/Clopidogrel
Ticlopidine is a thienopyridine that inhibits ADP-induced platelet aggregation. Two large trials, the Ticlopidine Aspirin Stroke Study (TASS) and the Canadian American Ticlopidine Study (CATS) showed benefits of this agent when compared with placebo. Stroke incidence was reduced by 34% compared with 20% among patients on aspirin.37,38 Ticlopidine, however, has fallen out of use entirely due to its side effects. A 1% incidence of neutropenia and at least 60 cases of thrombotic thrombocytopenic purpura (TTP) have been reported.39
Clopidogrel, an agent with close chemical relation to ticlopidine, was studied in the Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial.40 This trial compared clopidogrel to aspirin in a pool of patients with stroke and other forms of vascular disease (including MI and peripheral arterial disease [PAD]). Clopidogrel showed an absolute benefit of 8.7% when compared with aspirin. Subgroup analysis from the CAPRIE study suggests that the majority of patients who showed benefit were those who had PAD. Clopidogrel, like ticlopidine, has been shown to cause rare cases of TTP.41
Many practitioners will prescribe a combination of aspirin and clopidogrel. While such a combination may be reasonable on an empiric basis, no data exist for this regimen with specific regard to stroke prevention. Given the complementary mechanisms of these agents, however, an additive or perhaps synergistic effect may exist. This has been well-documented in vitro. Data from the cardiac literature also suggest that a combination of ASA and clopidogrel is efficacious in the prevention of thrombosis, particularly in coronary stents. These data may, therefore, be extrapolated to the stroke/TIA population.
ASA/Dipyridamole
Dipyridamole (DP), a phosphodiesterase inhibitor, may be combined with aspirin. The European Stroke Prevention Study (ESPS)-1 trial compared this combination to placebo showing a 38% reduction in stroke.42 When the combination was compared with aspirin alone, in multiple small studies, no benefit was observed.43,44 Using a long-acting DP preparation (200 mg) combined with aspirin (25 mg) and given twice a day, the ESPS-2 study showed a reduction in stroke risk of 37% compared with placebo and, more importantly, a 23.1% advantage over aspirin alone.45 These benefits are much more pronounced than those of clopidogrel. The most common side effects of the DP/ASA combination are gastrointestinal distress and headache. The latter symptom usually resolves during the first week of therapy. The combination drug, containing DP and ASA, is marketed in the United States under the trade name Aggrenox.® Some experts believe that there is an insufficient aspirin dosage contained in the Aggrenox® preparation. It is common practice, therefore, to supplement Aggrenox® with additional aspirin—either 81 mg b.i.d. or 325 mg q.d.
Warfarin
Anticoagulation with warfarin is indicated for patients with cardio-embolic stroke due to AF. In patients with acute stroke and AF, warfarin therapy may be withheld for the first few days, given the risk of hemorrhagic conversion. The advantage of warfarin over aspirin therapy in patients with AF is well recognized. This includes those with prior stroke or those with AF and another stroke risk factor such as age older than 75 years, hypertension, rheumatic mitral valve disease, or poor left ventricular function.46
The role of warfarin in the prevention of other causes of stroke is less well established. Warfarin may be prescribed in cases of cardiac structural abnormalities such as PFO or a dilated left ventricle. Furthermore, the role of warfarin to prevent recurrent stroke of presumed atherthrombotic etiology is also not clear. We await the results of the Warfarin Aspirin Intracranial Disease (WASID) study and the Warfarin Aspirin Recurrent Stroke Study (WARSS), to clarify this further.47 Warfarin should also be considered for stroke prevention in patients who fail antiplatelet therapy. A minority of patients may require both coumadin and aspirin for stroke prevention, particularly if antiplatelet therapy is needed in the setting of coronary artery disease. Such a combination may be achieved safely, particularly with close attention to PT/INR monitoring.
Surgical Management
CEA is the standard of care for patients with a history of stroke or TIA and a significantly stenotic ipsilateral carotid artery. The North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the European Carotid Surgery Trial (ECST) compared surgical and medical therapy in these patients.48,49 In NASCET, 659 patients with a 70-99% carotid stenosis and a nondisabling stroke or TIA in the prior 120 days, were randomized to receive surgical or medical management. The 2-year risk of ipsilateral stroke was 26% among those treated medically compared to 9% in the surgical group. Patients with the most severe levels of stenosis (ie, > 90%) had an even more marked benefit (34% vs 9%—2-year stroke risk in the medical vs the surgical arms).50 More recently, the NASCET investigators have released results of a similar evaluation among those patients with 50-69% carotid stenosis. A less marked difference was found. The 5-year stroke risk was 22.2% with medical as compared to 15.7% with surgical management. The benefit was most marked among men and in patients presenting with hemispheric TIA rather than purely ocular symptoms (transient monocular blindness).51 The overall benefit of an endarterectomy is dependent on the skill of the surgeon and the up-front surgical morbidity and mortality. In order to replicate the results of NASCET in general practice, the perioperative stroke or death rate should be less than 6%. This is particularly important among patients with carotid stenoses in the 50-69% range, since the overall benefit of surgery is much smaller.
Angioplasty and carotid stent placement is an option for symptomatic carotid stenosis. This procedure has been shown to be safe, but data are not available in direct comparison with endarterectomy. Immediate vessel patency rates after stenting have been shown to be favorable, but long-term restenosis rates are unclear.52 Stenting currently should be considered for patients unable to undergo CEA such as those with high surgical comorbidity due to cardiac disease or other factors or those patients with anatomical barriers to CEA, such as prior radiation therapy to the neck or a high-carotid bifurcation under the mandible.
Management—Conclusion
As shown in Figure 1, warfarin therapy should be considered for patients with AF and for those with large vessel intra-cranial disease. It may also be rarely used in cases of cryptogenic stroke, or in cases of lacunar stroke who fail antiplatelet therapy. In aspirin-naïve patients, this is the drug of choice for antiplatelet therapy. In patients who have received prior aspirin, combination therapy with dipyridamole or clopidogrel is advisable.
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Based on the available data, ASA/DP (Aggrenox®) should be the therapy of choice, particularly in aspirin-naïve patients. In patients who have received prior aspirin, a regimen of either ASA/DP or ASA/clopidogrel may be considered. CEA or stenting should be considered in patients with more than 70% internal carotid artery stenosis.
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