Acute Ischemic Stroke: Update on New Therapies

ABSTRACT: Establishing the time of symptom onset is essential to selecting the appropriate therapy. Intravenous tissue-type plasminogen activator (t-PA), administered within 3 hours of symptom onset, is the only FDA-approved treatment for acute ischemic stroke. Intra-arterial and combined intra-arterial-intravenous thrombolytic therapy may be considered for patients whose condition does not improve or who present within 3 to 6 hours of symptom onset. Other options for treating acute ischemic stroke are balloon angioplasty with or without stenting (for symptomatic patients with more than 50% intracranial stenosis in whom medical therapy has failed) and mechanical clot retrieval (for those with an NIH Stroke Scale score greater than 10 who present after the 3-hour window for intravenous t-PA and can be treated within 8 hours of symptom onset or who present within 3 hours of symptom onset but in whom intravenous thrombolysis is contraindicated).

Despite the significant progress in stroke prevention and treatment over the past 10 years, stroke remains the third leading cause of death in the United States.¹ Approximately 700,000 strokes occur every year; the majority are ischemic.¹

In 1996, the FDA approved the use of intravenous tissue-type plasminogen activator (t-PA). Although t-PA was expected to revolutionize the treatment of stroke, very few patients receive the drug in any given year. Delays in symptom recognition and hospital arrival have been cited as causes for lack of widespread use of the agent.

The phrase "time is brain" has been coined in discussions about stroke management to emphasize the vulnerability of the brain in tolerating ischemia. Hence, efforts have concentrated on decreasing the time from emergency department (ED) admission to intravenous t-PA administration and on extending the therapeutic window by either using intra-arterial t-PA or clot-retrieving devices.

Patients who present to the ED with an acute stroke should be screened and assessed without delay. Establishing a clear symptom onset time is essential in choosing the appropriate therapy. Contraindications for thrombolytic therapy should be quickly reviewed. A CT scan should be immediately obtained and reviewed for any early ischemic changes. Early ischemic changes visible on pretreatment CT scans include blurring of the gray matter- white matter distinction, blurring of the putaminal border, and sulcal effacement.^2,3 The goal is to initiate t-PA within 1 hour of ED admission. Blood pressure (BP) should be monitored and appropriately addressed before t-PA infusion. The choice of therapy is time-dependent.

Thrombolytic therapy has been used successfully for many years as an acute treatment for myocardial infarction. To date, intravenous t-PA, administered within 3 hours of symptom onset, is the only FDA-approved treatment for acute ischemic stroke.⁴ The recommended dose of intravenous t-PA, which is based on the National Institute of Neurological Disorders and Stroke (NINDS) recombinant t-PA (rt-PA) stroke study, is 0.9 mg/kg of body weight to a maximum of 90 mg of t-PA.⁴ Ten percent of the total dose should be given as a bolus and the rest infused over 1 hour. Because intra-arterial⁵ and combined intra-arterial-intravenous thrombolytic⁶ therapy have shown promising results, these options should be considered for patients who do not improve or who present within 3 to 6 hours of stroke onset, and the therapy should be instituted only in centers equipped for a multidisciplinary approach to stroke treatment.

Despite the proven effectiveness of thrombolysis, the risk of thrombolytic therapy-associated hemorrhagic transformation (HT) has prevented some physicians from administering t-PA.⁷ Rates of HT following thrombolysis have varied widely, ranging from 6% to 19.8%, depending on the thrombolytic agent, route of administration, and the time window allowed for the initiation of therapy.⁷ Historically, the most common factor associated with HT has been protocol violation, such as early CT changes and violation of the time window or blood pressure parameters. It is important to establish a specific and a priori institutional protocol for t-PA administration.

The mechanism of HT after cerebral ischemia is not clearly understood. However, several clinical, radiologic, biochemical, and hematologic factors have been associated with HT. Clinical factors include severe baseline neurologic deficits (NIH Stroke Scale [NIHSS] score greater than 20), congestive heart failure, older age, elevated baseline systolic BP,^2,4,8 cardioembolic stroke,⁹ and delayed administration of thrombolytic therapy.⁸ In the NINDS rt-PA study, patients with a systolic BP greater than 190 mm Hg and diastolic BP greater than 100 mm Hg on admission had a higher risk of intracerebral hemorrhage.¹⁰ Biochemical and hematologic factors, such as aspirin( use, low platelet count, and hyperglycemia, have also been invoked as potential risk factors for HT.^2,4,8,11

In experimental models, ultrasonography has been shown to promote the activity of fibrinolytic agents within minutes of exposure to a thrombus.^12,13 In a pilot study, Alexandrov and colleagues¹⁴ found that complete recanalization coupled with dramatic clinical recovery from stroke occurred at higher rates during transcranial Doppler (TCD) monitoring of blood flow after t-PA infusion compared with t-PA infusion alone. These findings were further confirmed in a randomized prospective clinical trial.¹⁵ Complete recanalization or dramatic clinical recovery within 2 hours after the administration of a t-PA bolus occurred in 49% of patients compared with 30% in control patients (P = .03).¹⁵ In centers where TCD is available, it may be worthwhile to use this modality to enhance thrombolysis.

The earliest reports of balloon angioplasty for intracranial atherosclerosis, published in the mid 1980s, have been associated with high complication rates. However, the development of improved microballoon catheters and smaller balloon expandable stents has significantly both ameliorated the complication rates and improved the success rates of these procedures. The Stenting of Symptomatic Atherosclerotic Lesions in the Vertebral or Intracranial Arteries trial evaluated the Neurolink intracranial stent system (Guidant Corp) for treatment of vertebral or intracranial artery stenosis.¹⁶

Successful stent placement was achieved in 95% of cases. Because of this study, the FDA granted the Neurolink stent a humanitarian device exemption for use in balloon angioplasty and stent placement to treat patients with significant intracranial and extracranial atherosclerotic disease.

Recently the Wingspan intracranial stent (Smart Therapeutics, Boston Scientific) also was approved by the FDA. This stent consists of balloon dilatation followed by deployment of a self-expanding microstent.¹⁷ Based on the current scientific evidence, the American Society of Interventional and Therapeutic Neuroradiology, the Society of Interventional Radiology, and the American Society of Neuroradiology recommend that balloon angioplasty with or without stenting should be considered in symptomatic patients who have failed medical therapy and have more than 50% intracranial stenosis.¹⁸

Several mechanical clot retrieval devices also have been used in patients with acute stroke. Among these, snares are usually deployed through microcatheters placed distal to the clot. The snare engages the clot and pulls it back through the catheter.¹⁹ Potential candidates for the procedure are patients who received intravenous or intra-arterial t-PA and in whom a clot was visualized on angiography within 6 hours of symptom onset.

The FDA recently approved the Mechanical Embolus Removal in Cerebral Ischemia (Merci) Retrieval System (Concentric Medical). This has expanded the potential therapeutic window up to 8 hours. Potential candidates include patients experiencing acute ischemic stroke with an NIHSS score greater than 10 who present after the 3-hour window for intravenous t-PA and can be treated within 8 hours of symptom onset or who present within 3 hours of symptom onset but in whom intravenous thrombolysis is contraindicated.²⁰

Hypertension is common in patients admitted for acute ischemic stroke, and a transient rise in BP also can be found in previously normotensive patients.^4,21 It is well established that BP control decreases the risk of stroke recurrence. However, in the acute phase, BP reduction may worsen an already compromised perfusion in brain tissue that is still viable. Therefore, it is best to avoid using antihypertensive medications unless systolic BP is elevated to greater than 220 mm Hg and diastolic BP is elevated to greater than 130 mm Hg.

If a patient has other medical conditions, such as acute myocardial ischemia or intracerebral hemorrhage, it is best to treat the BP so that the systolic BP is maintained at less than 170 mm Hg. In some clinical settings, BP augmentation may be needed.^22,23 Patients receiving intravenous t-PA will need tighter BP control. 

Although low BP is rarely encountered in patients with stroke (5% incidence), low BP is associated with a poor outcome.²⁴ Elevating BP with a vasopressor or intravenous fluid may be helpful. Patients with poor collaterals and those who are not candidates for rt-PA may benefit from BP augmentation.^22,23 In a retrospective study, Rordorf and colleagues²³ demonstrated that BP augmentation with phenylephrine could be performed without undue morbidity or mortality in acute stroke patients. In a randomized pilot study focusing on MRI perfusion-diffusion mismatch, Hillis and colleagues²² documented that induced BP elevation had a significantly positive effect on neurologic function and was associated with a reduction in hypoperfused tissue on perfusion-weighted MRI scans.

For patients with perfusion deficit who are not candidates for rt-PA or angioplasty, BP augmentation may be beneficial. Mean arterial pressure can be judiciously titrated with vasopressors to 120 to 140 mm Hg with frequent neurologic assessment. If no clinical improvement is seen within 72 hours of therapy, vasopressors are titrated down. In patients who have improvement with BP augmentation, an oral agent such as midodrine may be beneficial for long-term management.²² Although study results provide preliminary evidence that increasing BP is beneficial in select patients with acute-subacute stroke, this therapy cannot be recommended for most patients.²⁵ Potential risks of raising BP include increased risk of hemorrhage, cardiac ischemia, arrhythmias, and congestive heart failure. *