IMPORTANT NOTE: JAAPA CME activities consist of 2 articles. To obtain credit, you must also read Clostridium difficile: A new look at an old but increasingly deadly infection; the post-test will include questions related to both articles. AAPA Fellow members should complete and submit the post-test on the AAPA Web site by going to www.aapa.org and searching for keyword JAAPA post-tests. All others may complete and submit the post-test online at no charge at www.mycme.com. To obtain 1 hour of AAPA Category I CME credit, PAs must receive a score of 70% or better on each test taken.

KEY POINTS

■ Effective interventions are available for acute large-vessel ischemic stroke, but only 2.4% of stroke patients receive them. All must be delivered within 3 to 8 hours of symptom onset, with the shortest time to recanalization and thus reperfusion being the strongest determinant of a good outcome.

■ The primary advantage of IV rtPA is the relative ease and rapidity of administration. However, IV administration of rtPA has the disadvantage of introducing a large dose systemically, which increases the risk of unwanted bleeding.

■ Intra-arterial (IA) rtPA delivers a much smaller dose (2-4 mg) directly to the site of occlusion, reducing the systemic effects of IV administration, and it can be used within 6 hours of symptom onset. However, IA rtPA takes more time and more specialized resources to administer than IV rtPA.

■ Two mechanical clot extraction devices are also available for treating this type of stroke.

Stroke is the third leading cause of death and the first leading cause of disability in the United States. Approximately 795,000 new cases of stroke occur each year.1 Stroke is broadly divided into ischemic and hemorrhagic types. Ischemic stroke accounts for 87% of all strokes.1 Nearly half of these are caused by the sudden blockage of a large cerebral vessel.2 Acute ischemic stroke caused by a large-vessel occlusion carries a worse prognosis than small-vessel ischemic stroke, in terms of both death rate and long-term recovery.2

Onset of stroke is often sudden and dramatic. Patients may present with focal signs, such as arm weakness, facial droop, or slurred speech. The American Heart Association (AHA) has launched a public education campaign emphasizing the importance of quick recognition and treatment of stroke. This is because with the treatments available today, time matters.


If a blocked cerebral artery is reopened soon enough, stroke and symptom progression may be halted or even reversed. Despite campaigns for both public and professional awareness, less than 2.4% of patients suffering a large-vessel ischemic stroke receive intervention treatments that are available to reopen the blocked vessel.3


This article reviews the major treatments for large-vessel ischemic stroke, including IV recombinant tissue plasminogen activator (rtPA), intra-arterial (IA) rtPA, and mechanical clot retrieval. All these treatments must be used during the first "golden hours" following symptom onset, when cerebral artery recanalization may have great effect in reducing morbidity and mortality.


CASE REPORT


At 4:30 pm, a 37-year-old woman was sitting on the couch at a friend's house when she suddenly developed garbled speech and left-sided weakness. The patient was brought to a nearby hospital, where her medical history was carefully reviewed. There had been no recent surgery, trauma, or anticoagulation. Vital signs remained stable. Laboratory studies were ordered. Noncontrast CT revealed no intracranial hemorrhage. A teleconference with a major university hospital was called. The patient was assigned a National Institutes of Health Stroke Scale (NIHSS) score of 17. 


At 5:30 pm, the patient was given 70 mg of IV rtPA (0.9 mg/kg). She was then transported via helicopter to the university hospital. At arrival, her NIHSS remained stable at 17. CT arteriography revealed an abrupt cutoff of the right middle cerebral artery, as well as hypodensity in the temporal and parietal lobes suspicious for an evolving right middle cerebral artery (MCA) stroke. 


The patient was brought to the neurointervention suite for further evaluation and treatment. Cerebral angiography confirmed the CT arteriography finding of proximal right MCA blockage (Figure 1). At 8:30 pm, 4 mg of rtPA was injected directly into the clot via an intra-arterial microcatheter. At 9:00 pm, a MERCI Retriever device was deployed, and the right MCA was opened after just one pass (Figure 2). The next day, an echocardiogram revealed a previously undiscovered patent foramen ovale (PFO). Although no deep venous thrombosis was found, it was possible that a clot had traveled from the venous system through the PFO and into the brain to occlude the artery. 


Timely diagnosis, response, and intervention resulted in a good outcome for this patient. Three days after presenting to the hospital with aphasia and hemiparesis, she was discharged home with only minor residual symptoms. She was placed on anticoagulation therapy and referred to cardiology for repair of the PFO.


BACKGROUND


Often called a brain attack, a stroke occurs when blood flow to part of the brain is blocked and metabolic demand is not met. Ischemic cerebral tissue does not function normally, accounting for focal symptoms, such as facial droop, aphasia, or limb weakness. If the ischemia continues long enough, brain infarction occurs. In the case of large-vessel ischemic stroke, an initial core area of infarct is often surrounded by a watershed area of ischemic tissue called the penumbra. If circulation is restored during the first hours of a stroke, some or all of the penumbra may be salvaged. As time goes on, however, the penumbra converts to infarcted tissue.


As stroke volume increases, risk increases that opening a blocked vessel may result in catastrophic intracerebral hemorrhage rather than reperfusion,4,5 because necrotic, infarcted vessels cannot contain blood. This phenomenon, known as hemorrhagic conversion, imparts severe time limitations on the treatment of large-vessel ischemic stroke. In the same respect, if a stroke's volume initially exceeds more than one-third of the vessel's territory, intervention is usually not attempted because the risk of hemorrhage outweighs the chance of reperfusion.

Large-vessel strokes account for about 46% of all ischemic strokes (320,000) per year, with one large-vessel stroke occurring almost every 90 seconds.1,2 Large vessels (those greater than 2 mm) in the brain are any of the major cerebral arteries, including the internal carotid, middle cerebral, anterior cerebral, vertebral, or basilar arteries. These vessels may become suddenly blocked by one of two mechanisms: an embolus traveling from or through the heart, or thrombus formation. 


In thrombotic stroke, the stigmata of atherosclerosis are often present, including older age, high cholesterol levels, and hypertension. The rupture of atherosclerotic plaque in one of the large cerebral arteries leads to sudden clot or thrombus formation, much like what happens in an acute MI. 


In embolic stroke, large emboli are often cardiogenic and associated with atrial fibrillation, mechanical valves, or endocarditis. However, up to one-half of persons referred to stroke centers are younger than 65 years and often do not have preexisting heart disease or an "atherosclerotic" profile. In younger stroke victims, a role for PFO has been suggested. Under the right circumstances, an embolus may pass from the venous to the arterial system via an atrial septal defect and eventually block a cerebral artery.6


Blockage of a large cerebral vessel corresponds with a higher NIHSS score. The NIHSS score is a measure of stroke severity rated from 0 to 42 based on findings from a physical examination. A higher number reflects greater impairment. A score of 1 to 7 reflects a mild impairment; 8 to 15, moderate impairment; and greater than 15, severe impairment. Fischer and colleagues found that an NIHSS score greater than or equal to 12 had a 91% predictive positive value of a central large-vessel stroke.7 No matter the cause, large-vessel ischemic stroke is a true medical emergency. Actions taken during the first few hours significantly impact the extent of future disability.


INTRAVENOUS rtPA


In 1995, the National Institute of Neurological Disorders and Stroke (NINDS) determined that patients who were given IV rtPA within 3 hours of symptom onset were 30% more likely to have little or no disability at 3 months than patients given placebo.8 In 1996, the FDA approved recombinant tissue plasminogen activator for IV treatment of acute ischemic stroke.9 A serine protein found on the endothelial cells that line blood vessels, tissue plasminogen activator enzymatically converts plasminogen to plasmin. Plasmin is an enzyme that breaks down many blood proteins, notably fibrin, in a process called fibrinolysis, thereby dissolving clots. Marketed as alteplase, rtPA is a genetically engineered glycoprotein that is produced by recombinant DNA technology. Its indications include clot lysis in the setting of thromboembolism and acute ischemic stroke.


The primary advantage of IV rtPA is the relative ease and rapidity of administration. Once the patient has had an appropriate basic workup; CT to rule out intracranial hemorrhage; and an evaluation by a stroke neurologist, either in person or via teleconsult, 0.9 mg/kg of alteplase is given via combined IV bolus and 60-minute infusion. However, IV administration of rtPA has the disadvantage of introducing a large dose systemically, which increases the risk of unwanted bleeding. Thus, strict exclusion criteria must be observed when considering candidates for rtPA administration (see Table 1).


In 2000, Clarke and colleagues concluded that patients derived no benefit and even had an increased risk of intra­cerebral hemorrhage when IV rtPA was administered 3 hours after symptom onset.10 However, in 2008, these findings were revised by the European Cooperative Acute Stroke Study (ECASS) III. ECASS III showed that significant benefit may be achieved by extending the administration window of IV rtPA from 3 hours to 4.5 hours in an even more highly restricted patient group.4,9 Based on these and other findings, the AHA and the American Stroke Association issued an advisory in 2009 expanding the time window for the use of IV rtPA from 3 hours to 4.5 hours in a select subgroup of patients: Excluded are patients older than 80 years, those with an NIHSS score greater than 25, patients taking oral anticoagulants, and those with a history of both stroke and diabetes.11 


IV rtPA can be an effective first-line treatment for large-vessel occlusive stroke. Recanalization rates for IV rtPA alone have been reported as 6% to 31% for the middle cerebral artery and 13% to 30% for the internal carotid artery.12,13 Despite this proven efficacy, use of IV rtPA has been very limited. Although an estimated 28.7% of victims of ischemic stroke (both large-vessel and small-vessel) could benefit from IV rtPA, only 1% to 3% receive it.3 Reasons for low usage include delays in presenting to the hospital, lack of designated stroke centers, and lack of 24-hour CT availability, with delay in presentation being a major culprit.3


The effectiveness of IV rtPA administration appears to be highly time-dependent. An NINDS study compared outcomes at 3 months in patients treated with IV rtPA 0 to 90 minutes and 91 to 180 minutes after symptom onset. The researchers concluded that the 0- to 90-minute group was more likely to have a favorable outcome (odds ratio [OR], 2.11) compared with the 91- to 180-minute group (OR, 1.69).14


Until the advent of interventions using an intra-arterial catheter for large-vessel stroke, the outlook for patients was bleak. Often the result was death or disability. While IV rtPA remains a mainstay of treatment, its widespread use remains hampered by its multiple contraindications, the 3-hour time window for administration, and the relative resistance of a large clot burden to fibrinolysis.


INTRA-ARTERIAL rtPA


In 1998, the Prolyse in Acute Cerebral Thromboembolism (PROACT) II study explored the use of the plasminogen activator prourokinase delivered directly into middle cerebral artery clots within 6 hours of symptom onset. The study concluded that despite a slightly greater risk of intracerebral hemorrhage, plasminogen activator delivered in this manner resulted in significantly higher rates of recanalization than did placebo and better overall outcome at 90 days.15


PROACT II opened the door to the use of IA rtPA, which has several advantages. It delivers a much smaller dose (2-4 mg) directly to the site of occlusion, reducing the systemic effects of IV administration. Also, IA rtPA can be used within 6 hours of symptom onset. Thus, a patient who suffers a stroke during open-heart surgery or who arrives at the hospital too late for IV rtPA may be considered for IA rtPA.


Intra-arterial rtPA can be used either by itself or in addition to IV rtPA. Disadvantages of IA rtPA include the requirement for cerebral angiography in a dedicated neuroangiography suite, which lengthens time to actual drug delivery. Also, IA rtPA can only be given at a stroke center by a highly skilled neurointerventional physician to direct its delivery. Thus, it takes more time and more specialized resources to administer. Nonetheless, results have been promising.4,16


MECHANICAL THROMBECTOMY: 
MERCI RETRIEVER SYSTEM 


In 2004, the FDA approved use of the first mechanical intra-arterial thrombectomy device, the MERCI Retriever (Concentric Medical, Mountain View, CA) for use in large-
vessel occlusive stroke. The MERCI Retriever is passed through a catheter that has been placed just proximal to the clot. After being passed through the clot, the MERCI device forms a helical or corkscrew shape to help grab the clot. Under manual aspiration and withdrawal of the device back into the catheter, the clot may be removed and the vessel opened. The 10 types of available MERCI Retriever devices correspond to differences in vessel size and clot characteristics. 


A MERCI Retriever may be deployed up to 8 hours after symptom onset. Moreover, it can be used in patients who are either ineligible for or have not responded to IV rtPA therapy. The retriever may also be used in conjunction with IA rtPA. Theoretically, use of a mechanical thrombectomy device has several distinct advantages: a longer time 
window for treatment, greater efficacy in opening large-vessel occlusions, and potentially less risk of causing hemorrhage.17


In the Multi MERCI trial, later-generation MERCI retriever devices achieved 57.3% recanalization in treatable vessels and 69.5% recanalization when used in conjunction with IA rtPA. In this series of patients, whose NIHSS score averaged 19, favorable clinical outcome occurred in 36% of patients with overall mortality of 34%.18


MECHANICAL THROMBECTOMY: 
THE PENUMBRA DEVICE


The Penumbra system (Penumbra, Inc, Alameda, CA) recently gained approval for sale in the United States and is the second device now available for mechanical clot extraction (Figure 3). It uses an aspiration/debulking process to remove the clot. A separator is repeatedly passed into the clot to break it up, while continuous aspiration is maintained at -20 mm Hg through the guide catheter by the Penumbra machine. In the Penumbra Pivotal Stroke Trial, 125 patients with large-vessel ischemic stroke were treated with the device. Overall, 81.6% vessel revascularization was achieved. At 90 days, all-cause mortality was 32.8%, similar to the MERCI trial results, while 25% of patients achieved a favorable outcome.19


CONCLUSION


The woman in the case study presented earlier in this article benefited from all that modern medicine has to offer: She received IV rtPA within 2 hours of symptom onset, IA rtPA within 4.5 hours, and complete recanalization via the MERCI device at 5.5 hours. Administration of both IV and IA rtPA likely helped to soften the thrombus, which allowed the MERCI device to work more effectively. While the patient had some residual deficit, appropriate therapy and aftercare enabled her to return to a meaningful, independent life.


Reopening the lumen of a suddenly blocked cerebral artery offers the greatest hope for saving threatened brain tissue from progressing to infarction, as well as for limiting infarct size. Today's armamentarium includes IV rtPA, IA rtPA delivered directly to the clot, and two mechanical clot extraction devices. All these treatments must be delivered within 3 to 8 hours of symptom onset, with the shortest time to recanalization and thus reperfusion being the strongest determinant of a good outcome. 


Large-vessel occlusive stroke remains a devastating event that resists cure even under the most ideal treatment circumstances. As new therapies and technologies emerge and as hospital systems, the public, and clinicians work together to make timely treatment more widely available, outcomes like the one presented in our case study will become increasingly common. JAAPA

Robert Brach practices in the Department of Neurosurgery, Brigham and Women's Hospital, Boston, Massachusetts, and is an associate in surgery at Harvard Medical School, also in Boston. The author has indicated no relationships to disclose relating to the content of this article.



IMPORTANT NOTE: JAAPA CME activities consist of 2 articles. To obtain credit, you must also read Clostridium difficile: A new look at an old but increasingly deadly infection; the post-test will include questions related to both articles. AAPA Fellow members should complete and submit the post-test on the AAPA Web site by going to www.aapa.org and searching for keyword JAAPA post-tests. All others may complete and submit the post-test online at no charge at www.mycme.com. To obtain 1 hour of AAPA Category I CME credit, PAs must receive a score of 70% or better on each test taken.

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IMPORTANT NOTE: JAAPA CME activities consist of 2 articles. To obtain credit, you must also read Clostridium difficile: A new look at an old but increasingly deadly infection; the post-test will include questions related to both articles. AAPA Fellow members should complete and submit the post-test on the AAPA Web site by going to www.aapa.org and searching for keyword JAAPA post-tests. All others may complete and submit the post-test online at no charge at www.mycme.com. To obtain 1 hour of AAPA Category I CME credit, PAs must receive a score of 70% or better on each test taken.