Acute Stroke Intervention Stephen R. Ramee, MD, and Christopher J. White, MD Abstract: Ischemic strokes will make up most (480%) of the three-quarters of a million strokes that will occur in Americans this year. Reperfusion therapy is the fundamental strategy for the treatment of acute ischemic stroke. Reperfusion therapy may be accomplished noninvasively (intravenous thrombolysis) or invasively with catheter-based treatments (intra-arterial thrombolysis, thrombectomy, or angioplasty). Currently, a large majority of patients with acute ischemic stroke do not receive any form of reperfusion therapy owing to their delayed presentation (43 hours) and lack of skilled man power for on-demand endovascular treatment. Paradoxically, improved success rates for reperfusion have been reported with the newer thrombectomy catheters, called “stentreivers.” An option for broadening access for patients who need endovascular therapy would be to use interventional cardiologists with carotid stent experience who can help to provide 247365 coverage. (Curr Probl Cardiol 2014;39:59–76.) troke is the leading cause of disability and third leading cause of death in the United States after heart disease and cancer. Most strokes (80%) are ischemic. Stroke affects three-quarters of a million Americans each year resulting in nearly 150,000 deaths.1 Of the 3 million stroke survivors in the United States, approximately one-third are young adults who survive with long-term disability.2 The goal of therapy for acute ischemic stroke is early reperfusion because “time is brain.” The extent of ischemic brain injury is determined by (1) the time from the onset of symptoms to reperfusion and (2) the presence of collateral circulation including an intact circle of Willis. The “penumbra” is the region of the brain surrounding the infarct area where
S
Dr S.R. Ramee is a consultant and has received honoraria from Covidien. Curr Probl Cardiol 2014;39:59–76. 0146-2806/$ – see front matter http://dx.doi.org/10.1016/j.cpcardiol.2013.11.004
Curr Probl Cardiol, March 2014
59
the blood supply is significantly reduced, but viability is maintained owing to collateral flow. There is a premium on the early recognition stroke by the patient and the rapid assessment of patients who have had stroke by emergency physicians to reduce the time to treatment.3 Current treatment options include noninvasive intravenous (IV) thrombolysis or invasive catheter-based reperfusion therapies that include intra-arterial (IA) thrombolysis, mechanical thrombectomy, or balloon angioplasty with or without stent placement. Although rapid initiation of IV recombinant tissue plasminogen activator (rt-PA) with a “door-to-needle time” of less than 60 minutes is important for a good outcome, the American Heart Association’s “Get With The Guidelines-Stroke” national registry reported that fewer than 1 in 3 patients who have had stroke are treated in less than 60 minutes of arrival at the hospital.4 Although a Medicare national heart attack quality initiative has enabled interventional cardiologists to achieve dramatic reductions in door-to-balloon times,5 acute stroke therapy languishes without a mandate to provide early reperfusion. Amazingly, in 2013, a goal for door-totreatment time is not the “standard of care” for stroke therapy as it is for heart attacks.6 Currently, in the United States, most patients with acute ischemic stroke do not receive any form of reperfusion therapy, neither thrombolysis nor catheter-based therapy (CBT).7-9
Patient Selection The selection of therapy for patients who have had stroke depends upon several key factors. These include the severity of the stroke, time elapsed since the onset of the stroke, and the use of computed tomography (CT) or magnetic resonance imaging (MRI) or both.10
Stroke Severity The treatment of stroke with IV thrombolysis and catheter-directed therapy is associated with the risk of intracranial hemorrhage (ICH) and death. Accordingly, the stroke should be severe enough to justify taking this risk, usually meaning an National Institutes of Health Stroke Scale (NIHSS) Z8. Large-vessel occlusion includes the terminal internal carotid artery, first branch of the middle cerebral artery (MCA) (M1), and basilar artery. Hemiplegia with or without aphasia occurs with thrombotic occlusion of the carotid or M1distribution, and a locked-in syndrome occurs if the vertebrobasilar arteries are involved. Patients with the largest strokes have the most to gain from reperfusion therapy; however, they also have the highest risk of ICH associated with revascularization. 60
Curr Probl Cardiol, March 2014
Occluded vessels with a large clot burden, such as the large vessels described earlier, are likely to fail IV thrombolysis. Large-vessel occlusion can be diagnosed by neurologic examination and confirmed with CT or MRI. Because these patients are not likely to respond to IV thrombolysis, they should receive primary or rescue mechanical thrombectomy.11
Elapsed Time Time since onset of ischemic stroke has long guided therapy. Most trials of IV thrombolysis enrolled only patients within 3 hours of onset. For IA thrombolysis and mechanical thrombectomy, the time window can be extended to 6-8 hours. However, the best clinical results are obtained with the most rapid time to reperfusion. Because collaterals often exist in the posterior circulation, mechanical treatment of vertebrobasilar occlusions has been performed up to 48 hours after the onset of stroke.
Imaging The performance of emergent noncontrast CT scanning was used to exclude hemorrhagic stroke for most randomized trials of IV and IA thrombolysis. Noncontrast CT can demonstrate large-vessel occlusions (ie, terminal carotid, M1 [hyperdense MCA sign], and basilar artery occlusion) that are unlikely to respond to IV thrombolysis. It can also exclude patients from IV thrombolytic therapy who have hemorrhagic stroke, large completed infarcts, aneurysmal bleeds, and tumors. Advanced imaging with CT perfusion and MR perfusion are used to stratify the risk and benefits of treating patients with embolic stroke.12 Although there are no randomized comparisons, early data support the use of these new modalities as long as they do not delay the door-to-reperfusion times. Even though it is too early to recommend these advanced imaging studies in all patients with embolic stroke, in certain cases where the risk and benefits of intervention are not clearly defined, they may help better define those that are likely to benefit from IA thrombolysis and thrombectomy from those who are destined to have a poor outcome or a bleeding complication, such as ICH.13
IV Thrombolysis For rt-PA candidates (Table 1) presenting within 3-4.5 hours of symptom onset, the best indication of a positive treatment response is a CT scan with negative findings for bleeding with a moderate baseline clinical deficit (ie, NIHSS score of 4-12). The longer the duration of brain ischemia and the larger the neurologic deficit, the less likely patients will benefit from Curr Probl Cardiol, March 2014
61
TABLE1. Eligibility for thrombolysis in stroke
Indication: Ischemic stroke within 3-4.5 hours of onset of symptoms. Clinical contraindications: ○ Any history of ICH ○ SBP 4185 mm Hg and DBP 4110 mm Hg ○ Rapid improvement in neurologic status ○ Mild neurologic impairment ○ Symptoms of subarachnoid bleeding ○ Stroke or head trauma within the last 3 months ○ Gastrointestinal or genitourinary hemorrhage within 3 weeks ○ Major surgery within 3 weeks ○ Recent heart attack ○ Seizure with stroke ○ Taking oral anticoagulants ○ Received heparin within 48 hours Radiologic contraindications: ○ Evidence of ICH by CT scan. Laboratory contraindications: ○ INR 41.7 ○ Platelet count o100 K ○ Elevated aPTT level
Blood glucose level o50 mg/dL.
revascularization therapy. To separate those who will benefit from those who will not, it is helpful to define the infarct core and the ischemic penumbra with perfusion imaging by CT angiography or MRI. The size of the infarct core, which represents dead tissue, is a good predictor of poor neurologic outcomes and the risk of ICH. The size of the ischemic penumbra is a marker for potential benefit from successful recanalization.14 The window for IV thrombolysis can be extended to 4.5 hours after onset in low-risk patients with a favorable outcome in 52.4% compared with 45.2% among the placebo group (odds ratio ¼ 1.34; 95% CI: 1.021.76; P ¼ 0.04). Again, the incidence of ICH is higher in the rt-PA group (27%) compared with placebo (17.6%, P ¼ 0.001). There was no difference in mortality between the 2 groups.15,16 Currently the only FDA-approved therapy for acute ischemic stroke is the IV administration of rt-PA (Table 2).17A meta-analysis of 2775 patients with acute stroke treated with IV t-PA demonstrated that good outcomes were time dependent. Early treatment (o90 minutes of symptom onset) resulted in a 3-fold increase in good outcomes, whereas those treated between 180 and 270 minutes had a 1.4-fold increase in good outcomes compared with placebo.18 There was a 6-fold greater risk of ICH for the thrombolytic group (5.9%) compared with the placebo group (1.1%). The risk of ICH is higher in elderly patients, those with larger strokes, diabetes mellitus, any history of stroke, and thrombocytopenia. 62
Curr Probl Cardiol, March 2014
TABLE 2. Randomized trials of thrombolytic therapy for acute ischemic stroke Medications tested
Delivery
Dose of agent
NINDS t-PA Stroke 3 hours, 50% Trial (parts 1 and 2) treated in 90 minutes ECASS I 6 hours
t-PA
IV
0.9 mg/kg over 1 hour
624
t-PA
IV
620
ECASS II
6 hours
t-PA
IV
Atlantis A, 62 and 63 6 hours
t-PA
IV
Atlantis B
0-5 hours
t-PA
IV
ASK
4 hours
Streptokinase
IV
MAST I
6 hours
Streptokinase
IV
MAST E
6 hours
Streptokinase
IV
PROACT II
6 hours
Prourokinase plus IV heparin
IA
1.1 mg/kg over 1 hour 0.9 mg/kg over 1 hour 0.9 mg/kg over 1 hour 0.9 mg/kg over 1 hour 1.5 million units over 1 hour 1.5 million units over 1 hour 1.5 million units over 1 hour 9 mg over 2 hours
Name of study
Treatment window
No. of patients
800 142 613 (31 3 h) 340 622 310 180
The risk-to-benefit ratio for IV thrombolysis in ischemic stroke is narrow. At 3 months, about 11% more patients would experience a clinical benefit from IV lysis, whereas 6.4% would experience ICH. Unfortunately fewer than 10% of eligible patients who have had acute ischemic stroke receive reperfusion treatment in the United States.19 The number of patients who have had stroke and were needed to be treated with IV lysis to achieve an excellent outcome and avoid a stroke death or dependency is 7. For every 100 patients who have had stroke and were treated with IV thrombolysis within 3 hours, 32 will have an improved clinical outcome despite the 6 who will have an ICH. IV rt-PA has limited effectiveness in recanalizing stroke-related arteries with large clot burden. Recanalization rates range from less than 10% for internal carotid artery occlusions to approximately 50% for middle cerebral artery distal branch occlusions.20,21 Many experts suggest that when pretreatment CT angiography demonstrates proximal cerebral artery occlusion, endovascular therapy be offered owing to better outcomes.11
Catheter-Based Therapy IA Thrombolysis IA thrombolysis involves the selective placement of a catheter into the cerebral vessels. The benefit of a catheter-based intracranial therapy is the Curr Probl Cardiol, March 2014
63
ability to use smaller doses of lytic agents and to employ mechanical clot disruption and extraction with guidewires, balloons, and thrombectomy devices (Table 3). The concentrated IA delivery of the thrombolytic agent directly into an occluding thrombus assists in more rapid reperfusion and dissolution of the thrombus. IA thrombolysis has been shown to be effective in several trials. The Prolyse in Acute Cerebral Thromboembolism II trial randomized patients with occlusion of the MCA who presented within 6 hours of onset to either 9 mg of IA prourokinase plus heparin or heparin alone.22 The IA group achieved successful reperfusion in 66% compared with only 18% of the control group (P o 0.001). Clinically, at 90 days, 40% of the IA lysis group had slight or no neurologic disability compared with 25% of the control group (P ¼ 0.04). The IA lysis group had more symptomatic ICH, 11% vs 3% (P ¼ 0.03) in controls. The number needed to treat for 1 patient to achieve independent function was 7. This trial extended the efficacy for stroke treatment to 6 hours from the onset of their symptoms. There is a direct relationship between a longer time from onset to treatment and the risk of ICH.23 Contraindications to catheter-directed thrombolysis include recent brain surgery, unknown time of onset of the deficit, uncontrolled hypertension, and CT evidence of hemorrhage or tumor. The recently completed Interventional Management of Stroke III trial randomized 665 patients within 3 hours of receiving IV rt-PA to control
TABLE 3. Administration of intra-arterial thrombolysis to patients who have had acute ischemic stroke Indications Not eligible for IV rt-PA Acute ischemic stroke onset to treatment o6 hours Stroke is significant (disabling and life threatening) Suspected occlusion of a large artery (ie, nonlacunar stroke syndrome) No evidence of ICH on screening CT or MR imaging Contraindications Screening CT reveals extensive brain infarction (ie, more than one-third of middle cerebral artery territory ICH is suspected or evident on CT or MR imaging History of ICH or subarachnoid hemorrhage Significant dementia Patient has had a stroke within 3 months Bleeding diathesis, elevated international normalized ratio Z1.7, thrombocytopenia o100,000 cells/mm3 Relative contraindications Active treatment with heparin, high-dose aspirin, or clopidogrel
64
Curr Probl Cardiol, March 2014
group or to endovascular therapy group. The proportion of patients with good outcomes (modified Rankin score r2) did not differ between the groups. There was no difference at 90 days for mortality or ICH.24
Mechanical Thrombectomy Mechanical clot removal or thrombectomy is an alternative strategy to achieve stroke reperfusion in patients who are not candidates for IV thrombolysis (Figs 1 and 2). There are 2 approved devices (Merci, Concentric Medical, Mountain View, CA, and Penumbra, Penumbra Inc, San Leandro, CA) for mechanical thrombectomy during acute stroke intervention. The successful device delivery for both the Merci and Penumbra systems exceeds 90%, with successful target vessel recanalization obtained in 70%-80% of vessels. There seems an obligatory symptomatic ICH rate of about 10% with only a
FIG 1. (A) Angiogram of a subacute right middle cerebral artery occlusion. (B) Merci thrombectomy catheter across lesion. (C) Embolus retrieved. (D) Final angiogram after successful thrombectomy. (Adapted with permission from Fig 11 in White CJ, Abou-Chebl A, Cates CU et al. Stroke intervention catheter-based therapy for acute ischemic stroke. J Am CollCardiol. 2011;58:101–116).
Curr Probl Cardiol, March 2014
65
FIG 2. The Merci thrombectomy catheter (arrow).
25%-36% favorable neurologic improvement. In comparing the results of these embolectomy devices for acute stroke reperfusion, it is apparent that our ability to recanalize arteries does not directly correlate with good outcome. Successful recanalization had a positive effect on both neurologic outcome and mortality, but there is clearly room for improvement. It has been suggested that image-guided therapy could improve these results.25 New mechanical thrombectomy devices (Solitaire FR, Covidien, Mansfield, MA, and Trevo Retriever, Stryker Neurovascular, Mountain View, CA) are self-expanding stentlike devices (Fig 3), which offer improved deliverability compared with conventional mechanical thrombectomy catheters (Merci Retriever, Concentric Medical, Mountain View, CA, and PENUMBRA, Penumbra Inc, San Leandro, CA), which tend to be bulky and can be difficult to manipulate in the tortuous intracranial vessels that are encased in skull bone (Fig 4).26,27 In patients presenting within 4.5 hours of stroke onset with occlusion of a large intracranial vessel, one of the highest reperfusion rates (95%) for stroke thrombectomy was reported, with a mean “door-to-device” time of 95 ⫾ 33 minutes.28 This result is consistent with a recently published randomized trial demonstrating superiority of the Solitaire FR device 66
Curr Probl Cardiol, March 2014
FIG 3. The Solitaire catheter. Curr Probl Cardiol, March 2014
67
FIG 4. (A) The Solitaire catheter is pushed through the clot causing a stroke. (B) The Solitaire stent (a mesh cage) is then deployed into the clot and retrieved.
compared with the Merci Retriever (Fig 5).29 Almost two-thirds of these high-risk patients had a favorable clinical outcome (modified Rankin score (mRS) r2) at 3 months, with a very low risk of ICH (2.5%) and an acceptable mortality (12.5%). Recent data strongly support the linkage between early restoration of blood flow and good clinical outcomes. A 30-minute delay in onset to reperfusion delay caused a 20% increase in mortality and ICH, and each 30-minute delay in onset to reperfusion delay resulted in a 20% reduction in good or excellent outcomes.30 The demonstration that early endovascular reperfusion is similar in principle to early IV thrombolysis reperfusion mandates a system change in hospital care. We now must focus on a rapid transition from IV to endovascular therapies, minimizing time delays.
Angioplasty and Stent Placement Balloon angioplasty is commonly performed for residual stenoses following IA lysis or mechanical thrombectomy. Balloons are undersized 68
Curr Probl Cardiol, March 2014
to avoid arterial dissection and perforation. Often intracranial arterial lesions manifest acute recoil or flow-limiting dissections necessitating the use of bailout stenting. A strategy of immediate direct stent placement similar to how acute myocardial infarction is treated has been advocated. This technique of immediate direct stenting of the culprit lesion can minimize the time for reperfusion of the infarct zone.31-38 Three stent systems are currently FDA approved for intracranial (excluding acute stroke) use in the United States, Neuroform (Boston Scientific, Natick, MA), Wingspan (Boston Scientific, Natick, MA), and Enterprise (Codman Neurovascular or Cordis, Raynham, MA). These devices are all selfexpanding stents with extremely deliverable catheters to navigate the tortuous intracranial circulation. The Stent-Assisted Recanalization in Acute Ischemic Stroke trial was a prospective FDA-approved single-site registry designed to test the efficacy of direct stent placement in acute stroke. A total of 20 patients were enrolled with severe impairment (NIHSS = 14 ⫾ 3.8) with a duration of 313 ⫾ 114 minutes from symptom onset to intervention. On baseline angiography, 17 patients had thrombolysis in myocardial infarction (TIMI) 0 flow and 3 patients had TIMI 1 flow. All patients were successfully recanalized (TIMI 3 = 60% and TIMI 2 = 40%). Serious complications included ICH in 3 patients and the 1-month mortality rate was 25%. This rapid reperfusion strategy demonstrated marked improvement in discharge NIHSS (7.4) and at 1 month almost half of the patients were independently functioning with modified Rankin score of 1.39 This type of registry data
FIG 5. A bar graph showing results for success without ICH and good neurologic outcome (modified Rankin score o2) comparing the Solitaire and Merci devices.9 Curr Probl Cardiol, March 2014
69
TABLE 4. Stroke compared with heart attack therapy Stroke
Heart attack
Embolic atheromatous material or organized cardiac thrombus More organized thrombus Large volume of clot Resistant to lysis Cranial vessel tortuosity difficult to navigate with catheters
In situ thrombus Softer and less organized Lesser volume of clot Amenable to lysis Vessels less tortuous
suggest a potential role for aggressive direct stenting therapy in selected patients who have had stroke. Larger randomized trials will be needed to quantify the procedure’s risk-to-benefit ratio and to better determine optimal patient selection criteria.
Cardiologists Role in Stroke There are similarities in the treatment of acute stroke and acute myocardial infarction. There is a strong emphasis to achieve early reperfusion driven by early patient recognition, early hospital presentation, and early treatment initiation. However, there are significant differences between the treatment of stroke and heart attack, such as stroke thrombi are usually of embolic origin, making them older, more organized, and more resistant to lysis (Table 4). Also, the volume of clot is larger in patients who have had stroke, and cerebral vessel tortuosity can make CBT more difficult than the treatment of acute myocardial infarction. At the Ochsner Clinic, we have reported our experience with a multidisciplinary team including interventional cardiologists (ICs) to provide emergent endovascular therapy for patients who have had acute ischemic stroke and were ineligible for IV thrombolysis (Table 5).40,41 A stroke neurologist is first called to assess the patient who has had acute stroke and TABLE 5. Comparison of “real-world” catheter-based therapy patient in the Ochsner Clinic series with intravenous and intra-arterial thrombolysis for stroke treatment trials Study
Patients Age, NIHSS (n) males (%) baseline
Symptomatic ICH (%)
NINDS
168
69 y, 57
14
6.4
STARS
389
69 y 55
13
3.3
PROACT II Ochsner Clinic
121
64 y, 58
17
10
42
64 y, 44
16
12
Mortality at follow-up 17% at 3 months 13% at 1 month 25% at 3 months 9.5% at 1 month
Good outcome at follow-up (%) 39 35 26 45
NINDS, National Institute of Neurologic Disorders and Stroke; STARS, Standard Treatement with Alteplase to Reverse Stroke Study; PROACT II, PROlyse in Acute Cerebral Thromboembolism II. 70
Curr Probl Cardiol, March 2014
TABLE 6. Cardiologists strengths and weaknesses on the stroke intervention team Strengths Excellent catheter skills Experience with carotid stent placement and cerebral angiography Manage atherosclerotic risk factors for stroke Rapid response 24 7 to assist and relieve interventional neuroradiology Manage co-existent cardiac disease, that is, atrial fibrillation
Weaknesses Limited knowledge of: Cerebral anatomy CT and MRI interpretation Localization of deficit NIHSS and neurologic examination
determine the appropriateness of reperfusion therapy. The stroke neurologist would then call an interventional cardiologist for assistance when catheterbased interventional therapy is needed. Patients who have had stroke are eligible for CBT intervention if they are less than 8 hours from symptom onset. No specific cutoff or lower limit for their National Institutes of Health Stroke Scale (NIHSS) is used to exclude patients from intervention; rather, patients are eligible if they have a major deficit. The most important problem facing stroke therapy today is a lack of a national standard for reperfusion therapy and the absence of interventional therapy for patients who have had stroke and are not candidates for lysis. Unlike the national standard of care for heart attacks, with a national effort to minimize “door-to-balloon time” for early reperfusion, interventional stroke therapy is uncommon because of the paucity of neurointerventional physicians to provide this service around the clock in most communities.8 Although there are adequate numbers of neuroradiologists available to meet clinical demands during regular working hours, there are far too few to offer coverage for every night call for acute stroke therapy. There is, however, a large pool of skilled interventional cardiologists who are currently offering on-demand CBT for heart attacks and who have achieved cervicocerebral angiographic competence associated with carotid stent placement (Table 6).42 Michael H. Crawford, MD: Most acute strokes are ischemic in origin. The brain artery occluding thrombotic material can come from 4 sources: the heart, usually because of atrial fibrillation; an atherosclerotic ascending aorta; the external carotids or vertebral arteries; or intracerebral artery plaque rupture. There are considerable randomized controlled trial data supporting the efficacy of IV thrombolytic therapy for culprit artery recanalization and subsequent clinical improvement if it is given early in the course of an acute ischemic stroke in appropriate patients. There is a 6-fold increase in clinical cost of such therapy for ICH compared with IV heparin. Despite the proven efficacy of IV thrombolytic therapy, recanalization rates are low, especially in larger arteries and clinical improvement is modest. Also, many patients have contraindications for systemic thrombolysis. Thus, interest in catheter-delivered IA thrombolysis and mechanical clot retrieval systems Curr Probl Cardiol, March 2014
71
arose. The Prolyse in Acute Cerebral Thromboembolism II trial randomized patients with acute ischemic stroke within 4.5 hours of symptom onset to IV tPA vs IA prourokinase. The recanalization rate was 66% for IA therapy vs 18% for IV t-PA, and clinical outcomes and ICH were increased with IA administration. At the same time, mechanical clot retrieval systems were being tested with excellent recanalization and clinical outcomes in observational studies, and physicians were often combining the 2 therapies in some cases. To date the FDA has not approved any thrombolytic for IA use, but has approved 4 clot retrieval systems, despite a lack of randomized controlled trials demonstrating their clinical efficacy vs IV thrombolysis. This highlights the ease of medical device approval vs the approval of new pharmaceutical agents. Also, Medicare has approved payment for stroke treatment with mechanical devices. With clinicians clamoring for comparative efficacy data, several trials were organized and in the March 7, 2013 issue of the New England Journal of Medicine, 3 of these trials were reported with an accompanying editorial. Ciccone et al43 reported the results of the SYNTHESIS Expansion trial of 362 patients who have had acute ischemic stroke randomized to treatment within 4.5 hours of symptom onset to IV t-PA or IA t-PA. At 90-day follow-up, functional status and ICH rates were not significantly different. Importantly, the time from symptom onset to therapy was on average about 1 hour longer in the IA t-PA group. Broderick et al24 reported the results of the Interventional Management of Stroke III trial of 656 patients who have had acute ischemic stroke and were treated with an initial dose of IV t-PA for less than 3 hours from symptom onset and then randomized to continued t-PA to full dose or endovascular therapy (devices or IA t-PA per physician choice).24 The trial was stopped early for futility because there was no difference in functional recovery or ICH at 90 days. Also, stratification by the NIH stroke severity score did not demonstrate any advantage for endovascular therapy, despite better recanalization rates. The final article by Kidwell et al44 on the MR RESCUE trial was based upon the observation that brain perfusion studies showing a large ischemic penumbra and a small infarct predicted improved outcomes with successful reperfusion as compared with the opposite pattern.44 They randomized 118 patients within 8 hours of symptom onset with a large, anterior circulation cerebral artery occlusion to mechanical embolectomy vs IV thrombolysis. There was no difference in functional status, mortality, or ICH at the 90-day follow-up. Disappointingly, the ischemic penumbra-to-infarct ratio did not favor a therapy over the other, despite better overall outcomes in those with a high ratio. Are these 3 recent articles the waterloo for endovascular therapy? No, but they should hamper their unbridled use.45 Although, at less than 4.5 hours from symptom onset IV t-PA and current endovascular therapy have equivalent outcomes, there are many patients who cannot safely undergo systemic thrombolysis. These patients represent the primary indication for endovascular therapy. Other potential indications include patients with basilar artery thrombosis strokes. These patients have a high mortality and a more aggressive revascularization therapy seems appropriate in them for up to 16 hours after symptom onset. Also, patients presenting after more than 4.5 hours from symptom onset have poor results with IV thrombolysis and may be candidates for endovascular therapy up to 8 hours or more depending on the clinical situation. The Ochsner protocol as detailed by Drs Ramee and White is a reasonable approach in the absence of national guidelines. A caveat to the use of all aggressive ischemic stroke therapies is the timing issue. Clearly earlier is better for all therapies, but especially IV thrombolysis. Unfortunately, it is not always possible to determine the onset of symptoms. 72
Curr Probl Cardiol, March 2014
The patient may not be able to communicate and if no one witnessed the onset, timing becomes problematic. Not infrequently strokes occur during sleep, and the patient wakes up with the signs of stroke present, but the onset time is unknown. In these cases, the safest approach is to use the time that the patient was last reported or observed to be normal by themselves or others. In the case of a stroke that occurs during sleep this may set the onset at 8 hours or more before the time you see the patient when the risks of aggressive therapy could outweigh the potential benefits. Although these potential late arrivals may favor endovascular therapy over IV thrombolysis, considerable clinical judgment must be exercised in such cases.
REFERENCES 1. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation 2013;127:e6-245. 2. Adams HP, Jr, del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/ American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Circulation 2007;115:e478-534. 3. Adams HP, Jr, Adams RJ, Brott T, et al. Guidelines for the early management of patients with ischemic stroke: a scientific statement from the Stroke Council of the American Stroke Association. Stroke 2003;34:1056-83. 4. Fonarow GC, Smith EE, Saver JL, et al. Timeliness of tissue-type plasminogen activator therapy in acute ischemic stroke: patient characteristics, hospital factors, and outcomes associated with door-to-needle times within 60 minutes. Circulation 2011; 123:750-8. 5. Krumholz HM, Herrin J, Miller LE, et al. Improvements in door-to-balloon time in the United States, 2005 to 2010. Circulation 2011;124:1038-45. 6. Patel RD, Saver JL. Evolution of reperfusion therapies for acute brain and acute myocardial ischemia: a systematic, comparative analysis. Stroke 2013;44:94-8. 7. Demaerschalk BM, Yip TR. Economic benefit of increasing utilization of intravenous tissue plasminogen activator for acute ischemic stroke in the United States. Stroke 2005;36:2500-3. 8. Suzuki S, Saver JL, Scott P, et al. Access to intra-arterial therapies for acute ischemic stroke: an analysis of the US population. AJNR Am J Neuroradiol 2004;25:1802-6. 9. Cloft HJ, Rabinstein A, Lanzino G, et al. Intra-arterial stroke therapy: an assessment of demand and available work force. AJNR Am J Neuroradiol 2009;30:453-8. 10. Sacks D, Black CM, Cognard C, et al. Multisociety consensus quality improvement guidelines for intraarterial catheter-directed treatment of acute ischemic stroke, from the American Society of Neuroradiology, Canadian Interventional Radiology Association, Cardiovascular and Interventional Radiological Society of Europe, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Curr Probl Cardiol, March 2014
73
11. 12. 13.
14.
15. 16.
17.
18.
19.
20.
21. 22.
23.
24.
74
Society of NeuroInterventional Surgery, European Society of Minimally Invasive Neurological Therapy, and Society of Vascular and Interventional Neurology. J Vasc Interv Radiol 2013;24:151-63. Papanagiotou P, Roth C, Walter S, et al. Carotid artery stenting in acute stroke. J Am Coll Cardiol 2011;58:2363-9. Mackey J, Khatri P, Broderick JP. Increasing use of CT angiography in interventional study sites: the IMS III experience. AJNR Am J Neuroradiol 2010;31:E34. Turk A, Magarik JA, Chaudry I, et al. CT perfusion-guided patient selection for endovascular treatment of acute ischemic stroke is safe and effective. J Neurointerv Surg 2012;4:261-5. Abou-Chebl A. Endovascular treatment of acute ischemic stroke may be safely performed with no time window limit in appropriately selected patients. Stroke 2010;41:1996-2000. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359:1317-29. Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator: a science advisory from the American Heart Association/American Stroke Association. Stroke 2009;40:2945-8. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;333:1581-7. Hacke W, Donnan G, Fieschi C, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004;363:768-74. Reeves MJ, Arora S, Broderick JP, et al. Acute stroke care in the US: results from 4 pilot prototypes of the Paul Coverdell National Acute Stroke Registry. Stroke 2005;36: 1232-40. Wolpert SM, Bruckmann H, Greenlee R, et al. Neuroradiologic evaluation of patients with acute stroke treated with recombinant tissue plasminogen activator. The rt-PA Acute Stroke Study Group. AJNR Am J Neuroradiol 1993;14:3-13. Alexandrov AV, Grotta JC. Arterial reocclusion in stroke patients treated with intravenous tissue plasminogen activator. Neurology 2002;59:862-7. Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. J Am Med Assoc 1999;282:2003-11. Meyers PM, Schumacher HC, Higashida RT, et al. Indications for the performance of intracranial endovascular neurointerventional procedures: a scientific statement from the American Heart Association Council on Cardiovascular Radiology and Intervention, Stroke Council, Council on Cardiovascular Surgery and Anesthesia, Interdisciplinary Council on Peripheral Vascular Disease, and Interdisciplinary Council on Quality of Care and Outcomes Research. Circulation 2009;119:2235-49. Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med 2013;368:893-903. Curr Probl Cardiol, March 2014
25. Coutts SB, Goyal M. When recanalization does not improve clinical outcomes. Stroke 2009;40:2661. 26. Nogueira RG, Lutsep HL, Gupta R, et al. Trevo versus Merci retrievers for thrombectomy revascularisation of large vessel occlusions in acute ischaemic stroke (TREVO 2): a randomised trial. Lancet 2012;380:1231-40. 27. Roth C, Papanagiotou P, Behnke S, et al. Stent-assisted mechanical recanalization for treatment of acute intracerebral artery occlusions. Stroke 2010;41:2559-67. 28. Roth C, Reith W, Walter S, et al. Mechanical recanalization with flow restoration in acute ischemic stroke: the ReFlow (mechanical recanalization with flow restoration in acute ischemic stroke) study. JACC Cardiovasc Interv 2013;6:386-91. 29. Saver JL, Jahan R, Levy EI, et al. Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomised, parallelgroup, non-inferiority trial. Lancet 2012;380:1241-9. 30. Mazighi M, Chaudhry SA, Ribo M, et al. Impact of onset-to-reperfusion time on stroke mortality: a collaborative pooled analysis. Circulation 2013;127:1980-5. 31. Fiorella DJ, Levy EI, Turk AS, et al. Target lesion revascularization after wingspan: assessment of safety and durability. Stroke 2009;40:106-10. 32. Levy EI, Mehta R, Gupta R, et al. Self-expanding stents for recanalization of acute cerebrovascular occlusions. AJNR Am J Neuroradiol 2007;28:816-22. 33. Turk AS, Levy EI, Albuquerque FC, et al. Influence of patient age and stenosis location on wingspan in-stent restenosis. AJNR Am J Neuroradiol 2008;29: 23-7. 34. Brekenfeld C, Schroth G, Mattle HP, et al. Stent placement in acute cerebral artery occlusion: use of a self-expandable intracranial stent for acute stroke treatment. Stroke 2009;40:847-52. 35. Levy EI, Turk AS, Albuquerque FC, et al. Wingspan in-stent restenosis and thrombosis: incidence, clinical presentation, and management. Neurosurgery 2007;61: 644-50; [discussion 650-1]. 36. Zaidat OO, Wolfe T, Hussain SI, et al. Interventional acute ischemic stroke therapy with intracranial self-expanding stent. Stroke 2008;39:2392-5. 37. Mocco J, Tawk RG, Jahromi BS, et al. Endovascular intervention for acute thromboembolic stroke in young patients: an ideal population for aggressive intervention? J Neurosurg 2009;110:30-4. 38. Mathews MS, Sharma J, Snyder KV, et al. Safety, effectiveness, and practicality of endovascular therapy within the first 3 hours of acute ischemic stroke onset. Neurosurgery 2009;65:860-5; [discussion 865]. 39. Levy EI, Siddiqui AH, Crumlish A, et al. First Food and Drug Administrationapproved prospective trial of primary intracranial stenting for acute stroke: SARIS (stent-assisted recanalization in acute ischemic stroke). Stroke 2009;40:3552-6. 40. Ramee SR, Subramanian R, Felberg RA, et al. Catheter-based treatment for patients with acute ischemic stroke ineligible for intravenous thrombolysis. Stroke 2004;35: e109-11. 41. DeVries JT, White CJ, Collins TJ, et al. Acute stroke intervention by interventional cardiologists. Catheter Cardiovasc Interv 2009;73:692-8. Curr Probl Cardiol, March 2014
75
42. White CJ, Cates CU, Cowley MJ, et al. Interventional stroke therapy: current state of the art and needs assessment. Catheter Cardiovasc Interv 2007;70:471-6. 43. Ciccone A, Valvassori L, Nichelatti M, Sgoifo A, Ponzio M, Sterzi R, Boccardi E (for the SYNTHESIS Expansion Investigators). Endovascular treatment for acute ischemic stroke. N Engl J Med 2013;368:904-13. 44. Kidwell CS, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 2013;368:914-23. 45. Chimowitz MI. Endovascular treatment for acute ischemic stroke—still unproven. N Engl J Med 2013;368:952-5.
76
Curr Probl Cardiol, March 2014
S
Dr S.R. Ramee is a consultant and has received honoraria from Covidien. Curr Probl Cardiol 2014;39:59–76. 0146-2806/$ – see front matter http://dx.doi.org/10.1016/j.cpcardiol.2013.11.004
Curr Probl Cardiol, March 2014
59
the blood supply is significantly reduced, but viability is maintained owing to collateral flow. There is a premium on the early recognition stroke by the patient and the rapid assessment of patients who have had stroke by emergency physicians to reduce the time to treatment.3 Current treatment options include noninvasive intravenous (IV) thrombolysis or invasive catheter-based reperfusion therapies that include intra-arterial (IA) thrombolysis, mechanical thrombectomy, or balloon angioplasty with or without stent placement. Although rapid initiation of IV recombinant tissue plasminogen activator (rt-PA) with a “door-to-needle time” of less than 60 minutes is important for a good outcome, the American Heart Association’s “Get With The Guidelines-Stroke” national registry reported that fewer than 1 in 3 patients who have had stroke are treated in less than 60 minutes of arrival at the hospital.4 Although a Medicare national heart attack quality initiative has enabled interventional cardiologists to achieve dramatic reductions in door-to-balloon times,5 acute stroke therapy languishes without a mandate to provide early reperfusion. Amazingly, in 2013, a goal for door-totreatment time is not the “standard of care” for stroke therapy as it is for heart attacks.6 Currently, in the United States, most patients with acute ischemic stroke do not receive any form of reperfusion therapy, neither thrombolysis nor catheter-based therapy (CBT).7-9
Patient Selection The selection of therapy for patients who have had stroke depends upon several key factors. These include the severity of the stroke, time elapsed since the onset of the stroke, and the use of computed tomography (CT) or magnetic resonance imaging (MRI) or both.10
Stroke Severity The treatment of stroke with IV thrombolysis and catheter-directed therapy is associated with the risk of intracranial hemorrhage (ICH) and death. Accordingly, the stroke should be severe enough to justify taking this risk, usually meaning an National Institutes of Health Stroke Scale (NIHSS) Z8. Large-vessel occlusion includes the terminal internal carotid artery, first branch of the middle cerebral artery (MCA) (M1), and basilar artery. Hemiplegia with or without aphasia occurs with thrombotic occlusion of the carotid or M1distribution, and a locked-in syndrome occurs if the vertebrobasilar arteries are involved. Patients with the largest strokes have the most to gain from reperfusion therapy; however, they also have the highest risk of ICH associated with revascularization. 60
Curr Probl Cardiol, March 2014
Occluded vessels with a large clot burden, such as the large vessels described earlier, are likely to fail IV thrombolysis. Large-vessel occlusion can be diagnosed by neurologic examination and confirmed with CT or MRI. Because these patients are not likely to respond to IV thrombolysis, they should receive primary or rescue mechanical thrombectomy.11
Elapsed Time Time since onset of ischemic stroke has long guided therapy. Most trials of IV thrombolysis enrolled only patients within 3 hours of onset. For IA thrombolysis and mechanical thrombectomy, the time window can be extended to 6-8 hours. However, the best clinical results are obtained with the most rapid time to reperfusion. Because collaterals often exist in the posterior circulation, mechanical treatment of vertebrobasilar occlusions has been performed up to 48 hours after the onset of stroke.
Imaging The performance of emergent noncontrast CT scanning was used to exclude hemorrhagic stroke for most randomized trials of IV and IA thrombolysis. Noncontrast CT can demonstrate large-vessel occlusions (ie, terminal carotid, M1 [hyperdense MCA sign], and basilar artery occlusion) that are unlikely to respond to IV thrombolysis. It can also exclude patients from IV thrombolytic therapy who have hemorrhagic stroke, large completed infarcts, aneurysmal bleeds, and tumors. Advanced imaging with CT perfusion and MR perfusion are used to stratify the risk and benefits of treating patients with embolic stroke.12 Although there are no randomized comparisons, early data support the use of these new modalities as long as they do not delay the door-to-reperfusion times. Even though it is too early to recommend these advanced imaging studies in all patients with embolic stroke, in certain cases where the risk and benefits of intervention are not clearly defined, they may help better define those that are likely to benefit from IA thrombolysis and thrombectomy from those who are destined to have a poor outcome or a bleeding complication, such as ICH.13
IV Thrombolysis For rt-PA candidates (Table 1) presenting within 3-4.5 hours of symptom onset, the best indication of a positive treatment response is a CT scan with negative findings for bleeding with a moderate baseline clinical deficit (ie, NIHSS score of 4-12). The longer the duration of brain ischemia and the larger the neurologic deficit, the less likely patients will benefit from Curr Probl Cardiol, March 2014
61
TABLE1. Eligibility for thrombolysis in stroke
Indication: Ischemic stroke within 3-4.5 hours of onset of symptoms. Clinical contraindications: ○ Any history of ICH ○ SBP 4185 mm Hg and DBP 4110 mm Hg ○ Rapid improvement in neurologic status ○ Mild neurologic impairment ○ Symptoms of subarachnoid bleeding ○ Stroke or head trauma within the last 3 months ○ Gastrointestinal or genitourinary hemorrhage within 3 weeks ○ Major surgery within 3 weeks ○ Recent heart attack ○ Seizure with stroke ○ Taking oral anticoagulants ○ Received heparin within 48 hours Radiologic contraindications: ○ Evidence of ICH by CT scan. Laboratory contraindications: ○ INR 41.7 ○ Platelet count o100 K ○ Elevated aPTT level
Blood glucose level o50 mg/dL.
revascularization therapy. To separate those who will benefit from those who will not, it is helpful to define the infarct core and the ischemic penumbra with perfusion imaging by CT angiography or MRI. The size of the infarct core, which represents dead tissue, is a good predictor of poor neurologic outcomes and the risk of ICH. The size of the ischemic penumbra is a marker for potential benefit from successful recanalization.14 The window for IV thrombolysis can be extended to 4.5 hours after onset in low-risk patients with a favorable outcome in 52.4% compared with 45.2% among the placebo group (odds ratio ¼ 1.34; 95% CI: 1.021.76; P ¼ 0.04). Again, the incidence of ICH is higher in the rt-PA group (27%) compared with placebo (17.6%, P ¼ 0.001). There was no difference in mortality between the 2 groups.15,16 Currently the only FDA-approved therapy for acute ischemic stroke is the IV administration of rt-PA (Table 2).17A meta-analysis of 2775 patients with acute stroke treated with IV t-PA demonstrated that good outcomes were time dependent. Early treatment (o90 minutes of symptom onset) resulted in a 3-fold increase in good outcomes, whereas those treated between 180 and 270 minutes had a 1.4-fold increase in good outcomes compared with placebo.18 There was a 6-fold greater risk of ICH for the thrombolytic group (5.9%) compared with the placebo group (1.1%). The risk of ICH is higher in elderly patients, those with larger strokes, diabetes mellitus, any history of stroke, and thrombocytopenia. 62
Curr Probl Cardiol, March 2014
TABLE 2. Randomized trials of thrombolytic therapy for acute ischemic stroke Medications tested
Delivery
Dose of agent
NINDS t-PA Stroke 3 hours, 50% Trial (parts 1 and 2) treated in 90 minutes ECASS I 6 hours
t-PA
IV
0.9 mg/kg over 1 hour
624
t-PA
IV
620
ECASS II
6 hours
t-PA
IV
Atlantis A, 62 and 63 6 hours
t-PA
IV
Atlantis B
0-5 hours
t-PA
IV
ASK
4 hours
Streptokinase
IV
MAST I
6 hours
Streptokinase
IV
MAST E
6 hours
Streptokinase
IV
PROACT II
6 hours
Prourokinase plus IV heparin
IA
1.1 mg/kg over 1 hour 0.9 mg/kg over 1 hour 0.9 mg/kg over 1 hour 0.9 mg/kg over 1 hour 1.5 million units over 1 hour 1.5 million units over 1 hour 1.5 million units over 1 hour 9 mg over 2 hours
Name of study
Treatment window
No. of patients
800 142 613 (31 3 h) 340 622 310 180
The risk-to-benefit ratio for IV thrombolysis in ischemic stroke is narrow. At 3 months, about 11% more patients would experience a clinical benefit from IV lysis, whereas 6.4% would experience ICH. Unfortunately fewer than 10% of eligible patients who have had acute ischemic stroke receive reperfusion treatment in the United States.19 The number of patients who have had stroke and were needed to be treated with IV lysis to achieve an excellent outcome and avoid a stroke death or dependency is 7. For every 100 patients who have had stroke and were treated with IV thrombolysis within 3 hours, 32 will have an improved clinical outcome despite the 6 who will have an ICH. IV rt-PA has limited effectiveness in recanalizing stroke-related arteries with large clot burden. Recanalization rates range from less than 10% for internal carotid artery occlusions to approximately 50% for middle cerebral artery distal branch occlusions.20,21 Many experts suggest that when pretreatment CT angiography demonstrates proximal cerebral artery occlusion, endovascular therapy be offered owing to better outcomes.11
Catheter-Based Therapy IA Thrombolysis IA thrombolysis involves the selective placement of a catheter into the cerebral vessels. The benefit of a catheter-based intracranial therapy is the Curr Probl Cardiol, March 2014
63
ability to use smaller doses of lytic agents and to employ mechanical clot disruption and extraction with guidewires, balloons, and thrombectomy devices (Table 3). The concentrated IA delivery of the thrombolytic agent directly into an occluding thrombus assists in more rapid reperfusion and dissolution of the thrombus. IA thrombolysis has been shown to be effective in several trials. The Prolyse in Acute Cerebral Thromboembolism II trial randomized patients with occlusion of the MCA who presented within 6 hours of onset to either 9 mg of IA prourokinase plus heparin or heparin alone.22 The IA group achieved successful reperfusion in 66% compared with only 18% of the control group (P o 0.001). Clinically, at 90 days, 40% of the IA lysis group had slight or no neurologic disability compared with 25% of the control group (P ¼ 0.04). The IA lysis group had more symptomatic ICH, 11% vs 3% (P ¼ 0.03) in controls. The number needed to treat for 1 patient to achieve independent function was 7. This trial extended the efficacy for stroke treatment to 6 hours from the onset of their symptoms. There is a direct relationship between a longer time from onset to treatment and the risk of ICH.23 Contraindications to catheter-directed thrombolysis include recent brain surgery, unknown time of onset of the deficit, uncontrolled hypertension, and CT evidence of hemorrhage or tumor. The recently completed Interventional Management of Stroke III trial randomized 665 patients within 3 hours of receiving IV rt-PA to control
TABLE 3. Administration of intra-arterial thrombolysis to patients who have had acute ischemic stroke Indications Not eligible for IV rt-PA Acute ischemic stroke onset to treatment o6 hours Stroke is significant (disabling and life threatening) Suspected occlusion of a large artery (ie, nonlacunar stroke syndrome) No evidence of ICH on screening CT or MR imaging Contraindications Screening CT reveals extensive brain infarction (ie, more than one-third of middle cerebral artery territory ICH is suspected or evident on CT or MR imaging History of ICH or subarachnoid hemorrhage Significant dementia Patient has had a stroke within 3 months Bleeding diathesis, elevated international normalized ratio Z1.7, thrombocytopenia o100,000 cells/mm3 Relative contraindications Active treatment with heparin, high-dose aspirin, or clopidogrel
64
Curr Probl Cardiol, March 2014
group or to endovascular therapy group. The proportion of patients with good outcomes (modified Rankin score r2) did not differ between the groups. There was no difference at 90 days for mortality or ICH.24
Mechanical Thrombectomy Mechanical clot removal or thrombectomy is an alternative strategy to achieve stroke reperfusion in patients who are not candidates for IV thrombolysis (Figs 1 and 2). There are 2 approved devices (Merci, Concentric Medical, Mountain View, CA, and Penumbra, Penumbra Inc, San Leandro, CA) for mechanical thrombectomy during acute stroke intervention. The successful device delivery for both the Merci and Penumbra systems exceeds 90%, with successful target vessel recanalization obtained in 70%-80% of vessels. There seems an obligatory symptomatic ICH rate of about 10% with only a
FIG 1. (A) Angiogram of a subacute right middle cerebral artery occlusion. (B) Merci thrombectomy catheter across lesion. (C) Embolus retrieved. (D) Final angiogram after successful thrombectomy. (Adapted with permission from Fig 11 in White CJ, Abou-Chebl A, Cates CU et al. Stroke intervention catheter-based therapy for acute ischemic stroke. J Am CollCardiol. 2011;58:101–116).
Curr Probl Cardiol, March 2014
65
FIG 2. The Merci thrombectomy catheter (arrow).
25%-36% favorable neurologic improvement. In comparing the results of these embolectomy devices for acute stroke reperfusion, it is apparent that our ability to recanalize arteries does not directly correlate with good outcome. Successful recanalization had a positive effect on both neurologic outcome and mortality, but there is clearly room for improvement. It has been suggested that image-guided therapy could improve these results.25 New mechanical thrombectomy devices (Solitaire FR, Covidien, Mansfield, MA, and Trevo Retriever, Stryker Neurovascular, Mountain View, CA) are self-expanding stentlike devices (Fig 3), which offer improved deliverability compared with conventional mechanical thrombectomy catheters (Merci Retriever, Concentric Medical, Mountain View, CA, and PENUMBRA, Penumbra Inc, San Leandro, CA), which tend to be bulky and can be difficult to manipulate in the tortuous intracranial vessels that are encased in skull bone (Fig 4).26,27 In patients presenting within 4.5 hours of stroke onset with occlusion of a large intracranial vessel, one of the highest reperfusion rates (95%) for stroke thrombectomy was reported, with a mean “door-to-device” time of 95 ⫾ 33 minutes.28 This result is consistent with a recently published randomized trial demonstrating superiority of the Solitaire FR device 66
Curr Probl Cardiol, March 2014
FIG 3. The Solitaire catheter. Curr Probl Cardiol, March 2014
67
FIG 4. (A) The Solitaire catheter is pushed through the clot causing a stroke. (B) The Solitaire stent (a mesh cage) is then deployed into the clot and retrieved.
compared with the Merci Retriever (Fig 5).29 Almost two-thirds of these high-risk patients had a favorable clinical outcome (modified Rankin score (mRS) r2) at 3 months, with a very low risk of ICH (2.5%) and an acceptable mortality (12.5%). Recent data strongly support the linkage between early restoration of blood flow and good clinical outcomes. A 30-minute delay in onset to reperfusion delay caused a 20% increase in mortality and ICH, and each 30-minute delay in onset to reperfusion delay resulted in a 20% reduction in good or excellent outcomes.30 The demonstration that early endovascular reperfusion is similar in principle to early IV thrombolysis reperfusion mandates a system change in hospital care. We now must focus on a rapid transition from IV to endovascular therapies, minimizing time delays.
Angioplasty and Stent Placement Balloon angioplasty is commonly performed for residual stenoses following IA lysis or mechanical thrombectomy. Balloons are undersized 68
Curr Probl Cardiol, March 2014
to avoid arterial dissection and perforation. Often intracranial arterial lesions manifest acute recoil or flow-limiting dissections necessitating the use of bailout stenting. A strategy of immediate direct stent placement similar to how acute myocardial infarction is treated has been advocated. This technique of immediate direct stenting of the culprit lesion can minimize the time for reperfusion of the infarct zone.31-38 Three stent systems are currently FDA approved for intracranial (excluding acute stroke) use in the United States, Neuroform (Boston Scientific, Natick, MA), Wingspan (Boston Scientific, Natick, MA), and Enterprise (Codman Neurovascular or Cordis, Raynham, MA). These devices are all selfexpanding stents with extremely deliverable catheters to navigate the tortuous intracranial circulation. The Stent-Assisted Recanalization in Acute Ischemic Stroke trial was a prospective FDA-approved single-site registry designed to test the efficacy of direct stent placement in acute stroke. A total of 20 patients were enrolled with severe impairment (NIHSS = 14 ⫾ 3.8) with a duration of 313 ⫾ 114 minutes from symptom onset to intervention. On baseline angiography, 17 patients had thrombolysis in myocardial infarction (TIMI) 0 flow and 3 patients had TIMI 1 flow. All patients were successfully recanalized (TIMI 3 = 60% and TIMI 2 = 40%). Serious complications included ICH in 3 patients and the 1-month mortality rate was 25%. This rapid reperfusion strategy demonstrated marked improvement in discharge NIHSS (7.4) and at 1 month almost half of the patients were independently functioning with modified Rankin score of 1.39 This type of registry data
FIG 5. A bar graph showing results for success without ICH and good neurologic outcome (modified Rankin score o2) comparing the Solitaire and Merci devices.9 Curr Probl Cardiol, March 2014
69
TABLE 4. Stroke compared with heart attack therapy Stroke
Heart attack
Embolic atheromatous material or organized cardiac thrombus More organized thrombus Large volume of clot Resistant to lysis Cranial vessel tortuosity difficult to navigate with catheters
In situ thrombus Softer and less organized Lesser volume of clot Amenable to lysis Vessels less tortuous
suggest a potential role for aggressive direct stenting therapy in selected patients who have had stroke. Larger randomized trials will be needed to quantify the procedure’s risk-to-benefit ratio and to better determine optimal patient selection criteria.
Cardiologists Role in Stroke There are similarities in the treatment of acute stroke and acute myocardial infarction. There is a strong emphasis to achieve early reperfusion driven by early patient recognition, early hospital presentation, and early treatment initiation. However, there are significant differences between the treatment of stroke and heart attack, such as stroke thrombi are usually of embolic origin, making them older, more organized, and more resistant to lysis (Table 4). Also, the volume of clot is larger in patients who have had stroke, and cerebral vessel tortuosity can make CBT more difficult than the treatment of acute myocardial infarction. At the Ochsner Clinic, we have reported our experience with a multidisciplinary team including interventional cardiologists (ICs) to provide emergent endovascular therapy for patients who have had acute ischemic stroke and were ineligible for IV thrombolysis (Table 5).40,41 A stroke neurologist is first called to assess the patient who has had acute stroke and TABLE 5. Comparison of “real-world” catheter-based therapy patient in the Ochsner Clinic series with intravenous and intra-arterial thrombolysis for stroke treatment trials Study
Patients Age, NIHSS (n) males (%) baseline
Symptomatic ICH (%)
NINDS
168
69 y, 57
14
6.4
STARS
389
69 y 55
13
3.3
PROACT II Ochsner Clinic
121
64 y, 58
17
10
42
64 y, 44
16
12
Mortality at follow-up 17% at 3 months 13% at 1 month 25% at 3 months 9.5% at 1 month
Good outcome at follow-up (%) 39 35 26 45
NINDS, National Institute of Neurologic Disorders and Stroke; STARS, Standard Treatement with Alteplase to Reverse Stroke Study; PROACT II, PROlyse in Acute Cerebral Thromboembolism II. 70
Curr Probl Cardiol, March 2014
TABLE 6. Cardiologists strengths and weaknesses on the stroke intervention team Strengths Excellent catheter skills Experience with carotid stent placement and cerebral angiography Manage atherosclerotic risk factors for stroke Rapid response 24 7 to assist and relieve interventional neuroradiology Manage co-existent cardiac disease, that is, atrial fibrillation
Weaknesses Limited knowledge of: Cerebral anatomy CT and MRI interpretation Localization of deficit NIHSS and neurologic examination
determine the appropriateness of reperfusion therapy. The stroke neurologist would then call an interventional cardiologist for assistance when catheterbased interventional therapy is needed. Patients who have had stroke are eligible for CBT intervention if they are less than 8 hours from symptom onset. No specific cutoff or lower limit for their National Institutes of Health Stroke Scale (NIHSS) is used to exclude patients from intervention; rather, patients are eligible if they have a major deficit. The most important problem facing stroke therapy today is a lack of a national standard for reperfusion therapy and the absence of interventional therapy for patients who have had stroke and are not candidates for lysis. Unlike the national standard of care for heart attacks, with a national effort to minimize “door-to-balloon time” for early reperfusion, interventional stroke therapy is uncommon because of the paucity of neurointerventional physicians to provide this service around the clock in most communities.8 Although there are adequate numbers of neuroradiologists available to meet clinical demands during regular working hours, there are far too few to offer coverage for every night call for acute stroke therapy. There is, however, a large pool of skilled interventional cardiologists who are currently offering on-demand CBT for heart attacks and who have achieved cervicocerebral angiographic competence associated with carotid stent placement (Table 6).42 Michael H. Crawford, MD: Most acute strokes are ischemic in origin. The brain artery occluding thrombotic material can come from 4 sources: the heart, usually because of atrial fibrillation; an atherosclerotic ascending aorta; the external carotids or vertebral arteries; or intracerebral artery plaque rupture. There are considerable randomized controlled trial data supporting the efficacy of IV thrombolytic therapy for culprit artery recanalization and subsequent clinical improvement if it is given early in the course of an acute ischemic stroke in appropriate patients. There is a 6-fold increase in clinical cost of such therapy for ICH compared with IV heparin. Despite the proven efficacy of IV thrombolytic therapy, recanalization rates are low, especially in larger arteries and clinical improvement is modest. Also, many patients have contraindications for systemic thrombolysis. Thus, interest in catheter-delivered IA thrombolysis and mechanical clot retrieval systems Curr Probl Cardiol, March 2014
71
arose. The Prolyse in Acute Cerebral Thromboembolism II trial randomized patients with acute ischemic stroke within 4.5 hours of symptom onset to IV tPA vs IA prourokinase. The recanalization rate was 66% for IA therapy vs 18% for IV t-PA, and clinical outcomes and ICH were increased with IA administration. At the same time, mechanical clot retrieval systems were being tested with excellent recanalization and clinical outcomes in observational studies, and physicians were often combining the 2 therapies in some cases. To date the FDA has not approved any thrombolytic for IA use, but has approved 4 clot retrieval systems, despite a lack of randomized controlled trials demonstrating their clinical efficacy vs IV thrombolysis. This highlights the ease of medical device approval vs the approval of new pharmaceutical agents. Also, Medicare has approved payment for stroke treatment with mechanical devices. With clinicians clamoring for comparative efficacy data, several trials were organized and in the March 7, 2013 issue of the New England Journal of Medicine, 3 of these trials were reported with an accompanying editorial. Ciccone et al43 reported the results of the SYNTHESIS Expansion trial of 362 patients who have had acute ischemic stroke randomized to treatment within 4.5 hours of symptom onset to IV t-PA or IA t-PA. At 90-day follow-up, functional status and ICH rates were not significantly different. Importantly, the time from symptom onset to therapy was on average about 1 hour longer in the IA t-PA group. Broderick et al24 reported the results of the Interventional Management of Stroke III trial of 656 patients who have had acute ischemic stroke and were treated with an initial dose of IV t-PA for less than 3 hours from symptom onset and then randomized to continued t-PA to full dose or endovascular therapy (devices or IA t-PA per physician choice).24 The trial was stopped early for futility because there was no difference in functional recovery or ICH at 90 days. Also, stratification by the NIH stroke severity score did not demonstrate any advantage for endovascular therapy, despite better recanalization rates. The final article by Kidwell et al44 on the MR RESCUE trial was based upon the observation that brain perfusion studies showing a large ischemic penumbra and a small infarct predicted improved outcomes with successful reperfusion as compared with the opposite pattern.44 They randomized 118 patients within 8 hours of symptom onset with a large, anterior circulation cerebral artery occlusion to mechanical embolectomy vs IV thrombolysis. There was no difference in functional status, mortality, or ICH at the 90-day follow-up. Disappointingly, the ischemic penumbra-to-infarct ratio did not favor a therapy over the other, despite better overall outcomes in those with a high ratio. Are these 3 recent articles the waterloo for endovascular therapy? No, but they should hamper their unbridled use.45 Although, at less than 4.5 hours from symptom onset IV t-PA and current endovascular therapy have equivalent outcomes, there are many patients who cannot safely undergo systemic thrombolysis. These patients represent the primary indication for endovascular therapy. Other potential indications include patients with basilar artery thrombosis strokes. These patients have a high mortality and a more aggressive revascularization therapy seems appropriate in them for up to 16 hours after symptom onset. Also, patients presenting after more than 4.5 hours from symptom onset have poor results with IV thrombolysis and may be candidates for endovascular therapy up to 8 hours or more depending on the clinical situation. The Ochsner protocol as detailed by Drs Ramee and White is a reasonable approach in the absence of national guidelines. A caveat to the use of all aggressive ischemic stroke therapies is the timing issue. Clearly earlier is better for all therapies, but especially IV thrombolysis. Unfortunately, it is not always possible to determine the onset of symptoms. 72
Curr Probl Cardiol, March 2014
The patient may not be able to communicate and if no one witnessed the onset, timing becomes problematic. Not infrequently strokes occur during sleep, and the patient wakes up with the signs of stroke present, but the onset time is unknown. In these cases, the safest approach is to use the time that the patient was last reported or observed to be normal by themselves or others. In the case of a stroke that occurs during sleep this may set the onset at 8 hours or more before the time you see the patient when the risks of aggressive therapy could outweigh the potential benefits. Although these potential late arrivals may favor endovascular therapy over IV thrombolysis, considerable clinical judgment must be exercised in such cases.
REFERENCES 1. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation 2013;127:e6-245. 2. Adams HP, Jr, del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/ American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: The American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Circulation 2007;115:e478-534. 3. Adams HP, Jr, Adams RJ, Brott T, et al. Guidelines for the early management of patients with ischemic stroke: a scientific statement from the Stroke Council of the American Stroke Association. Stroke 2003;34:1056-83. 4. Fonarow GC, Smith EE, Saver JL, et al. Timeliness of tissue-type plasminogen activator therapy in acute ischemic stroke: patient characteristics, hospital factors, and outcomes associated with door-to-needle times within 60 minutes. Circulation 2011; 123:750-8. 5. Krumholz HM, Herrin J, Miller LE, et al. Improvements in door-to-balloon time in the United States, 2005 to 2010. Circulation 2011;124:1038-45. 6. Patel RD, Saver JL. Evolution of reperfusion therapies for acute brain and acute myocardial ischemia: a systematic, comparative analysis. Stroke 2013;44:94-8. 7. Demaerschalk BM, Yip TR. Economic benefit of increasing utilization of intravenous tissue plasminogen activator for acute ischemic stroke in the United States. Stroke 2005;36:2500-3. 8. Suzuki S, Saver JL, Scott P, et al. Access to intra-arterial therapies for acute ischemic stroke: an analysis of the US population. AJNR Am J Neuroradiol 2004;25:1802-6. 9. Cloft HJ, Rabinstein A, Lanzino G, et al. Intra-arterial stroke therapy: an assessment of demand and available work force. AJNR Am J Neuroradiol 2009;30:453-8. 10. Sacks D, Black CM, Cognard C, et al. Multisociety consensus quality improvement guidelines for intraarterial catheter-directed treatment of acute ischemic stroke, from the American Society of Neuroradiology, Canadian Interventional Radiology Association, Cardiovascular and Interventional Radiological Society of Europe, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Curr Probl Cardiol, March 2014
73
11. 12. 13.
14.
15. 16.
17.
18.
19.
20.
21. 22.
23.
24.
74
Society of NeuroInterventional Surgery, European Society of Minimally Invasive Neurological Therapy, and Society of Vascular and Interventional Neurology. J Vasc Interv Radiol 2013;24:151-63. Papanagiotou P, Roth C, Walter S, et al. Carotid artery stenting in acute stroke. J Am Coll Cardiol 2011;58:2363-9. Mackey J, Khatri P, Broderick JP. Increasing use of CT angiography in interventional study sites: the IMS III experience. AJNR Am J Neuroradiol 2010;31:E34. Turk A, Magarik JA, Chaudry I, et al. CT perfusion-guided patient selection for endovascular treatment of acute ischemic stroke is safe and effective. J Neurointerv Surg 2012;4:261-5. Abou-Chebl A. Endovascular treatment of acute ischemic stroke may be safely performed with no time window limit in appropriately selected patients. Stroke 2010;41:1996-2000. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359:1317-29. Del Zoppo GJ, Saver JL, Jauch EC, et al. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator: a science advisory from the American Heart Association/American Stroke Association. Stroke 2009;40:2945-8. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 1995;333:1581-7. Hacke W, Donnan G, Fieschi C, et al. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004;363:768-74. Reeves MJ, Arora S, Broderick JP, et al. Acute stroke care in the US: results from 4 pilot prototypes of the Paul Coverdell National Acute Stroke Registry. Stroke 2005;36: 1232-40. Wolpert SM, Bruckmann H, Greenlee R, et al. Neuroradiologic evaluation of patients with acute stroke treated with recombinant tissue plasminogen activator. The rt-PA Acute Stroke Study Group. AJNR Am J Neuroradiol 1993;14:3-13. Alexandrov AV, Grotta JC. Arterial reocclusion in stroke patients treated with intravenous tissue plasminogen activator. Neurology 2002;59:862-7. Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. J Am Med Assoc 1999;282:2003-11. Meyers PM, Schumacher HC, Higashida RT, et al. Indications for the performance of intracranial endovascular neurointerventional procedures: a scientific statement from the American Heart Association Council on Cardiovascular Radiology and Intervention, Stroke Council, Council on Cardiovascular Surgery and Anesthesia, Interdisciplinary Council on Peripheral Vascular Disease, and Interdisciplinary Council on Quality of Care and Outcomes Research. Circulation 2009;119:2235-49. Broderick JP, Palesch YY, Demchuk AM, et al. Endovascular therapy after intravenous t-PA versus t-PA alone for stroke. N Engl J Med 2013;368:893-903. Curr Probl Cardiol, March 2014
25. Coutts SB, Goyal M. When recanalization does not improve clinical outcomes. Stroke 2009;40:2661. 26. Nogueira RG, Lutsep HL, Gupta R, et al. Trevo versus Merci retrievers for thrombectomy revascularisation of large vessel occlusions in acute ischaemic stroke (TREVO 2): a randomised trial. Lancet 2012;380:1231-40. 27. Roth C, Papanagiotou P, Behnke S, et al. Stent-assisted mechanical recanalization for treatment of acute intracerebral artery occlusions. Stroke 2010;41:2559-67. 28. Roth C, Reith W, Walter S, et al. Mechanical recanalization with flow restoration in acute ischemic stroke: the ReFlow (mechanical recanalization with flow restoration in acute ischemic stroke) study. JACC Cardiovasc Interv 2013;6:386-91. 29. Saver JL, Jahan R, Levy EI, et al. Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomised, parallelgroup, non-inferiority trial. Lancet 2012;380:1241-9. 30. Mazighi M, Chaudhry SA, Ribo M, et al. Impact of onset-to-reperfusion time on stroke mortality: a collaborative pooled analysis. Circulation 2013;127:1980-5. 31. Fiorella DJ, Levy EI, Turk AS, et al. Target lesion revascularization after wingspan: assessment of safety and durability. Stroke 2009;40:106-10. 32. Levy EI, Mehta R, Gupta R, et al. Self-expanding stents for recanalization of acute cerebrovascular occlusions. AJNR Am J Neuroradiol 2007;28:816-22. 33. Turk AS, Levy EI, Albuquerque FC, et al. Influence of patient age and stenosis location on wingspan in-stent restenosis. AJNR Am J Neuroradiol 2008;29: 23-7. 34. Brekenfeld C, Schroth G, Mattle HP, et al. Stent placement in acute cerebral artery occlusion: use of a self-expandable intracranial stent for acute stroke treatment. Stroke 2009;40:847-52. 35. Levy EI, Turk AS, Albuquerque FC, et al. Wingspan in-stent restenosis and thrombosis: incidence, clinical presentation, and management. Neurosurgery 2007;61: 644-50; [discussion 650-1]. 36. Zaidat OO, Wolfe T, Hussain SI, et al. Interventional acute ischemic stroke therapy with intracranial self-expanding stent. Stroke 2008;39:2392-5. 37. Mocco J, Tawk RG, Jahromi BS, et al. Endovascular intervention for acute thromboembolic stroke in young patients: an ideal population for aggressive intervention? J Neurosurg 2009;110:30-4. 38. Mathews MS, Sharma J, Snyder KV, et al. Safety, effectiveness, and practicality of endovascular therapy within the first 3 hours of acute ischemic stroke onset. Neurosurgery 2009;65:860-5; [discussion 865]. 39. Levy EI, Siddiqui AH, Crumlish A, et al. First Food and Drug Administrationapproved prospective trial of primary intracranial stenting for acute stroke: SARIS (stent-assisted recanalization in acute ischemic stroke). Stroke 2009;40:3552-6. 40. Ramee SR, Subramanian R, Felberg RA, et al. Catheter-based treatment for patients with acute ischemic stroke ineligible for intravenous thrombolysis. Stroke 2004;35: e109-11. 41. DeVries JT, White CJ, Collins TJ, et al. Acute stroke intervention by interventional cardiologists. Catheter Cardiovasc Interv 2009;73:692-8. Curr Probl Cardiol, March 2014
75
42. White CJ, Cates CU, Cowley MJ, et al. Interventional stroke therapy: current state of the art and needs assessment. Catheter Cardiovasc Interv 2007;70:471-6. 43. Ciccone A, Valvassori L, Nichelatti M, Sgoifo A, Ponzio M, Sterzi R, Boccardi E (for the SYNTHESIS Expansion Investigators). Endovascular treatment for acute ischemic stroke. N Engl J Med 2013;368:904-13. 44. Kidwell CS, et al. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med 2013;368:914-23. 45. Chimowitz MI. Endovascular treatment for acute ischemic stroke—still unproven. N Engl J Med 2013;368:952-5.
76
Curr Probl Cardiol, March 2014
