Background and Objectives for the Technical Brief

Definition and Prevalence of Ischemic Stroke

Stroke is the third leading cause of death following diseases of the heart and cancer.^1,2 A majority of strokes are classified as ischemic in nature (87 percent), with intracerebral hemorrhage (10 percent) and subarachnoid hemorrhage stroke (3 percent) accounting for the rest.² Every year in the United States, approximately 795,000 people develop a new or recurrent stroke, with 610,000 first attacks and 185,000 recurrent attacks.² Stroke occurs more commonly in females than males, especially at older ages.³ Blacks have a two-fold higher risk of first-ever stroke than Caucasians, with age-adjusted incidences of 6.6 per 1000 in black men as compared with 3.6 in Caucasian men.³ In 2006, 43.6 deaths occurred due to stroke per 100,000 people in the Unites States, averaging out to one death due to stroke every 3 to 4 minutes.^2,4 In 2005, the overall mortality rate from stroke was approximately 44.7 per 100,000 for Caucasian males, 70.5 per 100,000 for black males, 44.0 per 100,000 for Caucasian females, and 60.7 per 100,000 for black females.⁵ Lower mortality rates were seen in Hispanic, Asian and American Indian populations as compared with Caucasian populations.²

Stroke is the leading causes of long-term disability in the United States. Thirty percent of stroke survivors require outpatient rehabilitation services^6,7 and 15 to 30 percent of patients remain permanently disabled.² Costs associated with acute stroke were estimated to approach $68.9 billion in 2009, with inpatient hospital costs accounting for 70 percent of the total cost in the first-year after stroke.^2,8 Significant decreases in health-related quality of life are also seen following a stroke.² Studies have shown that at-risk patients view the consequences of experiencing an ischemic stroke as being worse than death.⁹ Additionally, evidence has demonstrated the significant impact of ischemic stroke on caregiver burden and quality of life in caregivers.^10-12

Reperfusion Strategies for Treatment of Ischemic Stroke

The pathophysiologic basis for an acute ischemic stroke begins with the occlusion of an intracranial vessel either by an embolus or a local thrombus, reducing blood flow to the downstream brain region.¹³ If blood flow is not restored to the affected area, ischemia and eventual cell death will occur in a time-dependent fashion.¹³ Currently available treatment options for acute ischemic stroke focus on restoring cerebral perfusion to the affected area as quickly as possible thereby reducing or preventing brain infarction and minimizing long-term disability and stroke-related mortality.¹⁴

Some thrombolytic agents, including recombinant tissue plasminogen activator (alteplase, rtPA), restore cerebral perfusion by activating plasminogen at the site of the occlusion, subsequently dissolving the clot.¹⁵ Intravenous (IV) rtPA has been approved by the United States Food and Drug Administration (FDA) for the treatment of acute ischemic stroke and is currently recommended for use within the first 3 hours of onset of symptoms.¹⁴ The National Institute of Neurological Disorders and Stroke (NINDS) rtPA Stroke Study Group conducted a randomized, double-blind trial evaluating the benefits of IV rtPA treatment (0.9 mg/kg) administered within 3 hours of ischemic stroke onset (n=624).¹⁶ At 3 months, patients receiving IV rtPA had more favorable results [odds ratio (OR) 1.7, 95 percent confidence interval (CI) 1.2 to 2.6] than the group receiving placebo as measured by four commonly utilized tools to assess stroke-related deficits and disabilities. The global odds ratio for improvement included improvements in the Barthel Index (OR 1.6, 95 percent CI 1.1 to 2.5), modified Rankin Scale (mRS) (OR 1.7, 95 percent CI 1.1 to 2.5), Glasgow Outcome Scale (GOS) (OR 1.6, 95 percent CI 1.1 to 2.5) and the National Institute of Health Stroke Scale (NIHSS) (OR 1.7, 95 percent CI 1.0 to 2.8).

Use of IV rtPA beyond the 3 hour timeframe has been limited. However, in a pooled analysis of 6 randomized, placebo-controlled trials evaluating IV rtPA in stroke, researchers found that although better results were achieved with earliest possible use of IV rtPA, there were potential benefits when used beyond the 3-hour window.¹⁷ Patients who received IV rtPA between 3 and 4.5 hours after stroke onset were at an increased odds of a favorable outcome (a composite of stroke-related disabilities, severity of disabilities and abilities to conduct activities of daily living) as compared with placebo (OR 1.4, 95 percent CI 1.05 to 1.85). The subsequently published European Cooperative Acute Stroke Study (ECASS III), which was powered based on the prior discussed meta-analysis, specifically evaluated the benefits of IV rtPA administered between 3 and 4.5 hours after symptom onset.¹⁸ When compared with placebo, patients receiving IV rtPA had significantly higher odds of a more favorable outcome (OR 1.34, 95 percent CI 1.02 to 1.76), with no differences in mortality (p=0.68) but higher incidence of intracranial hemorrhage seen (p = 0.001).¹⁸ In addition, two observational studies, the Safe Implementation of Thrombolysis in Stroke Monitoring Study (SITS-MOST)¹⁹ and the SITS-international stroke treatment registry (SITS-ISTR)20 confirmed the benefits of rtPA use at 3-4.5 hours after ischemic stroke. Based on these findings the American Heart Association and American Stroke Association issued a scientific advisory in 2009 recommending the use of IV rtPA in eligible patients presenting within 3 to 4.5 hours after the onset of stroke symptoms (Class I recommendation, B level of evidence).²¹

Despite appropriate IV rtPA use, rates of recanalization remain highly variable ranging from 30 to 92 percent during the initial 6 to 24 hours after treatment.²² Recanalization rates vary depending on the site of the occlusion, with events in large cerebral vessels having particularly high clot burden which may not adequately respond to IV rtPA. More importantly, delays in arriving in the emergency department and unavailability of IV rtPA in some centers make thrombolytic reperfusion therapy viable in less than 5% of patients with acute stroke.²³

In patients who have either failed IV rtPA therapy or who are either ineligible for or have contraindications to IV rtPA use, neurothrombectomy devices have been examined. A neurothrombectomy device is defined by the Food and Drug Adminstration (FDA) as a device intended to retrieve or destroy blood clots in the cerebral neurovasculature by mechanical, laser, ultrasound technologies, or combination of technologies.

These devices may offer a number of potential advantages when compared to pharmacologic thrombolysis including: more rapid achievement of recanalization vs IV rtPA; enhanced efficacy in treating large vessel occlusions; and greater efficacy with a lower risk for hemorrhagic events.²⁴ These putative advantages of neurothrombectomy devices have not been confirmed in direct comparisons against intravenous therapy. A variety of neurothrombectomy devices employing a variety of mechanisms including clot retrievers, aspiration/suction devices, snare-like devices, ultrasonography technologies and lasers, have been or are currently under study in patients with acute ischemic stroke. The Merci® retriever was the first endovascular device to receive FDA clearance in 2004 to “restore blood flow in the neurovasculature by removing thrombus in patients experiencing ischemic stroke.^25-27 Subsequently, the Penumbra System® was cleared by the FDA in 2007 “for use in the revascularization of patients with acute ischemic stroke secondary to intracranial large vessel occlusive disease within 8 hours of system onset.” Both of these clearances were granted through the FDA 510(k) process resulting in significant controversy given the relatively low number of patients included in the studies available at the time of clearance as well as the lack of clinical outcomes reported.²⁵ Various ongoing clinical trials are currently evaluating the impact of these, as well as other, endovascular devices for the treatment of acute ischemic stroke.

The Key Questions

Population: The population patients with acute ischemic stroke.

Intervention: The intervention is the use of a neurothromectomy device with or without intravenous or intraarterial thrombolytic therapy.

Comparators: Trials do not have to have comparators.

Outcomes: The outcomes are broken up into adverse events (e.g., failure to deploy the device or remove the clot, device breakage/fracture, perforation, dissection, thrombus formation proximal, adjacent, or distal to the clot site, vasospasm or hemorrhage (intracerebral and other)), intermediate outcomes (e.g. recanalization), and final health outcomes (e.g. mortality and impact of therapy on the mRS, NIHSS, Barthel index, and GOS scales).

Timing: The timing is not restrictive, as long as the intervention was initiated within the period of the acute ischemic stroke.

Setting: The setting is not limited.

Question 1: What are the different types of neurothrombectomy devices in use or in development for treatment of acute ischemic stroke?

a. What are the existing FDA indications for each device?
b. Which devices are being are being used off-label for this indication?
c. What is the status of FDA approval for each device?
d. What are the theoretical advantages and disadvantages of the devices compared to other treatment options?
e. What are the potential safety issues and harms associated with the use of the devices?
f. What is the extent of utilization of the different devices?

Question 2: From a systematic literature scan of studies on different types of neurothrombectomy devices, provide a synthesis of the following variables:

a. Type(s) of devices.
b. Study design and size.
c. Patient characteristics.
d. Comparator used in comparative studies.
e. Length of follow-up.
f. Concurrent or prior therapy.
g. Outcomes measured.
h. Adverse events, harms and safety issues reported.

Question 3: What are the variables associated with use of the devices that may impact outcomes (e.g., time to deployment, training/expertise of the interventionalist, location of infarct, concurrent therapies)?

Analytic Framework

To guide our assessment of studies examining the association between neurothrombectomy devices with benefits and harms in our target population, we developed an analytic framework mapping specific linkages from comparisons to subpopulations of interest, mechanisms of benefit, and outcomes of interest (Figure 2.1). It is a logic chain that supports the link from the intervention to the outcomes of interest.

Figure 2.1. Analytic Framework for Neurothrombectomy Devices for Treatment of Acute Ischemic Stroke

Legend: GOS = Glasgow Outcome Scale; IV/IA = intravenous or intraarterial; mRS = modified Rankin Scale; NIHSS = National Institute of Health Stroke Scale.

Narrative for Figure 2.1:

In this analytic framework figure, the links between the use of an intervention in a population and outcomes are described. The population includes patients experiencing an acute ischemic stroke. The intervention is the use of a neurothromectomy device with or without IV or IA thrombolytic therapy. While most of these trials do not have comparators, the comparator in clinical practice would be no reperfusion therapy or thrombolytic therapy alone. The outcomes are broken up into adverse events, intermediate outcomes, and final health outcomes. The adverse events of note include failure of the device to employ, breakage or fracture, perforation, dissection, adjacent thrombosis, vasospasm, and hemorrhage. The intermediate outcome is recanalization. The final health outcomes include mortality and impact of therapy on the mRS, NIHSS, Barthel index, and GOS scales.

Methods

A. Criteria for Inclusion/Exclusion of Studies in the Review.

We will develop of list of neurothrombectomy devices based on the FDA’s guidance definition of a neurothrombectomy device, published literature and create a list of current manufacturing companies. After verifying products in current clinical practice and those in development, we will ask the Scientific Resource Center (SRC) at the Oregon Evidence-based Practice Center to contact the different manufacturers. We will finalize a database of the available neurothrombectomy devices with information and data provided to us. In addition, we will search the FDA Center for Devices and Radiological Health (CDRH) database to identify neurothrombectomy devices that have received FDA approval.

Two investigators will independently screen citations at the abstract level to identify potentially relevant studies. All potentially eligible citations will be retrieved for full text review and examined for eligibility. We will include human studies of any design or case reports/series which included patients with an acute ischemic stroke and report any clinical outcome (e.g., recanalization, mortality, mRS, or outcome score including NIHSS, Barthel Index or GOS) or any harm (e.g., failure to deploy the device or remove the clot; device breakage/fracture; perforation or dissection; thrombus formation proximal, adjacent, or distal to the clot site; vasospasm; or intracerebral or other hemorrhage). No language restrictions will be used.

B. Searching for the Evidence: Literature Search Strategies for Identification of Relevant Studies to Answer the Key Questions.

Two independent investigators will conduct systematic literature searches of MEDLINE, the Cochrane Central Register of Controlled Trials, SCOPUS and Web of Science as well as the Cochrane Database of Systematic Reviews, from the earliest possible date until September 2009. No language restrictions will be imposed. In addition, a manual search of references from reports of studies or review articles will be conducted. A preliminary search strategy, including proposed search terms, is listed in Appendix 1. We will also conduct a grey literature search for abstracts, studies and available devices utilizing Google and specific search terms. Additionally, we will survey enrolling and ongoing clinical trials through ClinicalTrials.gov.

C. Data Abstraction and Data Management

Through the use of a standardized data abstraction tool, two reviewers will independently collect data, with disagreement resolved by a third reviewer. The following information will be obtained from each study, where applicable: author identification, year of publication, source of study funding, study design characteristics (prospective single arm study, retrospective study, randomized controlled trial, nonrandomized comparative study, case series or reports), study population (including study inclusion and exclusion criteria, duration of patient follow-up), patient baseline characteristics (age, gender), disease severity (baseline NIHSS, baselne TIMI flow), location of occluded artery, time from symptom onset to device deployment or angiography, use of concurrent standard medical therapies (including use of concurrent IV/IA thrombolysis, angioplasty, stents), whether outcomes assessment was blinded, and the device used. Effectiveness outcomes will include: recanalization as measured by post-TIMI flow grade (0/1=no recanalization, 2=partial recanalization, 3=complete recanalization) or similar methodology, mortality, mRS (≤2=good outcome, ≥3=poor outcome), NIHSS score [including a NIHSS decrease ≥ 4 points deemed significant by the FDA), Barthel Index and GOS score. Harms will include: failure to deploy the device or remove the clot (technical success), device breakage/fracture, perforation, dissection, thrombus formation (proximal, adjacent, or distal to the clot site), vasospasm, or hemorrhage (including symptomatic and asymptomatic intracranial and subarachnoid hemorrhage from vessel injury and other).

D. Assessment of Methodological Quality of Individual Studies

We will assess the study design and classify it as prospective, retrospective enrolling consecutive patients, and case reports/series. For prospective and retrospective studies enrolling consecutive patients, we will assess if outcome assessment was blinded.

E. Data Synthesis

We will utilize in depth tables summarizing what is known about the relevant trials and a study density figure to summarize the totality of information available in this technical brief. Quantitative synthesis will not be employed.

F. Grading the Evidence for Each Key Question

This is not applicable for technical briefs.

References

1. Lopez AD, Mathers CD, Ezzati M, et al. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 2006;367:1747-57.
2. Lloyd-Jones D, Adams R, Carnethon M, et al. Heart disease and stroke statistics 2009 update: a report from the American Heart Association statistics committee and stroke statistics subcommittee. Circulation 2009;119:480-6.
3. Lisabeth LD, Ireland JK, Risser JM, et al. Stroke risk after transient ischemic attack in a population-based setting. Stroke 2004;35:1842-6.
4. Heron MP, Hoyert DL, Xu J, et al. Deaths: preliminary data for 2006. Natl Vital Stat Rep 2008;56(16):1-52.
5. National Center for Health Statistics. Centers for Disease Control and Prevention Web site. Compressed Mortality File: Underlying Cause of Death, 1979-2005. Available at: http://wonder.cdc.gov/mortSQL.html. Accessed September 22, 2009.
6. Centers for Disease Control and Prevention. Prevalence of disabilities and associated health conditions among adults: United States, 1999. MMWR Morb Mortal Wkly Rep 2001;50:120-5.
7. Centers for Disease Control and Prevention. Outpatient rehabilitation among stroke survivors: 21 states and the District of Columbia. MMWR Morb Mortal Wkly Rep 2007;56:504-7.
8. Taylor TN, Davis PH, Torner JC, et al. Lifetime costs of stroke in the United States. Stroke 1996;27:1459-66.
9. Samsa GP, Matchar DB, Golstein L, et al. Utilities for major stroke: results from a survey of preferences among persons at increased risk for stroke. Am Heart J 1998;136:703-13.
10. Dirnagl U, Iadecola C, Moskowitz MA. Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 1999;22:391-7.
11. Albers GW, Amarenco P, Easton, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008;133:630S-69S.
12. Lyden PD, ed. Thrombolytic therapy for acute stroke. 2nd ed. New York: Springer-Verlag; 2005.
13. McCullagh E, Brigstocke G, Donaldson N, et al. Determinants of caregiving burden and quality of life in caregivers of stroke patients. Stroke 2005;36:2181-6.
14. Rigby H, Gubitz G, Eskes G, et al. Caring for stroke survivors: baseline and 1-year determinants of caregiver burden. Int J Stroke 2009;4:152-8.
15. Carod-Artal FJ, Ferreira Coral L, Trizotto DS, et al. Burden and perceived health status among caregivers of stroke patients. Cerebrovasc Dis 2009;28:475-80.
16. NINDS rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333:1581-7.
17. Hacke W, Donnan G, Fieschi C, et al, for the ATLANTIS Trials Investigators, the ECASS Trials Investigators, and the NINDS rt-PA Study Group Investigators. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet 2004; 363: 768-74.
18. 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.
19. Wahlgren N, Ahmed N, Davalos A, et al, for the SITS-MOST Investigators. Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke – Monitoring Study (SITS-MOST): an observational study. Lancet 2007;369:275-82.
20. Wahlgren N, Ahmed N, Davalos A, et al, for the SITS Investigators. Thrombolysis with alteplase 3-4.5 h after acute ischaemic stroke (SITS-ISTR): an observational study. Lancet 2008;372:1303-9.
21. 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.
22. Zangerle A, Kiechl S, Spiegel M, et al. Recanalization after thrombolysis in stroke patients: predictors and prognostic implications. Neurology 2007;68:39-44.
23. Brott T, Bogousslavsky J. Treatment of acute ischemic stroke. N Engl J Med. 2000;343:710-22.
24. Thomassen L, Bakke SJ. Endovascular reperfusion therapy in acute ischaemic stroke. Acta Neurol Scand 2007;115(Suppl 187):22-9.
25. Becker KJ, Brott TG. Approval of the MERCI Clot Retriever: a critical review. Stroke 2005;36:400-3.
26. Nogueira RG, Schwamm LH, Hirsch JA. Endovascular approaches to acute stroke, part 1: drugs, devices, and data. Am J Neuroradiol 2009;30:649-61.
27. Lutsep HL. Mechanical endovascular recanalization therapies. Curr Opin Neurol 2008;21:70-5.

Definition of Terms

Summary of Protocol Amendments

None

Appendix 1

Search Terms and Citations

MEDLINE (OVID)

1. thrombectomy
2. embolectomy
3. endovascular recanalization
4. endovascular embolectomy
5. mechanical thrombolysis
6. mechanical embolus removal
7. mechanical thrombus removal
8. endovascular intervention
9. endovascular device
10. mechanical device
11. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10
12. stroke
13. acute stroke
14. cerebrovascular accident
15. cva
16. vascular accident
17. artery occlusion
18. cerebral ischemia
19. acute ischemic stroke
20. 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19
21. 11 and 20

CENTRAL (OVID)

1. thrombectomy
2. embolectomy
3. endovascular recanalization
4. endovascular embolectomy
5. mechanical thrombolysis
6. mechanical embolus removal
7. mechanical thrombus removal
8. endovascular intervention
9. endovascular device
10. mechanical device
11. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 10
12. stroke
13. acute stroke
14. cerebrovascular accident
15. cva
16. vascular accident
17. artery occlusion
18. cerebral ischemia
19. acute ischemic stroke
20. 12 or 13 or 14 or 15 or 16 or 17 or 18 or 19
21. 11 and 20

Appendix 2