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Editorials |

Neurothrombectomy Devices for Acute Ischemic Stroke: A State of Uncertainty FREE

Pooja Khatri, MD, MSc
[+] Article and Author Information

From University of Cincinnati, Cincinnati, OH 45267-0525.


Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M11-0028.

Requests for Single Reprints: Pooja Khatri, MD, MSc, Department of Neurology, University of Cincinnati, 260 Stetson Street, Suite 2300, Cincinnati, OH 45267-0525; e-mail, pooja.khatri@uc.edu.


Ann Intern Med. 2011;154(4):285-287. doi:10.7326/0003-4819-154-4-201102150-00308
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In this issue, Baker and colleagues (1) review the available evidence for using neurothrombectomy devices to treat acute ischemic stroke. This review, performed by the University of Connecticut/Hartford Hospital Evidence-based Practice Center (funded by the Agency for Healthcare Research Quality of the U.S. Department of Health and Human Services), identified 87 primary studies of neurothrombectomy devices. Of the studies, 62 were case reports or series and only 18 were prospective cohorts; 3 of these reported blinded assessments of clinical outcomes. Existing studies have focused on recanalization end points rather than final health outcomes. The authors conclude that there is uncertainty about the types of patients who are most likely to derive clinical benefit from mechanical revascularization, and they call for randomized trials of neurothrombectomy. The field of acute ischemic stroke is at a critical juncture, with a dire need for more therapies established by randomized trials.

Currently, we have just 1 established therapy: intravenous administration of recombinant tissue plasminogen activator (rt-PA) within 4.5 hours of ischemic stroke symptom onset (23). Although this therapy has a substantial effect on clinical outcomes by leading to 1 fewer disabled patient for every 8 patients treated within 3 hours, it still leaves more than half of treated patients disabled. It is linked to Centers for Medicare & Medicaid Services (CMS) reimbursement of approximately $16 000 to hospitals (4). In addition, 1 small, randomized trial and a meta-analysis of 3 independent trials suggest clinical benefit associated with intra-arterial administration within 6 hours of stroke onset of a lytic that is no longer commercially available (recombinant prourokinase) (56). On the basis of these data, endovascular delivery of a different lytic agent, rt-PA, is now used as a treatment option without specific additional reimbursement from CMS beyond that of intravenously delivered rt-PA. Finally, we have neurothrombectomy devices, the subject of Baker and colleagues' review, which offer great hope for more effectively and more rapidly achieving recanalization of occluded proximal cerebral arteries.

Unfortunately, we lack randomized trials to document that neurothrombectomy devices improve patient outcomes. Single-group prospective studies of both the MERCI Retriever (Concentric Medical, Mountain View, California) and the Penumbra System (Penumbra, Alameda, California) have shown reasonable safety and possibly improved outcomes compared with historical controls treated with heparin alone (79). Both have received 510(k) clearance from the U.S. Food and Drug Administration (FDA), based on similarity to predicate devices, as a way to restore blood flow in previously occluded arteries and are linked to CMS hospital reimbursement of approximately $28 000 (4).

The literature on the use of endovascular device therapies for acute ischemic stroke leaves us with more questions than answers. Both FDA-cleared devices are labeled for initiation within 8 hours of stroke symptom onset, on the basis of uncontrolled studies. Yet, we do not know when ischemia becomes irreversible in most patients, and no data support a clinical benefit of initiating recanalization beyond 6 hours by any method. Eight hours is probably far too late to derive benefit for at least some patients (1011). Some clinicians advocate using multimodal imaging studies to identify patients who present more than 8 hours after stroke onset with potentially reversible injury, but these methods remain unvalidated (12). Although available data suggest that recanalization is helpful, we do not know whether the patients in whom recanalization is attempted but fails, or is achieved too late, are harmed. Furthermore, recanalization alone, a common study end point, is certainly only 1 piece of the puzzle. Current data show a striking discrepancy between technically successful recanalization (43% to 100%) and good clinical outcome (21% to 48%) at 3 months. It should also be noted that the quality of available studies is difficult to ascertain and is believed to vary.

Despite uncertain evidence, use of endovascular device therapies is increasing in the United States. According to Medicare Provider Analysis and Review databases, the use of embolectomy has more than doubled from 2007 to 2009 and now comprises 11% of acute stroke treatments (13). At the same time, ongoing randomized studies are struggling to meet recruitment goals (1415). Physicians may decline to participate in randomized studies for various reasons.

Individual physicians may be so convinced that a given treatment works that they see randomization as unethical. Further education is needed to help clinicians understand how to choose among therapies in an evidence-based manner. A hierarchy for choosing among treatment options has been proposed: 1) standard care based on high-level evidence (from randomized trials); 2) a randomized clinical trial, if no standard is proven; 3) a nonrandomized registry, if no trial is available; or 4) consensus-based guidelines and personal experience, if no registry is available (16).

Yet, even physicians who understand evidence-based medicine may find that participation in trials can create administrative, political, and financial challenges. A hospital administrator who has just developed a neurointerventional program for his or her cutting-edge stroke center may find that supporting randomization of patients to medical therapies is counterproductive for referrals and sends a confusing message to the community regarding the necessity of the program. From a financial perspective, current randomized trials of acute stroke lead to hospital reimbursement based on the treatment group of randomization. Thus, the hospital may turn away the neurothrombectomy-related payment of $28 000 in favor of either the stroke-with-thrombolysis–related payment of $16 000 or the stroke-without-thrombolysis–related payment of $10 000. Device registries, in contrast, allow collection of the neurothrombectomy-related payment for each case, in addition to further payment for data collection.

The uncertainty about the effectiveness of neurothrombectomy is unsettling. If neurothrombectomy is clinically effective, then current rates of use are distressingly low, and resources must be devoted to making this therapy available to all who would benefit. There are good reasons to believe that neurothrombectomy devices may be superior to intravenous rt-PA during the 4.5-hour window or medical management beyond 4.5 hours. Baker and colleagues (1) show that technically successful recanalization is the strongest predictor of good clinical outcome and that the FDA-cleared devices seem to achieve this more frequently. However, if neurothrombectomy devices do not provide net benefit beyond that of intravenous rt-PA, then our current use of these devices is wasteful and perhaps even harmful. Medicine provides many examples of promising therapies based on strong nonrandomized data that ultimately fail to fulfill their promise when subjected to rigorous randomized trials (1718). Delays in recanalization related to mobilization of neurointerventional teams may diminish its benefits compared with thrombolytic therapy. Stroke may mimic the myocardial infarction experience such that if the time from door to endovascular treatment is greater than 90 minutes, intravenous thrombolysis alone is of greater benefit among patients who arrive within 3 hours of symptom onset (19). In addition, there may be risks associated with general anesthesia, which is electively performed for neurothrombectomy cases at many neurointerventional centers (2021).

Instead of adding patients to further case series or registries, we should devote efforts to conduct definitive randomized trials. It is premature to compare different devices until we first establish the clinical benefit of neurothrombectomy over thrombolysis. Until then, expansion of the use of neurothrombectomy is unjustified.

References

Baker WL, Colby JA, Tongbram V, Talati R, Silverman IE, White CM. et al.  Neurothrombectomy devices for the treatment of acute ischemic stroke: state of the evidence. Ann Intern Med. 2011; 154:243-52.
 
.  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.
PubMed
CrossRef
 
Del Zoppo GJ, Saver JL, Jauch EC, Adams HP Jr, American Heart Association Stroke Council.  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.
PubMed
 
Centers for Medicare and Medicaid Services (CMS), HHS.  Medicare program; changes to the hospital inpatient prospective payment system for acute care hospitals and fiscal year 2010 rates; and changes to the long-term care hospital prospective payment system and rate years 2010 and 2009 rates.Final rules and interim final rule with comment period. Fed Regist. 2009; 74:43753-4236.
PubMed
 
Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C. et al.  Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA. 1999; 282:2003-11.
PubMed
 
Fields JD, Khatri P, Nesbit GM, Liu KC, Barnwell SL, Lutsep HL, et al.  Meta-analysis of randomized intra-arterial thrombolytic trials for the treatment of acute stroke due to middle cerebral artery occlusion. J Neurointerv Surg. [Forthcoming].
 
Josephson SA, Saver JL, Smith WS, Merci and Multi Merci Investigators.  Comparison of mechanical embolectomy and intraarterial thrombolysis in acute ischemic stroke within the MCA: MERCI and Multi MERCI compared to PROACT II. Neurocrit Care. 2009; 10:43-9.
PubMed
 
Smith WS, Sung G, Starkman S, Saver JL, Kidwell CS, Gobin YP, et al. MERCI Trial Investigators.  Safety and efficacy of mechanical embolectomy in acute ischemic stroke: results of the MERCI trial. Stroke. 2005; 36:1432-8.
PubMed
 
Bose A, Henkes H, Alfke K, Reith W, Mayer TE, Berlis A, et al. Penumbra Phase 1 Stroke Trial Investigators.  The Penumbra System: a mechanical device for the treatment of acute stroke due to thromboembolism. AJNR Am J Neuroradiol. 2008; 29:1409-13.
PubMed
 
Khatri P, Abruzzo T, Yeatts SD, Nichols C, Broderick JP, Tomsick TA, IMS I and II Investigators.  Good clinical outcome after ischemic stroke with successful revascularization is time-dependent. Neurology. 2009; 73:1066-72.
PubMed
 
Mazighi M, Serfaty JM, Labreuche J, Laissy JP, Meseguer E, Lavallée PC, et al. RECANALISE investigators.  Comparison of intravenous alteplase with a combined intravenous-endovascular approach in patients with stroke and confirmed arterial occlusion (RECANALISE study): a prospective cohort study. Lancet Neurol. 2009; 8:802-9.
PubMed
 
Mishra NK, Albers GW, Davis SM, Donnan GA, Furlan AJ, Hacke W. et al.  Mismatch-based delayed thrombolysis: a meta-analysis. Stroke. 2010; 41:25-33.
PubMed
 
Khatri P, Adeoye O, Kleindorfer DO.  US rates of mechanical embolectomy for acute ischemic stroke treatment are increasing [Abstract]. Stroke. 2010;41:e361.
 
Interventional Management of Stroke (IMS) III Trial (IMS III) [clinical trial]. Accessed athttp://clinicaltrials.gov/ct2/show/NCT00359424on 7 January 2011.
 
Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) [clinical trial]. Accessed athttp://clinicaltrials.gov/ct2/show/NCT00389467on 7 January 2011.
 
Lyden PD, Meyer BC, Hemmen TM, Rapp KS.  An ethical hierarchy for decision making during medical emergencies. Ann Neurol. 2010; 67:434-40.
PubMed
 
Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Writing Group for the Women's Health Initiative Investigators.  Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002; 288:321-33.
PubMed
 
Haynes RB, Mukherjee J, Sackett DL, Taylor DW, Barnett HJ, Peerless SJ.  Functional status changes following medical or surgical treatment for cerebral ischemia. Results of the extracranial-intracranial bypass study. JAMA. 1987; 257:2043-6.
PubMed
 
Boersma E, Maas AC, Deckers JW, Simoons ML.  Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour. Lancet. 1996; 348:771-5.
PubMed
 
Nichols C, Carrozzella J, Yeatts S, Tomsick T, Broderick J, Khatri P.  Is peri-procedural sedation during acute stroke therapy associated with poorer functional outcomes? J Neurointerv Surg. 2010; 2:67-70.
PubMed
 
Abou-Chebl A, Lin R, Hussain MS, Jovin TG, Levy EI, Liebeskind DS. et al.  Conscious sedation versus general anesthesia during endovascular therapy for acute anterior circulation stroke: preliminary results from a retrospective, multicenter study. Stroke. 2010; 41:1175-9.
PubMed
 

Figures

Tables

References

Baker WL, Colby JA, Tongbram V, Talati R, Silverman IE, White CM. et al.  Neurothrombectomy devices for the treatment of acute ischemic stroke: state of the evidence. Ann Intern Med. 2011; 154:243-52.
 
.  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.
PubMed
CrossRef
 
Del Zoppo GJ, Saver JL, Jauch EC, Adams HP Jr, American Heart Association Stroke Council.  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.
PubMed
 
Centers for Medicare and Medicaid Services (CMS), HHS.  Medicare program; changes to the hospital inpatient prospective payment system for acute care hospitals and fiscal year 2010 rates; and changes to the long-term care hospital prospective payment system and rate years 2010 and 2009 rates.Final rules and interim final rule with comment period. Fed Regist. 2009; 74:43753-4236.
PubMed
 
Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C. et al.  Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA. 1999; 282:2003-11.
PubMed
 
Fields JD, Khatri P, Nesbit GM, Liu KC, Barnwell SL, Lutsep HL, et al.  Meta-analysis of randomized intra-arterial thrombolytic trials for the treatment of acute stroke due to middle cerebral artery occlusion. J Neurointerv Surg. [Forthcoming].
 
Josephson SA, Saver JL, Smith WS, Merci and Multi Merci Investigators.  Comparison of mechanical embolectomy and intraarterial thrombolysis in acute ischemic stroke within the MCA: MERCI and Multi MERCI compared to PROACT II. Neurocrit Care. 2009; 10:43-9.
PubMed
 
Smith WS, Sung G, Starkman S, Saver JL, Kidwell CS, Gobin YP, et al. MERCI Trial Investigators.  Safety and efficacy of mechanical embolectomy in acute ischemic stroke: results of the MERCI trial. Stroke. 2005; 36:1432-8.
PubMed
 
Bose A, Henkes H, Alfke K, Reith W, Mayer TE, Berlis A, et al. Penumbra Phase 1 Stroke Trial Investigators.  The Penumbra System: a mechanical device for the treatment of acute stroke due to thromboembolism. AJNR Am J Neuroradiol. 2008; 29:1409-13.
PubMed
 
Khatri P, Abruzzo T, Yeatts SD, Nichols C, Broderick JP, Tomsick TA, IMS I and II Investigators.  Good clinical outcome after ischemic stroke with successful revascularization is time-dependent. Neurology. 2009; 73:1066-72.
PubMed
 
Mazighi M, Serfaty JM, Labreuche J, Laissy JP, Meseguer E, Lavallée PC, et al. RECANALISE investigators.  Comparison of intravenous alteplase with a combined intravenous-endovascular approach in patients with stroke and confirmed arterial occlusion (RECANALISE study): a prospective cohort study. Lancet Neurol. 2009; 8:802-9.
PubMed
 
Mishra NK, Albers GW, Davis SM, Donnan GA, Furlan AJ, Hacke W. et al.  Mismatch-based delayed thrombolysis: a meta-analysis. Stroke. 2010; 41:25-33.
PubMed
 
Khatri P, Adeoye O, Kleindorfer DO.  US rates of mechanical embolectomy for acute ischemic stroke treatment are increasing [Abstract]. Stroke. 2010;41:e361.
 
Interventional Management of Stroke (IMS) III Trial (IMS III) [clinical trial]. Accessed athttp://clinicaltrials.gov/ct2/show/NCT00359424on 7 January 2011.
 
Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) [clinical trial]. Accessed athttp://clinicaltrials.gov/ct2/show/NCT00389467on 7 January 2011.
 
Lyden PD, Meyer BC, Hemmen TM, Rapp KS.  An ethical hierarchy for decision making during medical emergencies. Ann Neurol. 2010; 67:434-40.
PubMed
 
Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Writing Group for the Women's Health Initiative Investigators.  Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002; 288:321-33.
PubMed
 
Haynes RB, Mukherjee J, Sackett DL, Taylor DW, Barnett HJ, Peerless SJ.  Functional status changes following medical or surgical treatment for cerebral ischemia. Results of the extracranial-intracranial bypass study. JAMA. 1987; 257:2043-6.
PubMed
 
Boersma E, Maas AC, Deckers JW, Simoons ML.  Early thrombolytic treatment in acute myocardial infarction: reappraisal of the golden hour. Lancet. 1996; 348:771-5.
PubMed
 
Nichols C, Carrozzella J, Yeatts S, Tomsick T, Broderick J, Khatri P.  Is peri-procedural sedation during acute stroke therapy associated with poorer functional outcomes? J Neurointerv Surg. 2010; 2:67-70.
PubMed
 
Abou-Chebl A, Lin R, Hussain MS, Jovin TG, Levy EI, Liebeskind DS. et al.  Conscious sedation versus general anesthesia during endovascular therapy for acute anterior circulation stroke: preliminary results from a retrospective, multicenter study. Stroke. 2010; 41:1175-9.
PubMed
 

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