Stroke Management

Educational Objectives

The goal of this program is to improve the management of stroke. After hearing and assimilating this program, the clinician will be better able to:

Review the results of the National Institute of Neurological Disorders and Stroke (NINDS) trial.

Evaluate the inclusion and exclusion criteria for use of tissue plasminogen activator (tPA) in stroke.

Discuss informed consent for use of tPA in stroke and required documentation in patient’s medical record whether tPA used or not.

Identify when intra-arterial administration of tPA is appropriate.

Describe the devices used for mechanical clot disruption.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any per­sonal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Miller is on the Speakers’ Bureau of sanofi-aventis. Dr. Lex and the planning committee reported noth­ing to disclose.

Acknowledgements

Dr. Lex was recorded at Giant Steps in Emergency Medicine, held July 16-19, 2008, in San Diego, CA, and sponsored by the American Academy of Emergency Medicine. Dr. Miller was recorded at the 6th Annual Emergency Medicine Symposium, held December 5, 2008, in Los Angeles, CA, and sponsored by the Cedars-Sinai Medical Center, Depart­ment of Emergency Medicine. The Audio-Digest Foundation thanks the speakers and the sponsors for their coopera­tion in the production of this program.

Fibrinolytics in Acute Stroke: What’s All the Fuss?

Joseph R. Lex, Jr, MD, Associate Professor, Department of Emergency Medicine, Temple University School of Medicine, Philadelphia, PA

Studies: previously shown that thrombolytics ineffective; European Cooperative Acute Stroke Study (ECASS) 1 (1995)  —interval from onset of symptoms, or window in which tissue plasminogen activator (tPA) used, 6 hr, with dose of 1.1 mg/kg; with longer window and higher dose, no difference found between placebo and treated group; ECASS 2  —  interval 6 hr, but tPA dose 0.9 mg/kg; no increase in mortality, but no benefit either; rate of intracere­bral hemorrhage increased £5 times baseline; Alteplase Thrombolysis for Acute Noninterventional Therapy in Isch­emic Stroke (ATLANTIS) study  —  shorter window (3-5 hr); tPA dose 0.9 mg/kg; no difference in outcome between treated and placebo group

National Institute of Neurological Disorders and Stroke (NINDS) trial: 50% of participants randomized to tPA, 50% to placebo; interval from onset limited to 3 hr; dose 0.9 mg/kg; all neurologic outcome measures showed improvement in tPA-treated group; symptomatic intracranial hemorrhage (ICH) at 36 hr, 6.4% in treated group (0.6% in placebo group) or 10-fold increase; however, mortality rate not different, with trend toward improve­ment in treated group; 12% absolute benefit in modified Rankin scale, 11% in Glasgow scale, and 14% in Na­tional Institutes of Health Stroke Scale (NIHSS); conclusion  —  treat 7 to 8 patients with tPA to have one additional patient with better outcome (no neurologic deficit); disadvantage  —  6% absolute increase in number of cases of symptomatic ICH; treat 16 patients to have one additional symptomatic ICH; if treating 100 patients who meet tPA criteria (ie, arrive within 3 hr, have work-up performed, and have no absolute or relative contrain­dications), 12 will have absolute benefit, and 6 will have symptomatic ICH; 2 patients will have minimal or no deficit for every 1 patient with symptomatic ICH; patients excluded if  —  blood pressure (BP) >185/110 mm Hg; aggressive treatment of BP required; anticoagulated within 48 hr; received antiplatelet treatment within 24 hr; American Heart Association (AHA; August 2000)  —  upgraded recommendation of tPA for stroke from optional (class 2b) to definitely recommended (class 1a)

Analysis of NINDS data: Mann et al  —  looked at raw data from NINDS trial; found large group with negative NI­HSS score had initial deficit of, eg, facial droop, dysarthric speech, tingling in one hand (not devastating stroke); 19% of treated patients had NIHSS score in 0 to 5 range, while only 4% of patients in placebo group had initial stroke score of 0 to 5; in those with NIHSS score >20, 18% in treated group and 27.5% in placebo group; middle groups equivalent (those with NIHSS score of 6-20 well distributed); problematic that patients with no initial deficit skewed results; when results equalized, found that simple random assignment accounted for 4% of abso­lute benefit, reducing benefit to 12% from 16%; new summary  —  if treating 100 patients who meet tPA criteria, 8 will have absolute benefit, but 6 will have symptomatic ICH; aim for 3-hr window;  in NINDS trial, median time to treatment 89 min

NINDS in clinical practice: must consider tPA, but patient selection difficult; maximize risk-benefit ratio; avoid hemorrhage, if possible; stroke needs to be of adequate severity, but not too severe; <2% of stroke patients meet criteria; <2% of hospitals now offer tPA

Phase IV tPA use: phase IV trial  —  after approval and release of drug; rarely done; currently voluntary; no penalty for not doing; phase IV data on tPA  —   from community and academic centers, single hospitals, and groups of hos­pitals; found that treatment given to 1.8% to 22% of eligible stroke patients; had 9% to 67% protocol violations in study (violating protocol causes more harm than good); compared to NINDS trial  —  age 63 to 71 yr (68 yr in NINDS); median NIHSS score, 10 to 15 (14 in NINDS); median time to treatment, 126 to 165 min (89 min in NINDS); good outcomes in 30% to 95% (31%-54% in NINDS); mean mortality 14% (17% in NINDS); symptom­atic ICH 3.3% to 15.5%, with mean of 5.2% (6.4% in NINDS); conclusions  —  despite deviations from protocol, re­sults good;  most common protocol violation going beyond 3-hr window; possible to duplicate NINDS population and results

Statements on use of tPA: American College of Emergency Physicians  —  insufficient evidence to endorse  use of in­travenous (IV) tPA in clinical practice when systems not in place to ensure that inclusion or exclusion criteria estab­lished by NINDS guidelines for tPA use in stroke followed; Society for Academic Emergency Medicine  —  not yet clear whether treatment risk outweighed by likely therapeutic benefit; endorsed creation of national research initia­tive, including registry; American Academy of Emergency Medicine  —  objective evidence of efficacy, safety, and applicability of tPA for acute ischemic stroke insufficient to warrant its classification as standard of care; adminis­tration of thrombolytic agents to stroke patients should be carried out only in setting of approved research protocol or formal clinical practice protocol; <2% of community hospitals using tPA for acute ischemic stroke

Inclusion and exclusion criteria: inclusion criteria  —  include clinical diagnosis of ischemic stroke causing measur­able neurologic deficit; administration of tPA initiated £3 hr after onset of symptoms or from time patient last seen normal; age ³18 yr; patient or family member who understands potential risks and benefits; exclusion criteria  —  stroke or head trauma in past 3 mo; symptoms suggestive of subarachnoid hemorrhage, even in presence of normal CT of brain; history of ICH; major surgery within previous 14 days; gastrointestinal or urinary tract hemorrhage in past 21 days; myocardial infarction (MI) in last 3 mo (but indicated for acute MI); arterial puncture in noncom­pressible site in past 7 days; rapid improvement of stroke symptoms; minor or isolated neurologic signs; seizure, if residual impairments thought possibly result of postictal state; presentation consistent with acute MI or post-MI pericarditis; persistent hypertension, defined as systolic BP >185 mm Hg or diastolic BP >110 mm Hg, or requiring aggressive therapy to control BP; pregnancy; active bleeding or acute trauma; too high or too low blood glucose; if patient on anticoagulant and international normalized ratio (INR) >1.7 or partial thromboplastin time greater than normal range; CT evidence of hemorrhage

Informed consent: speaker thinks not necessary because tPA has Class 1a recommendation from AHA (standard of care) and approved by Food and Drug Administration (FDA) for treatment of acute ischemic stroke; critical to ex­plain risks and benefits to patient and document discussion in medical record; what to tell patient  —  if nothing done, 40% chance for good recovery within 3 mo; if tPA given, 52% chance for good recovery after 3 mo, meaning 1 in 8 chance drug of benefit; no evidence that tPA makes any difference before 3 mo; NINDS trial showed im­provement at 3 mo; if tPA used, 1 in 16 chance of developing hemorrhage in brain; despite increase in brain bleed­ing, risk for death at 3 mo approximately same with or without tPA; tPA not lifesaving drug but functionality-saving drug

Required documentation in chart: diagnosis of stroke; patient has symptoms fixed and consistent with acute isch­emic stroke; systematic neurologic examination to develop approximate NIHSS score; time of onset and how con­firmed; interpretation of CT reviewed and cleared by radiologist aware of potential use of tPA; BP stabilized without extraordinary intervention and consistently <185/110 mm Hg, allowing for safe IV tPA use; discussion with patient and family that with tPA, 30% greater chance of good outcome at 3 mo, 10 times greater risk for symp­tomatic brain hemorrhage, mortality rate same at 3 mo, regardless of tPA use, and 2 patients will improve for every one that develops symptomatic brain hemorrhage; include name(s) of relative(s) who were part of and consented to use of tPA; contraindications or reasons not to treat with tPA

Conclusions: patient selection difficult (<2% of stroke patients meet criteria for consideration of tPA); histories unre­liable and must have exact time of onset; old habits (tendency not to intervene in stroke) persist; first do no harm; data support use of IV tPA when NINDS protocol strictly followed; outcomes similar to NINDS achievable; sooner probably better, but therapeutic window  3 hr; in practice, relatively few patients receive tPA; thoroughly document decision-making for all patients, whether tPA used or not

Stroke: Extending the Three-hour Window with
New Techniques

Chad Miller, MD, Assistant Professor of Neurosurgery and Neurology, David Geffen School of Medicine at the University of California, Los Angeles, and Neuro-Critical Care Intensivist, Department of Neurosurgery, Ce­dars-Sinai Medical Center, Los Angeles, CA

Thrombolytics: tenecteplase  —  has longer half-life and less hemorrhage in cardiac patients; has more specific fibrin binding; in preliminary studies in stroke, shown to have similar efficacy and reduced bleeding rates compared to tPA

Caveats with use of IV tPA: patients with major strokes respond less favorably, although all types of stroke respond to tPA; risk for hemorrhages  —  most severe in patients with largest deficit; most likely in patients with embolic in­farcts and in elderly patients; treatment most effective if administered early, regardless of guidelines or criteria used; if medication used in patient >80 yr of age, need to recognize that data for this group sparse, and risk for hem­orrhage more significant; revascularization leads to improved outcomes, but not effective most of time; 13% of pa­tients in NINDS trial deteriorated after initial improvement; reocclusion should be suspected when vessel opened up; unless medication continued, vessel reoccludes; »30% of patients who receive IV tPA recanalize, and one-third of these reocclude; need to improve method of administration, particularly in those who have partial opening and in those who have early recanalization (tend to have reocclusion)

Intra-arterial administration of tPA: goal to receive all benefits of IV tPA, administer locally, and to reduce sys­temic side effects, including bleeding; Prolyse in Acute Cerebral Thromboembolism (PROACT) II study  —  landmark study; utilized prourokinase (proUK; no longer used); could be used £6 hr after onset of symptoms, if patients not candidates for tPA; angiography performed, microcatheter placed directly on clot, and 9 mg of intra-ar­terial proUK given; heparin given to both groups; particularly in patients with more severe strokes, modified Rankin scale scores improved, denoting good outcomes on follow-up assessment at 90 days; recanalization rate 66% (double that of IV tPA); thrombolysis in MI (TIMI) free flow (complete re-established flow through vessel) occurred at reduced rate, so most partial recanalization; adverse effects include symptomatic hemorrhages 10% of time (within first 24 hr); data basis for intra-arterial administration of alteplase and tPA; AHA recommendation  —  treatment with intra-arterial thrombolytics should be option for patients who present with major stroke within 6 hr due to middle cerebral artery (MCA) occlusion; if patients present within 3 hr, IV tPA option, but not recommenda­tion; other considerations  —  some agents require heparinization to maintain canalization and patency of vessel, so role of glycoprotein IIb/IIIa inhibitors currently elucidated with stroke; from PROACT II study, number needed to treat, 7; benefit  —  more efficacious and keeps vessel open; drawback  —  requires skilled individual to perform pro­cedure

Interventional Management of Stroke (IMS) study: included adults £80 yr of age who presented within 3 hr; given IV therapy at two-thirds dose; angiography performed and if recanalized, nothing further done; if patient still had clot, intra-arterial tPA administered into clot bed; time to treatment  —patients presented at »2 hr after and received treatment within 4 hr; single-arm study; results  —  symptomatic hemorrhage greater but still similar to IV tPA group; improvement in efficacy, compared to NINDS placebo; concluded that combined therapy favorable to pla­cebo and possibly comparable to IV tPA; also looked at ultrasonographic (US) microcatheter to assist with mechan­ical thrombolysis; microcatheter inserted into clot provides ultrasonic wave to clot (thought to increase surface area for tPA access, with potential to improve recanalization rate); compared patients who received intra-arterial therapy and intravascular US to NINDS placebo and tPA groups; in all cases, performance superior to placebo group and even suggested as favorable way for administration of intra-arterial tPA; Grotta and Alexandrov  —  US lysis en­hancement made easier to use; instead of microcatheter, used transcranial Doppler at 2 Hz to lyse clot; randomized controlled trial comparing IV tPA to IV tPA with extracranial US thrombolysis; patients who received US had re­canalization at 2 hr, compared to those who received only IV tPA; able to recanalize twice as frequently, compared to those who received IV tPA only

Mechanical clot disruption: through intravascular stenting, intravascular snares (microcatheter placed into clot and used to disrupt or retrieve clot), direct angioplasty (clot compressed against side of vascular wall), and suction de­vices (to suck clot in and eat away surface of clot to achieve recanalization); Mechanical Embolus Removal in Ce­rebral Ischemia (MERCI) retrieval device  —  in MERCI trial, patients presented after 3 hr (no longer eligible for IV tPA) and underwent mechanical embolectomy; successful in obtaining recanalization »50% of time (improvement over IV tPA); predictors of good outcomes include those where vessel able to open, younger patients, better NIHSS scores at admission, and faster procedural time; multi-MERCI trial  —  international trial that looked at utility of clot retrieval for patients not eligible for IV tPA or who received IV tPA but did not recanalize; patients had significant strokes (average NIHSS score of 19); one-third of patients received IV tPA before procedure; improvement in re­canalization attributed to IV tPA and familiarity with device (improved procedural skill); mortality not statistically significant but improving; hemorrhage rates low, despite fact that patients received tPA in addition to mechanical retrieval; few complications, but if present, just as prevalent or more prevalent in those who did not receive tPA; pa­tients difficult to treat  —  those with internal carotid artery (ICA) occlusions and “T” occlusions (clots at distal ICA and extend into MCA and anterior cerebral artery vasculature) recognized to not respond favorably to IV tPA; those who received IV tPA had significantly high mortality rate (50%-70%), and if different device used to recanalize, likelihood for reasonable outcome much better; Penumbra stroke system  —  not FDA-approved; undergoing trials; suction (not clot disruption) device; used to recanalize vasculature; compared to multi-MERCI results; generally, multi-MERCI group had larger clot burdens and more large vessel occlusions; high rates of revascularization achieved

Suggested Reading

Alexandrov AV et al: Ultrasound-enhanced systemic thrombo-lysis for acute ischemic stroke. N Engl J Med 351:2170, 2004; Bose A et al: The Penumbra System: a mechanical device for the treatment of acute stroke due to thromboembolism. AJNR Am J Neuroradiol 29:1409, 2008; Cocho D et al: Reasons for exclusion from thrombolytic therapy following acute ischemic stroke. Neurology 64:719, 2005; Georgiadis D et al: Does acute occlusion of the carotid T invariably have a poor outcome? Neurology 63:22, 2004; Hoffman JR: Tissue plasminogen activator (tPA) for acute ischaemic stroke: why so much has been made of so little. Med J Aust 179:333, 2003;  Josephson SA et al: Comparison of mechanical embolectomy and intraarterial thrombolysis in acute ischemic stroke within the MCA: MERCI and Multi MERCI compared to PROACT II. Neurocrit Care10:43, 2009; Mann J: tPA for acute stroke: balancing baseline imbalances. CMAJ 166:1651, 2002;  Mikulik R et al: Ac­curacy of serial National Institutes of Health Stroke Scale scores to identify artery status in acute ischemic stroke. Circulation 115:2660, 2007; Noser EA et al: Aggressive mechanical clot disruption: a safe adjunct to thrombolytic therapy in acute stroke? Stroke 36:292, 2005; Qureshi AI et al: Time to hospital arrival, use of thrombolytics, and in-hospital outcomes in isch­emic stroke. Neurology 64:2115, 2005; Saqqur M et al: Symptomatic intracerebral hemorrhage and recanalization after IV rt-PA: a multicenter study. Neurology 71:1304, 2008; Smith WS et al: Mechanical thrombectomy for acute ischemic stroke: final results of the Multi MERCI trial. Stroke 39:1205, 2008; Uchino K et al: Safety and feasibility of a lower dose intravenous TPA therapy for ischemic stroke beyond the first three hours. Cerebrovasc Dis19:260, 2005; Wunderlich MT et al: Recanalization after intravenous thrombolysis: does a recanalization time window exist? Neurology 68:1364, 2007; Zangerle A et al: Recan­alization after thrombolysis in stroke patients: predictors and prognostic implications. Neurology 68:39, 2007.