- Email: [email protected]
IIIa Inhibitors, and Cilostazol TBA
Conclusions Wi!h current techniqlle and eqllipment, intracraniaI angioplasty/stenting can be performed safely and preliminary reslllts indicate !hat !his may be an efficacious therapy. The restenosis rate appears to be higher when stenting is performed, ra!her !han angioplasty aIone; simiJar to the high rate ol' restenosis repOlted in smal! vessels in the cardiology literature. Fur!her technological deveIopments, such as the release ol' stents coated wi!h immllnosllppressive drugs, willlikely improve the restenosis rate associated with stenting and lead to increased use ol' stents. 2:00 p.m.
Break 2:30 p.m.
Stroke News: Warfarin, Aspirin, Statins, Ub/ma InWbitors, and Cilostazol TRA john j. "Buddy" Conn01'S, 111, MD St. joseph 's Hospital Tampa, PL Acute Stroke Therapy Background The oniy form ol' acute stroke !herapy !hat has been proven to be efficacious is emergent restoration ol' blood flow. Other !herapies aimed at protecting !he brain from !he effects ol' ischemia (neuroprotectanl agents, hypothermia, hyperbaric oxygen, ete.) are promising but have not been shown to be effective to date. Until recently, attention has been focused on fibrinolytic agents; both intravenous and local intra-arterial approaches have been explored. The NationaI Institute ol' Neurological Disorders and Stroke (NINDS) Trial demonstrated that intravenous administration ol' tissue plasminogen activator (t-PA) wi!hin three hours ol' onset ol' symptoms was associated with improved outcome at three mon!hs (1). There are several drawbacks to intravenous therapy, however. The window for treatment is very short, a large amount ol' thrombolytic agent must be given (increasing the likelihood ol' hemorrhagic complications), and the rate ol' recanalization is tOG slow in !he presence ol' a large vessel ocdusion. Direct local intra-arterial infusion ol' !he fibrinolytic agent addresses these concerns. The Prolyse in Acute Cerebral Thromboembolism (PROACT) Trial demonstrated the efficacy and safety ol' intra-arterial thrombolysis in aCllte middle cerebral artery ocdusion (2).
Fibrinolytic Agents The determination ol' the optimal fibrinolytic agent has been problematie. Streptokinase was evaluated in several early triais but its llse was associated with an unacceptably high rate ol' intracranial hemorrhage. The PROACT trial employed recombinant prourokinase, which has not received FDA approval at !his time. Much ol' !he dinical experience in acute intra-arterial thrombolysis has been gained using urokinase. Uroki-
P5U
nase is an enzyme produced by !he kidney. Although no randomized trial has proved its usefuJness, its use has been felt to be associated with an acceptabIe safety and efficacy profile. Experience in treatment ol' peripheral arteriaI ocdusion has demonstrated !hat !he major drawbacks to the llse ol' urokinase are its cost and !he need for prolonged infusions (3,4). Unfortunately, due to manufacturing issues, urokinase is not currently avaiJable (5). Currently available fibrinolytic agents are forms ol' recombinant t-PA: aIteplase, reteplase, and tenectepIase. AltepIase was !he agent employed in the NINDS Tria!. Alteplase is the recombinant form ol' the naturally occurring t-PA molecuIe, while reteplase and tenecteplase are genetically engineered fragments ol' native t-PA. There have been no published reports ol' experience with !he use ol' reteplase or tenecteplase in the setting ol' acute stroke. There has been some early experience with reteplase, which has several features !hat may make it preferabIe to alteplase for use in intra-arterial thrombolysis for acute stroke. Reteplase is capable ol' dot penetration whiJe alteplase binds to the surface ol' the dot. When given intravenously, reteplase is administered as a double bolus and the dose is not weight-adjusted; alteplase is given as a bolus and infusion and !he dose is weight-adjusted. Reteplase continues to dissolve dot faster at higher doses, while increasing the dose ol' alteplase beyond a certain point results in decreased !hrombolysis. Ano!her drawback to !he use ol' alteplase is its stability in solution. Dilution beyond 0.5 mg/nu results in precipitation because ol' dilution ol' the stabiliz.ing agent. Reteplase, however, is soluble and can be diluted as needed and is stable in solution at low concentrations. The optimum dose for intracranial intra-arterial fibrinolysis has not been estabJished for any fibrinolytic agent. Indeed, there is not much data avaiJable on the use ol' reteplase or tenectepJase in peripheral vascular ocdusion. The use ol' combination intravenous and intra-arteria] fibrinolytic agent in the setting ol' acute stroke has been considered. There have been promising early results, but no defmite benefit has beenshown to date (6). The rationale for this combined therapy is that treatment can be instituted white the angiography team is being mobilized, resulting in less delays in initiation ol' !herapy. The major risk associated wi!h fibrinolytic!herapy is intracranial hemorrhage; hemorrhagic complications elsewhere in !he body are aIso ol' concern. There is some indication !hat the risk ol' bleeding is greater with alteplase than wi!h reteplase (7).
Antiplatelet Agents Recently, there has been increased interest in the role ol' antiplatelet agents in acute stroke !herapy and thrombolysis in generał (S-lO). The dass ol' antiplatelet agents utilized in acute !hrombolysis is the GP Ub/IIIa receptor inhibitors. There are currently three GP Ub/IIIa receptor inhibitors available: abcixirnab, ept.ifibatide, and tirofi-
ban. Results of an eady study indicate that intravenous abciximab may be beneficial and safe in the setting of acute stroke (10). There are important differences between these agents. AlI three exhibit rapid binding to platełets « 1 minute). Abci.ximab has a prolonged płatelet-bound hałf-life, whiłe the other two agents rapidly dissociate from platelets. Most of the initial abciximab bolus binds to platelets; the remainder is rapidly cleared. The platelet-bound portion is cleared as płatelets are removed from the system. In contrast, the other two agents have short platelet-bound and long plasma half-lives. Greater concentrations and longer infusions of these agents are needed to maintain adequate platelet blockade. The binding characteristics of the three agents differ. Abciximab binds to O'vf3 3 with affinity equal to that for the GP lIb/IIIa receptor; its affinity for Mac-1 receptors is less. The other agents bind only to GP lIb/IIIa receptors. Abci.ximab may have a greater effect in reducing thrombin generation. There is indication that prolonged platelet blockade may be important. Im.rnediately following vessel injury, the vessel surface is highly thrombogenic and plateletreactive, leading to platelet aggregation, thrombosis, spasm, and possible restenosis. The vessel wall then undergoes passivation as it heals and loses platelet reactivity and thrombogeneity. This can take up to 8 hours in norma l vessels and several days in atherosclerotic vessels (11,12). Although prolonged activity may be of value, reversibility is also an issue. Although abcix.imab in particular results in prolonged platelet blockade, its effects can be reversed with platelet transfusion (13). The reversal of eptifibatide and tirofiban depends on renal clearance; platelet function will normalize within a few hours of stopping infusion in patients with norma! renal function. Platelet infusion is ineffective in reversing these agents. These agents are not associated with the increased risk of intracranial bleeds (or bleeding in generał) seen with fibrinolytic agents (14). When there is vessel wall injury, a platelet monolayer forms at the injury site; this is the beginning of hemostasis. This binding is mediated by GP Ib/lIa receptors and is not błocked by GP lIb/IIIa inhibitors.
Combination Therapy There are two types of thrombus that form at sites of vessel injury. "\Vhite" thrombus is rich in platelets but contains relatively little fibrin, while "red" thrombus contains fibrin. White thrombus is typical of arterial and partially occlusive thrombus, while red thrombus is associated with venous clots and complete occlusion. Platelet accumulation is greatest at sites of plaque ruptme. Fibrinolytic therapy has limited effect on white thrombus, while antiplatelet therapy is effective. Indeed, plate!ets exhibit reaccumulation at the ciot surface as fibrinolysis occurs. Both types of agents are effective against red thrombus. Thus, a combination of antiplate-
let and fibrinolytic therapy may be the optima! approach. Inhibition of platelet aggregation may result in increased susceptibility to fibrinolysis and a decreased rate of reocclusion (14). The use of GP II b/IIIa receptor inhibitors in conjunction with a reduced dose of fibrinolytic agent has yielded promising results in the coronary circulation (15). In the Thorombosis in Myocardial Infarction (TIMI) 14 Trial, fibrinolytic alone, abci.ximab alone, and combination therapy were compared. The fibrinolytic agents studied included alteplase, reteplase, and streptokinase. It was shown that combination therapy improved outcome. Not only is reperfusion accelerated and reocclusion minimized; the decreased dose of fibrinolytic agent required may reduce the risk of intracranial hemorrhage. The current standard of care is to use a reduced dose of fibrinolytic agent with GP Ub/Ula inhibitor therapy. Clinical evidence also suggests that combination therapy can reduce microvascular obstruction, which may lead to improved outcomes.
Interventional Stmke Therapy Outcomes Registry (INSTOR) The foregoing discussion demonstrates the uncertainty regarding the appropriate drug or combination of drugs (and dosages) for use in the emergency treatment of acute ischemic stroke. In addition, there is inadequate knowledge regarding the appropriate patient population and timing of therapy. A voluntary national regisby is therefore being established to acquire data concerning interventional therapy for the purpose of optimizing therapeutic outcomes for stroke victims. Data to be collected include patient demographics, agents and doses used, outcomes, and complications. The outcome at three months will be the primary measurement of efficacy. A standardized data collection form is being developed in order to facilitate the analysis of the data. The above discussion does suggest several treatment options. These include low dose intra-arterial alteplase or reteplase, high dose intra-arteriał alteplase or reteplase, combination intravenous and intra-arterial alteplase or reteplase, and combination intravenous abciximab and intra-arterial reteplase. In order to improve the likelihood of obtaining useful data, standardized protocols have been established for use at the discretion of participating physicians. The bolus and infusion doses of the agents are specified in the protocols, along with clinical and radiographic inclusion and exclusion criteria. Stroke Prevention Antiplatelet Therapy Antiplatelet therapy has been shown to reduce the risk of subsequent vascular events in patients with recent ischemic stroke or TIA. There are several oral antiplatelet agents that have been shown to be effective in clinical triais of patients with ischemic stroke and/or TIA. Ali are effective in preventing recurrent vascular events in pa-
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tients who have hacl an ischemic stroke. In general, in patients with ischemic stroke or TIA, antiplatelet therapy recluces the risk of subseqllent stroke, myocarclial infarction (MI) or vasclllar cleath by 22%. Aspirin works by inhibiting the enzyme cyelo-oxygenase in the platelet thereby inhibiting the procluction of thromboxane A2. The absence of thromboxane A2 leacls to inhibition of platelet aggregation. Tielopicline (Tielicl) ancl e1opiclogrel (Plavix) are thienopyriclines ancl inhibit platelet aggregation by blocking ADP bincling on the platelet sUI·face. Dipyramiclole inhibits the re-lIptake of aclenosine, a potent platelet inhibitor, by recl bloocl cells. The extenclecl release formulation of clipyriclamoJe ancl asp irin (Aggrenox) is supposecl to offer benefit over the immecliate release formulation (Persantine) by avoicling freqllent trough levels that are inacleqllate to maintain continllous inhibition of platetet function. Aspirin is a cost effective method of stroke prevention for most patients althollgh the optima I effective ciose remains unclear. Earlier triais leci to consensus recommenclations for higher closes of aspirin (>900 mg), however subseqllent studies of lower closes «325 mg) also established effectiveness. Few triais have clirectly comparecl high ancl low closes of aspirin. In 1998, the FDA proviclecl a statement recommclencling closes between 50 mg ancl 325 mg to prevent reCllrrent stroke. There is vely little clifference in effectiveness between the antiplatelet agents listecl above. They are al! effective ancl there is no elear eviclence establishing their benefit over asp irin alone. Although TASS repoltecl benefit of tielopidine over asp irin for redllcing stroke risk in patients with recent ischemic stroke or TlA, there was no effect on stroke-free sllrvival, ancl no clifference for the primary endpoint of preventing stroke and cleath (16). In the CAPRIE trial, approximately 20,000 patients with recent ischemic stroke, myocardial infarction or peripheral alteria! clisease were ranclomizecl to receive clopiclogrel or asprin (17). For the primary endpoint of MI, stroke Ol' vascular cleath, e1opiclogrel was more effective than aspirin but the relative benefit (9%) ancl absolute benefit (0.5%) was quite smalI. Also, for the patients entered in the CAPRIE trial with a recent schemic stroke there was no benefit of e1opiclogrel over aspirin. In the ESPS-2 triaj, patients with recent ischemic stroke 01' TIA were stucliecl lIsing combination therapy with extencleclrelease clipyramidole ancl low close aspirin (Aggrenox) (18). The combination therapy was shown to be more effective in preventing stroke than aspirin. However, the combination therapy was not more effective in preventing the primary enclpoint of stroke or cleath. The risk of serious bleecling is low with al! of the antiplatelet preparations. The more common but minor side effects may limil compliance. Aspirin containing preparations can cause clyspepsia, especially at the higher cIoses. Dipyramiclole containing preparations cause heaclache in some patients. C1opiclogrel appears to have fewer sicie effects compared with tiC!opicline ancl is preferrecl for this reason. Tielopicline causes neutropenia
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in about 2% of patients ancl requires blood monitoring evely 2 weeks cIuring the first 3 months of therapy. Many patients have an ischemic stroke or TIA while tak ing claily aspirin. These patients can be consiclerecl to have failecI aspirin therapy. Appropriate steps in management inelllde risk factor moclmcation and cIetermining the callse of the ischemic event. For patients with atria! fibrillation and possibly those with other cardiac or aortic conclitions, warfarin therapy is incllcatecl lInless there are conlrainclications. Patients with s/mptomatic caroticl stenosis ShOlllcl be consiclerecl for enclarterectomy. The benefit of changing to another antiplatelet regimen has not been establishecl but this seems appropriate. There are no stlldies of patients failing aspirin therapy to cletermine what the best antiplatelet regimen sholllcl be in this situation. AcceptabJe approaches inelucle using combination therapy with extendecl release clipyramiclole ancl aspirin 01' aspirin combined with clopiclogrel. Ongoing studies are testing the effect of this larter combination therapy in patients with ischemic stroke. Wa/jarin The relative benefit of warfarin verSllS aspirin differs depencling on stroke sllbtype. Warfarin is clearly more effective in patients with certain cardiac conclitions sllch as atria! fibrillation ONR 2.0-3.0), however, it is no berter than aspirin in patients without a carcliac source of embolism. The Warfarin Aspirin Recurrent Stroke Stucly (WARSS) showecl that aspirin (325 mg) ancl warfarin ONR 1.4-2.8) have eqllivalent effects in patients with ischemic stroke 01' TIA withollt a carclioembolic source (19). Evaluation of preclefinecl sllbsets of patients within WARSS also clicl not show benefit. For example, patients with a patent foramen ovaJe, those with anti-phospholipid antibodies, and those with aortic atherosclerosis did not clerive more benefit from warfarin than asp irin. This trial shows that carefll! consicleration of the llnclerlying etiology is requirecl when cIeciding whether to treat a patient with warfarin. There has been some concern expressed regarcling the lower range of INR vallles llsecl in the stucly. Critics have argllecl that the design of the trial clid not test the range most commonly llsecl (INR 2.0:-3.0). No relationship between INR value and the risk of recurrent stroke was fOllncl sllggesting that the reason for the łack of benefit of warfarin was not cllle to the range of INR vallles chosen. Statins Statin meclications were clesignecl to limit atheroselerosis but also appeal' to have aclditional beneficial effects by promoring plaqlle stabilization, provicling an anti-inflammatOlY effect (clecreasecl CRP) and redlIcing the risk of thrombosis. Clinical triais show a c1ecreasecl stroke risk in patients with coronaly anely clisease ancl moclest elevations of lipicls. No stucly has establishecl the benefit of stalin meclication in patients with ischemic stroke. Based
on the evidence of benefit in patients who are at risk for vascular events, statins should be considered in all ischemic stroke and TIA patients who have LDL levels higher than 130. Which statin is most effective in patients who have had an ischemic stroke or TIA has not been determined. An ongoing study will be the first to determine if atorvastatin is effective in patients with ischemic stroke or 11A (SPARCL). ACE lnhibitors Angiotensin converting enzyme inhibitors (ACE-!) were designed to treat hypertension. However, they have many other beneficial effects. These effeets include antiatherogenesis, endothelial celi modulation, and platetelet inhibition. Two studies of have shown a substantial reduction in stroke risk. The HOPE trial studied the effects of ramipril in patients at high risk for ischemic events and found a beneficial effect (20). The combined endpoint of MI, stroke or vascułar death was significantly reduced. Furthermore, the endpoint of stroke was also reduced. PROGRESS tested the effects of combining perindopril with a diuretic, indapamide, in patients with ischemic stroke, TIA or intracerebral hemorrhage and found that the combination therapy dramatically reduced the risk of recurrent stroke (21). No benefit for perindopril therapy alone was found although the study was not designed to test this. These two studies suggest that patients with stroke or TIA should be considered for treatment with an ACE-l especially if there are other vascular risk factors present. Combination therapy with a diuretic may be warranted to maintain łongterm blood pressure control and maximize benefit. National consensus guidelines on the use of ACE-I after stroke are needed to incorporate the nndings of these recently published clinical triaIs
References l. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. New Engl
J Med 1995; 333:1581-1587. 2. Furlan A, Higashida R, Weschler L, et al. lntra-arteria] prourokinase for acute ischemic stroke: The PROACT II study: A randomized controlled trial. JAMA 1999; 282:2003-2011. 3. Graor RA, OlinJ, Bartholomew JR, et al. Efficacy and safety of intraarteriał local infusion of streptokinase, urokinase, or tissue plasminogen activator for peripheraJ arteriaJ occlusion: A retrospective review. J Vasc Med Biol 1990; 2:310-315. 4. Ouriel K, Kolassa M, DeWeese JA, et al. Economic implications of thrombolysis or operation as the initiał treatment modality in acute peripheral arteria! occlusion. Surgery 1995; 118:810-814.
Combinecl intravenous and intra-arterial r-TPA versus intra-arterial therapy of acute ischemic sU"oke: Emergency Management of Stroke (EMS) Bridging Trial. Stroke 1999; 30:2598-2605 7 McNamara TO, ChenJL, Temmins CJ, et al. Bleeding associated with intrathrombus infusions of rt-PA for peripheral arterial and venous occlusion [abstractJ. Am J Cardiol 1999; 84(suppl 6A);37P. 8. Harker LA. Therapeutic inhibition of platelet function in stroke. Cerebrovasc Dis 1998; 8Csuppl 5);818. 9. Winkley JM, Adams HP Jr. Potentiał roje of abciximab in ischemic cerebrovascular disease. Am J Cardiol 2000; 8547c-5lc 10. The Abciximab in lschemic Stroke lnvestigators. Abciximab in acute ischemic stroke: A randomized, double blind, placebo controlled dose-escalation study. Stroke 2000; 31:601-609. 11. Wientz JR, Sanborn TA, Haudenschild CC, et al. Platelet accumuJation in experimental angioplasty: Time course and relation to vascular injUlY. Circulation 1987; 75:636-642 12. Coller BS. GP lIb/lIla antagonists: The first antiintegrin receptor therapeutics. J Clin Invest 1997; 99:1467-1471 13. Wagner CL, Cunningham MR, Wyancl MS, et al. Reversal of the anti-płatelet effects of chimeric 7E3 Fab treatment by płatełet transfusion in cynomolgus monkeys (abstract). Thromb Haemost 1995; 73:1586. 14. Topol EJ. Toward a new frontier in myocardial reperfusion therapy: Emerging platelet prominence. Circulation 1998; 97:211-218. 15. Antman EM, Giugliano RP, Gibson CM, et al. Abciximab facilitates the rate and extent of thrombolysis: Results of the Thrombolysis in Myocardial lnfarction (11M!) 14 Trial. Circulation 1999; 99:2720-2732. 16. Hass WK, EastonJD, Adams HP Jr, et al. A randomizecl trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Engl J Med 1989; 321:501-507. 17. CAPRIE Steering Committee. A randomised, blinded tria I of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE). Lancet 1996; 348: 13291339. 18. Diener HC, Cunha L, Forbes C, et al. European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondalY prevention of stroke. J Neurol Sci 1996; ]43:1-13.
5. Ouriel K Urokinase and the US Food and Drug Administration. J Vasc Surg 1999; 30:957-958.
19. Mohr JP, Thompson JL, Lazar RM, et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 2001; 345: 1444-1451.
6. Lewandowski CA, Frankel M, Tomsick TA, et al.
20. Yusuf S, Sleight P, Pogue J, et al. Effects of an
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angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Eng1 J Med 2000; 342:145-153.
• 1 of the 90 who received lA therapy was thought to have smali vessel disease as the cause of the stroke.
21. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood pressure-lowering regimen among 6,105 individuals with previous strake or transient ischemic attack. Lancet 2001; 358:10331041.
Who Gets What? tPA Options Blood pressure, time windowand CT exclusions are strictly adhered to in aj[ of the following protocols. Specific consent forms are signed for off-labe1 use of tPA and when the stroke is severe, statistics regarding increased risk of hemorrhage are discussed with the family and patient (when possible). • lf the patient presents with a mild stroke (NIHSS 4-10) within the 3 hour window, we might elect to use IV tPA alone according to the FOA approved protoc01 of 0.9 mgm/kgm 10% bolus, the rest over one hour. (No special consent is required). • lf the patient with an NlHSS of 4 -1 Ohas aphasia or severe hemiparesis, we may e1ect to use the combined lV/lA pratocol usually reserved for more severe strokes (see next bul1et). • lf the patient has a moderate to severe stroke (NIHSS >10) within 3 hours, we administer IV tPA at 0.6mgm/kgm 15% bolus, the rest over 30 minutes and prepare to go to angiography. If the patient improves significantly, we may cancel the angiogram. lf, on angiography, we find a clot (usually lCA, T-lesion, MI, M2, or basi1ar) we use intraarterial tPA usual1y to a maximum dose of 20-25 mgm so that the total dose is approximately 0.9 mgm/kgm. • lf the patient has a moderate to severe stroke (NlHSS > 10) and presents after 3 hours but before 6 hours, we consider intra-arterial tPA a10ne, particularly if the CT head scan is negative. The dose of lA tPA will depend on a more sophisticated evaluation of how the col1aterals look on the angiogram. • Other situations in which lA alone is general1y se1ected include: post procedure (cardiac catheterization) cases, post-operative cases, patients on coumadin, very e1derly patients or patients with a remote history if intracranial hemorrhage. • If the patient is rapidly improving at 3 hours, we will hold the IV tPA and closely monitor the patient. lf deterioration occurs, the patient is taken to the angiography suite and given lA therapy if a clot is located. • If there is atotal lCA occlusion, we may push the catheter through the clot and search for a distal embolus which is often present at MI. We can then come back and angioplasty and stent the carotid Jesion. • For basilar attery occlusions and retinal artery occlusions, we may extend the 6-hour time windowo
2:50 p.m. Patient Se1ection for Interventiona1 Therapy Marilyn Reimel~ MD Mid-America Brain and Stroke Institute Saint Luke's Hospital Kansas City, MO Background The Stroke Center at Saint Luke's Hospital in Kansas City opened in 1993 with the goal of standardizing care for the large patient volume and coordinating communication among the many practitioners who are important in the management of stroke. No one had imagined routine acute intervention, and a neur010gist in the emergency roor~ was a reportable siting. Two peop1e changed the landscape. Graham Lee, MOa neurointerventional radiologist came to Kansas City from NYC because Kansas resembled the plains of Rhodesia where he grew up. Having trained with Dr. Berenstein in NYC, he had used intra-arteria1 urokinase to 1yse clots in acute stroke. His early successes in reversing strokes at Saint Luke's changed our mindset permanently. We viewed every case as a possible "save" unless proven othelwise by time or circumstance. When Tom Brott, MO al10wed the Saint Luke's team to be one of Cincinnati's contributing hospitals in the NlNOS tPA trial, we discovered "ful1 speed ahead." We became friends with EMS, bonded
with the nurses and physicians in the emergency department, and neurologists became as at home in the EO as the cardi010gists. Current Practice Since 1999, we have used tPA for intra-arterial (IA) as wel1 as intravenous (IV) 1ysis. A recent review of our interventional cases from January of 2000 tllrough June 2002 revea1ed the fol1owing data: • 142/781 08.2%) of ischemic strakes were treated with tPA • 52/142 (36%) IV; 55/142 (39%) lA; 35/142 (25%) IV folIowed by lA • Overall hospital mortality rate was 12.7% with the lowest rate in the IV group at 5.8%. • Symptomatic hemorrhage rate was 9.2% (IV = 1.9%, lA=14.6%, IV/lA=11.4%) • Patients who received lA therapy were statistical1y 01der and presented with a higher NIHSS score. • 57% (51/90) of patients who received lA therapy a10ne or in combination with IV therapy were found to have a cardiac source for the stroke.
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HolU This Works • The strake neurologist is the point person for these protocoJs.
Break 2:30 p.m.
Stroke News: Warfarin, Aspirin, Statins, Ub/ma InWbitors, and Cilostazol TRA john j. "Buddy" Conn01'S, 111, MD St. joseph 's Hospital Tampa, PL Acute Stroke Therapy Background The oniy form ol' acute stroke !herapy !hat has been proven to be efficacious is emergent restoration ol' blood flow. Other !herapies aimed at protecting !he brain from !he effects ol' ischemia (neuroprotectanl agents, hypothermia, hyperbaric oxygen, ete.) are promising but have not been shown to be effective to date. Until recently, attention has been focused on fibrinolytic agents; both intravenous and local intra-arterial approaches have been explored. The NationaI Institute ol' Neurological Disorders and Stroke (NINDS) Trial demonstrated that intravenous administration ol' tissue plasminogen activator (t-PA) wi!hin three hours ol' onset ol' symptoms was associated with improved outcome at three mon!hs (1). There are several drawbacks to intravenous therapy, however. The window for treatment is very short, a large amount ol' thrombolytic agent must be given (increasing the likelihood ol' hemorrhagic complications), and the rate ol' recanalization is tOG slow in !he presence ol' a large vessel ocdusion. Direct local intra-arterial infusion ol' !he fibrinolytic agent addresses these concerns. The Prolyse in Acute Cerebral Thromboembolism (PROACT) Trial demonstrated the efficacy and safety ol' intra-arterial thrombolysis in aCllte middle cerebral artery ocdusion (2).
Fibrinolytic Agents The determination ol' the optimal fibrinolytic agent has been problematie. Streptokinase was evaluated in several early triais but its llse was associated with an unacceptably high rate ol' intracranial hemorrhage. The PROACT trial employed recombinant prourokinase, which has not received FDA approval at !his time. Much ol' !he dinical experience in acute intra-arterial thrombolysis has been gained using urokinase. Uroki-
P5U
nase is an enzyme produced by !he kidney. Although no randomized trial has proved its usefuJness, its use has been felt to be associated with an acceptabIe safety and efficacy profile. Experience in treatment ol' peripheral arteriaI ocdusion has demonstrated !hat !he major drawbacks to the llse ol' urokinase are its cost and !he need for prolonged infusions (3,4). Unfortunately, due to manufacturing issues, urokinase is not currently avaiJable (5). Currently available fibrinolytic agents are forms ol' recombinant t-PA: aIteplase, reteplase, and tenectepIase. AltepIase was !he agent employed in the NINDS Tria!. Alteplase is the recombinant form ol' the naturally occurring t-PA molecuIe, while reteplase and tenecteplase are genetically engineered fragments ol' native t-PA. There have been no published reports ol' experience with !he use ol' reteplase or tenecteplase in the setting ol' acute stroke. There has been some early experience with reteplase, which has several features !hat may make it preferabIe to alteplase for use in intra-arterial thrombolysis for acute stroke. Reteplase is capable ol' dot penetration whiJe alteplase binds to the surface ol' the dot. When given intravenously, reteplase is administered as a double bolus and the dose is not weight-adjusted; alteplase is given as a bolus and infusion and !he dose is weight-adjusted. Reteplase continues to dissolve dot faster at higher doses, while increasing the dose ol' alteplase beyond a certain point results in decreased !hrombolysis. Ano!her drawback to !he use ol' alteplase is its stability in solution. Dilution beyond 0.5 mg/nu results in precipitation because ol' dilution ol' the stabiliz.ing agent. Reteplase, however, is soluble and can be diluted as needed and is stable in solution at low concentrations. The optimum dose for intracranial intra-arterial fibrinolysis has not been estabJished for any fibrinolytic agent. Indeed, there is not much data avaiJable on the use ol' reteplase or tenectepJase in peripheral vascular ocdusion. The use ol' combination intravenous and intra-arteria] fibrinolytic agent in the setting ol' acute stroke has been considered. There have been promising early results, but no defmite benefit has beenshown to date (6). The rationale for this combined therapy is that treatment can be instituted white the angiography team is being mobilized, resulting in less delays in initiation ol' !herapy. The major risk associated wi!h fibrinolytic!herapy is intracranial hemorrhage; hemorrhagic complications elsewhere in !he body are aIso ol' concern. There is some indication !hat the risk ol' bleeding is greater with alteplase than wi!h reteplase (7).
Antiplatelet Agents Recently, there has been increased interest in the role ol' antiplatelet agents in acute stroke !herapy and thrombolysis in generał (S-lO). The dass ol' antiplatelet agents utilized in acute !hrombolysis is the GP Ub/IIIa receptor inhibitors. There are currently three GP Ub/IIIa receptor inhibitors available: abcixirnab, ept.ifibatide, and tirofi-
ban. Results of an eady study indicate that intravenous abciximab may be beneficial and safe in the setting of acute stroke (10). There are important differences between these agents. AlI three exhibit rapid binding to platełets « 1 minute). Abci.ximab has a prolonged płatelet-bound hałf-life, whiłe the other two agents rapidly dissociate from platelets. Most of the initial abciximab bolus binds to platelets; the remainder is rapidly cleared. The platelet-bound portion is cleared as płatelets are removed from the system. In contrast, the other two agents have short platelet-bound and long plasma half-lives. Greater concentrations and longer infusions of these agents are needed to maintain adequate platelet blockade. The binding characteristics of the three agents differ. Abciximab binds to O'vf3 3 with affinity equal to that for the GP lIb/IIIa receptor; its affinity for Mac-1 receptors is less. The other agents bind only to GP lIb/IIIa receptors. Abci.ximab may have a greater effect in reducing thrombin generation. There is indication that prolonged platelet blockade may be important. Im.rnediately following vessel injury, the vessel surface is highly thrombogenic and plateletreactive, leading to platelet aggregation, thrombosis, spasm, and possible restenosis. The vessel wall then undergoes passivation as it heals and loses platelet reactivity and thrombogeneity. This can take up to 8 hours in norma l vessels and several days in atherosclerotic vessels (11,12). Although prolonged activity may be of value, reversibility is also an issue. Although abcix.imab in particular results in prolonged platelet blockade, its effects can be reversed with platelet transfusion (13). The reversal of eptifibatide and tirofiban depends on renal clearance; platelet function will normalize within a few hours of stopping infusion in patients with norma! renal function. Platelet infusion is ineffective in reversing these agents. These agents are not associated with the increased risk of intracranial bleeds (or bleeding in generał) seen with fibrinolytic agents (14). When there is vessel wall injury, a platelet monolayer forms at the injury site; this is the beginning of hemostasis. This binding is mediated by GP Ib/lIa receptors and is not błocked by GP lIb/IIIa inhibitors.
Combination Therapy There are two types of thrombus that form at sites of vessel injury. "\Vhite" thrombus is rich in platelets but contains relatively little fibrin, while "red" thrombus contains fibrin. White thrombus is typical of arterial and partially occlusive thrombus, while red thrombus is associated with venous clots and complete occlusion. Platelet accumulation is greatest at sites of plaque ruptme. Fibrinolytic therapy has limited effect on white thrombus, while antiplatelet therapy is effective. Indeed, plate!ets exhibit reaccumulation at the ciot surface as fibrinolysis occurs. Both types of agents are effective against red thrombus. Thus, a combination of antiplate-
let and fibrinolytic therapy may be the optima! approach. Inhibition of platelet aggregation may result in increased susceptibility to fibrinolysis and a decreased rate of reocclusion (14). The use of GP II b/IIIa receptor inhibitors in conjunction with a reduced dose of fibrinolytic agent has yielded promising results in the coronary circulation (15). In the Thorombosis in Myocardial Infarction (TIMI) 14 Trial, fibrinolytic alone, abci.ximab alone, and combination therapy were compared. The fibrinolytic agents studied included alteplase, reteplase, and streptokinase. It was shown that combination therapy improved outcome. Not only is reperfusion accelerated and reocclusion minimized; the decreased dose of fibrinolytic agent required may reduce the risk of intracranial hemorrhage. The current standard of care is to use a reduced dose of fibrinolytic agent with GP Ub/Ula inhibitor therapy. Clinical evidence also suggests that combination therapy can reduce microvascular obstruction, which may lead to improved outcomes.
Interventional Stmke Therapy Outcomes Registry (INSTOR) The foregoing discussion demonstrates the uncertainty regarding the appropriate drug or combination of drugs (and dosages) for use in the emergency treatment of acute ischemic stroke. In addition, there is inadequate knowledge regarding the appropriate patient population and timing of therapy. A voluntary national regisby is therefore being established to acquire data concerning interventional therapy for the purpose of optimizing therapeutic outcomes for stroke victims. Data to be collected include patient demographics, agents and doses used, outcomes, and complications. The outcome at three months will be the primary measurement of efficacy. A standardized data collection form is being developed in order to facilitate the analysis of the data. The above discussion does suggest several treatment options. These include low dose intra-arterial alteplase or reteplase, high dose intra-arteriał alteplase or reteplase, combination intravenous and intra-arterial alteplase or reteplase, and combination intravenous abciximab and intra-arterial reteplase. In order to improve the likelihood of obtaining useful data, standardized protocols have been established for use at the discretion of participating physicians. The bolus and infusion doses of the agents are specified in the protocols, along with clinical and radiographic inclusion and exclusion criteria. Stroke Prevention Antiplatelet Therapy Antiplatelet therapy has been shown to reduce the risk of subsequent vascular events in patients with recent ischemic stroke or TIA. There are several oral antiplatelet agents that have been shown to be effective in clinical triais of patients with ischemic stroke and/or TIA. Ali are effective in preventing recurrent vascular events in pa-
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tients who have hacl an ischemic stroke. In general, in patients with ischemic stroke or TIA, antiplatelet therapy recluces the risk of subseqllent stroke, myocarclial infarction (MI) or vasclllar cleath by 22%. Aspirin works by inhibiting the enzyme cyelo-oxygenase in the platelet thereby inhibiting the procluction of thromboxane A2. The absence of thromboxane A2 leacls to inhibition of platelet aggregation. Tielopicline (Tielicl) ancl e1opiclogrel (Plavix) are thienopyriclines ancl inhibit platelet aggregation by blocking ADP bincling on the platelet sUI·face. Dipyramiclole inhibits the re-lIptake of aclenosine, a potent platelet inhibitor, by recl bloocl cells. The extenclecl release formulation of clipyriclamoJe ancl asp irin (Aggrenox) is supposecl to offer benefit over the immecliate release formulation (Persantine) by avoicling freqllent trough levels that are inacleqllate to maintain continllous inhibition of platetet function. Aspirin is a cost effective method of stroke prevention for most patients althollgh the optima I effective ciose remains unclear. Earlier triais leci to consensus recommenclations for higher closes of aspirin (>900 mg), however subseqllent studies of lower closes «325 mg) also established effectiveness. Few triais have clirectly comparecl high ancl low closes of aspirin. In 1998, the FDA proviclecl a statement recommclencling closes between 50 mg ancl 325 mg to prevent reCllrrent stroke. There is vely little clifference in effectiveness between the antiplatelet agents listecl above. They are al! effective ancl there is no elear eviclence establishing their benefit over asp irin alone. Although TASS repoltecl benefit of tielopidine over asp irin for redllcing stroke risk in patients with recent ischemic stroke or TlA, there was no effect on stroke-free sllrvival, ancl no clifference for the primary endpoint of preventing stroke and cleath (16). In the CAPRIE trial, approximately 20,000 patients with recent ischemic stroke, myocardial infarction or peripheral alteria! clisease were ranclomizecl to receive clopiclogrel or asprin (17). For the primary endpoint of MI, stroke Ol' vascular cleath, e1opiclogrel was more effective than aspirin but the relative benefit (9%) ancl absolute benefit (0.5%) was quite smalI. Also, for the patients entered in the CAPRIE trial with a recent schemic stroke there was no benefit of e1opiclogrel over aspirin. In the ESPS-2 triaj, patients with recent ischemic stroke 01' TIA were stucliecl lIsing combination therapy with extencleclrelease clipyramidole ancl low close aspirin (Aggrenox) (18). The combination therapy was shown to be more effective in preventing stroke than aspirin. However, the combination therapy was not more effective in preventing the primary enclpoint of stroke or cleath. The risk of serious bleecling is low with al! of the antiplatelet preparations. The more common but minor side effects may limil compliance. Aspirin containing preparations can cause clyspepsia, especially at the higher cIoses. Dipyramiclole containing preparations cause heaclache in some patients. C1opiclogrel appears to have fewer sicie effects compared with tiC!opicline ancl is preferrecl for this reason. Tielopicline causes neutropenia
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in about 2% of patients ancl requires blood monitoring evely 2 weeks cIuring the first 3 months of therapy. Many patients have an ischemic stroke or TIA while tak ing claily aspirin. These patients can be consiclerecl to have failecI aspirin therapy. Appropriate steps in management inelllde risk factor moclmcation and cIetermining the callse of the ischemic event. For patients with atria! fibrillation and possibly those with other cardiac or aortic conclitions, warfarin therapy is incllcatecl lInless there are conlrainclications. Patients with s/mptomatic caroticl stenosis ShOlllcl be consiclerecl for enclarterectomy. The benefit of changing to another antiplatelet regimen has not been establishecl but this seems appropriate. There are no stlldies of patients failing aspirin therapy to cletermine what the best antiplatelet regimen sholllcl be in this situation. AcceptabJe approaches inelucle using combination therapy with extendecl release clipyramiclole ancl aspirin 01' aspirin combined with clopiclogrel. Ongoing studies are testing the effect of this larter combination therapy in patients with ischemic stroke. Wa/jarin The relative benefit of warfarin verSllS aspirin differs depencling on stroke sllbtype. Warfarin is clearly more effective in patients with certain cardiac conclitions sllch as atria! fibrillation ONR 2.0-3.0), however, it is no berter than aspirin in patients without a carcliac source of embolism. The Warfarin Aspirin Recurrent Stroke Stucly (WARSS) showecl that aspirin (325 mg) ancl warfarin ONR 1.4-2.8) have eqllivalent effects in patients with ischemic stroke 01' TIA withollt a carclioembolic source (19). Evaluation of preclefinecl sllbsets of patients within WARSS also clicl not show benefit. For example, patients with a patent foramen ovaJe, those with anti-phospholipid antibodies, and those with aortic atherosclerosis did not clerive more benefit from warfarin than asp irin. This trial shows that carefll! consicleration of the llnclerlying etiology is requirecl when cIeciding whether to treat a patient with warfarin. There has been some concern expressed regarcling the lower range of INR vallles llsecl in the stucly. Critics have argllecl that the design of the trial clid not test the range most commonly llsecl (INR 2.0:-3.0). No relationship between INR value and the risk of recurrent stroke was fOllncl sllggesting that the reason for the łack of benefit of warfarin was not cllle to the range of INR vallles chosen. Statins Statin meclications were clesignecl to limit atheroselerosis but also appeal' to have aclditional beneficial effects by promoring plaqlle stabilization, provicling an anti-inflammatOlY effect (clecreasecl CRP) and redlIcing the risk of thrombosis. Clinical triais show a c1ecreasecl stroke risk in patients with coronaly anely clisease ancl moclest elevations of lipicls. No stucly has establishecl the benefit of stalin meclication in patients with ischemic stroke. Based
on the evidence of benefit in patients who are at risk for vascular events, statins should be considered in all ischemic stroke and TIA patients who have LDL levels higher than 130. Which statin is most effective in patients who have had an ischemic stroke or TIA has not been determined. An ongoing study will be the first to determine if atorvastatin is effective in patients with ischemic stroke or 11A (SPARCL). ACE lnhibitors Angiotensin converting enzyme inhibitors (ACE-!) were designed to treat hypertension. However, they have many other beneficial effects. These effeets include antiatherogenesis, endothelial celi modulation, and platetelet inhibition. Two studies of have shown a substantial reduction in stroke risk. The HOPE trial studied the effects of ramipril in patients at high risk for ischemic events and found a beneficial effect (20). The combined endpoint of MI, stroke or vascułar death was significantly reduced. Furthermore, the endpoint of stroke was also reduced. PROGRESS tested the effects of combining perindopril with a diuretic, indapamide, in patients with ischemic stroke, TIA or intracerebral hemorrhage and found that the combination therapy dramatically reduced the risk of recurrent stroke (21). No benefit for perindopril therapy alone was found although the study was not designed to test this. These two studies suggest that patients with stroke or TIA should be considered for treatment with an ACE-l especially if there are other vascular risk factors present. Combination therapy with a diuretic may be warranted to maintain łongterm blood pressure control and maximize benefit. National consensus guidelines on the use of ACE-I after stroke are needed to incorporate the nndings of these recently published clinical triaIs
References l. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. New Engl
J Med 1995; 333:1581-1587. 2. Furlan A, Higashida R, Weschler L, et al. lntra-arteria] prourokinase for acute ischemic stroke: The PROACT II study: A randomized controlled trial. JAMA 1999; 282:2003-2011. 3. Graor RA, OlinJ, Bartholomew JR, et al. Efficacy and safety of intraarteriał local infusion of streptokinase, urokinase, or tissue plasminogen activator for peripheraJ arteriaJ occlusion: A retrospective review. J Vasc Med Biol 1990; 2:310-315. 4. Ouriel K, Kolassa M, DeWeese JA, et al. Economic implications of thrombolysis or operation as the initiał treatment modality in acute peripheral arteria! occlusion. Surgery 1995; 118:810-814.
Combinecl intravenous and intra-arterial r-TPA versus intra-arterial therapy of acute ischemic sU"oke: Emergency Management of Stroke (EMS) Bridging Trial. Stroke 1999; 30:2598-2605 7 McNamara TO, ChenJL, Temmins CJ, et al. Bleeding associated with intrathrombus infusions of rt-PA for peripheral arterial and venous occlusion [abstractJ. Am J Cardiol 1999; 84(suppl 6A);37P. 8. Harker LA. Therapeutic inhibition of platelet function in stroke. Cerebrovasc Dis 1998; 8Csuppl 5);818. 9. Winkley JM, Adams HP Jr. Potentiał roje of abciximab in ischemic cerebrovascular disease. Am J Cardiol 2000; 8547c-5lc 10. The Abciximab in lschemic Stroke lnvestigators. Abciximab in acute ischemic stroke: A randomized, double blind, placebo controlled dose-escalation study. Stroke 2000; 31:601-609. 11. Wientz JR, Sanborn TA, Haudenschild CC, et al. Platelet accumuJation in experimental angioplasty: Time course and relation to vascular injUlY. Circulation 1987; 75:636-642 12. Coller BS. GP lIb/lIla antagonists: The first antiintegrin receptor therapeutics. J Clin Invest 1997; 99:1467-1471 13. Wagner CL, Cunningham MR, Wyancl MS, et al. Reversal of the anti-płatelet effects of chimeric 7E3 Fab treatment by płatełet transfusion in cynomolgus monkeys (abstract). Thromb Haemost 1995; 73:1586. 14. Topol EJ. Toward a new frontier in myocardial reperfusion therapy: Emerging platelet prominence. Circulation 1998; 97:211-218. 15. Antman EM, Giugliano RP, Gibson CM, et al. Abciximab facilitates the rate and extent of thrombolysis: Results of the Thrombolysis in Myocardial lnfarction (11M!) 14 Trial. Circulation 1999; 99:2720-2732. 16. Hass WK, EastonJD, Adams HP Jr, et al. A randomizecl trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Engl J Med 1989; 321:501-507. 17. CAPRIE Steering Committee. A randomised, blinded tria I of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE). Lancet 1996; 348: 13291339. 18. Diener HC, Cunha L, Forbes C, et al. European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondalY prevention of stroke. J Neurol Sci 1996; ]43:1-13.
5. Ouriel K Urokinase and the US Food and Drug Administration. J Vasc Surg 1999; 30:957-958.
19. Mohr JP, Thompson JL, Lazar RM, et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 2001; 345: 1444-1451.
6. Lewandowski CA, Frankel M, Tomsick TA, et al.
20. Yusuf S, Sleight P, Pogue J, et al. Effects of an
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angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Eng1 J Med 2000; 342:145-153.
• 1 of the 90 who received lA therapy was thought to have smali vessel disease as the cause of the stroke.
21. PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood pressure-lowering regimen among 6,105 individuals with previous strake or transient ischemic attack. Lancet 2001; 358:10331041.
Who Gets What? tPA Options Blood pressure, time windowand CT exclusions are strictly adhered to in aj[ of the following protocols. Specific consent forms are signed for off-labe1 use of tPA and when the stroke is severe, statistics regarding increased risk of hemorrhage are discussed with the family and patient (when possible). • lf the patient presents with a mild stroke (NIHSS 4-10) within the 3 hour window, we might elect to use IV tPA alone according to the FOA approved protoc01 of 0.9 mgm/kgm 10% bolus, the rest over one hour. (No special consent is required). • lf the patient with an NlHSS of 4 -1 Ohas aphasia or severe hemiparesis, we may e1ect to use the combined lV/lA pratocol usually reserved for more severe strokes (see next bul1et). • lf the patient has a moderate to severe stroke (NIHSS >10) within 3 hours, we administer IV tPA at 0.6mgm/kgm 15% bolus, the rest over 30 minutes and prepare to go to angiography. If the patient improves significantly, we may cancel the angiogram. lf, on angiography, we find a clot (usually lCA, T-lesion, MI, M2, or basi1ar) we use intraarterial tPA usual1y to a maximum dose of 20-25 mgm so that the total dose is approximately 0.9 mgm/kgm. • lf the patient has a moderate to severe stroke (NlHSS > 10) and presents after 3 hours but before 6 hours, we consider intra-arterial tPA a10ne, particularly if the CT head scan is negative. The dose of lA tPA will depend on a more sophisticated evaluation of how the col1aterals look on the angiogram. • Other situations in which lA alone is general1y se1ected include: post procedure (cardiac catheterization) cases, post-operative cases, patients on coumadin, very e1derly patients or patients with a remote history if intracranial hemorrhage. • If the patient is rapidly improving at 3 hours, we will hold the IV tPA and closely monitor the patient. lf deterioration occurs, the patient is taken to the angiography suite and given lA therapy if a clot is located. • If there is atotal lCA occlusion, we may push the catheter through the clot and search for a distal embolus which is often present at MI. We can then come back and angioplasty and stent the carotid Jesion. • For basilar attery occlusions and retinal artery occlusions, we may extend the 6-hour time windowo
2:50 p.m. Patient Se1ection for Interventiona1 Therapy Marilyn Reimel~ MD Mid-America Brain and Stroke Institute Saint Luke's Hospital Kansas City, MO Background The Stroke Center at Saint Luke's Hospital in Kansas City opened in 1993 with the goal of standardizing care for the large patient volume and coordinating communication among the many practitioners who are important in the management of stroke. No one had imagined routine acute intervention, and a neur010gist in the emergency roor~ was a reportable siting. Two peop1e changed the landscape. Graham Lee, MOa neurointerventional radiologist came to Kansas City from NYC because Kansas resembled the plains of Rhodesia where he grew up. Having trained with Dr. Berenstein in NYC, he had used intra-arteria1 urokinase to 1yse clots in acute stroke. His early successes in reversing strokes at Saint Luke's changed our mindset permanently. We viewed every case as a possible "save" unless proven othelwise by time or circumstance. When Tom Brott, MO al10wed the Saint Luke's team to be one of Cincinnati's contributing hospitals in the NlNOS tPA trial, we discovered "ful1 speed ahead." We became friends with EMS, bonded
with the nurses and physicians in the emergency department, and neurologists became as at home in the EO as the cardi010gists. Current Practice Since 1999, we have used tPA for intra-arterial (IA) as wel1 as intravenous (IV) 1ysis. A recent review of our interventional cases from January of 2000 tllrough June 2002 revea1ed the fol1owing data: • 142/781 08.2%) of ischemic strakes were treated with tPA • 52/142 (36%) IV; 55/142 (39%) lA; 35/142 (25%) IV folIowed by lA • Overall hospital mortality rate was 12.7% with the lowest rate in the IV group at 5.8%. • Symptomatic hemorrhage rate was 9.2% (IV = 1.9%, lA=14.6%, IV/lA=11.4%) • Patients who received lA therapy were statistical1y 01der and presented with a higher NIHSS score. • 57% (51/90) of patients who received lA therapy a10ne or in combination with IV therapy were found to have a cardiac source for the stroke.
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HolU This Works • The strake neurologist is the point person for these protocoJs.