INTERVENTIONAL USE OF PLASMINOGEN ACTIVATORS IN CENTRAL NERVOUS SYSTEM DISEASES

CURRENT CONCEPTS OF THROMBOSIS

0025-7125/98 $8.00

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INTERVENTIONAL USE OF PLASMINOGEN ACTIVATORS IN CENTRAL NERVOUS SYSTEM DISEASES Gregory J. del Zoppo, MD, and Arthur A. Sasahara, MD

Improvement in disability outcome, demonstrated by one large prospective placebo-controlled (level I) trial of intravenous recombinant tissue plasminogen activator (rt-PA) in acute ischemic stroke, supports the efficacy of PA delivery in clinical focal cerebral ischemia.l4IAlthough there has been considerable interest in the systemic delivery of PAS as a treatment modality, experience has provided a clearer view of the limitations and future requirements of this approach. A review of the experiences with invasive approaches for delivery of PAS in the central nervous system is warranted, in the light of the advances in systemic delivery. The early rationale for the acute delivery of PAS in acute cerebrovas42 In testing the cular thrombosis has been summarized el~ewhere.~~, potential for thrombolytic agents to mediate recanalization and improvement in disability outcome after ischemic stroke, a significant association with symptomatic hemorrhage has been e ~ p 0 s e d .The l ~ ~relative balance between efficacy and safety is particularly relevant for PAS in ischemic stroke. This article examines reported experience with interventional delivery of PAS in acute thrombotic or thromboembolic stroke, dural This work has been supported in part by grant NS 29645 of the National Institutes of Health.

From the Department of Molecular and Experimental Medicine, The Scripps Research Institute and the Division of Hematology/Medical Oncology, Scripps Clinic and Research Foundation (GJdZ), La Jolla, California; and the Department of Medicine, Harvard Medical School, and Brigham and Women’s Hospital (AAS), Boston, Massachusetts

MEDICAL CLINICS OF NORTH AMERICA VOLUME 82 * NUMBER 3 * MAY 1998

545

546

DEL ZOPPO & SASAHARA

venous sinus thrombosis, cerebellar hemorrhage, and retinal ischemia. Each of these approaches is experimental at present. The techniques and direction with each are in evolution. FOCAL CEREBROVASCULAR ISCHEMIA

The salient features of processes leading to focal cerebral ischemia of the brain and the relevance of this setting to PA delivery are summarized here. The rationale for the acute intervention with PAS in stroke rests on the premise that the majority of strokes result from arterialthrombotic events.42Approximately 80% to 90% of focal cerebral ischemic events presenting as ischemic strokes are due to atherothrombotic or embolic occlusions.135Angiography-based studies of symptomatic carotid territory arterial thrombosis have demonstrated that cerebral arterial occlusion decreases with time from stroke onset. Within 6 hours of symptom onset, 76% to 81% of patients had documented occlusions,38, 40, 47 which decreased to 58.7% at 24 and lower frequencies beyond.48,78 Within hours of arterial occlusion, recanalization spontaneously occurs in up to 16.7% of patients, as demonstrated in two small 152 Prospective angiography-based studies angiography-based have also shown that a number of PAS, by systemic or intra-arterial delivery, produce arterial patency in a frequency in excess of the 20% seen in thrombotic stroke patients who receive no treatment. The success of both approaches depends on occlusion location. For instance, occlusions of the proximal internal carotid artery (ICA) and carotid artery T have a lower recanalization frequency than middle cerebral artery (MCA) branch lesions when exposed to systemic, regional, or local PA infusion.36,40, 42, lo4,lo5*lo7 The most recent angiography-based studies have excluded patients with proximal ICA occlusions, including those with tandem ICA-MCA obstructions. HEMORRHAGIC TRANSFORMATION ACCOMPANYING FOCAL CEREBRAL ISCHEMIA

All PAS carry the risk of intracranial hemorrhage.', 42 The possibility that exposure of the ischemic zone to a PA may increase the size or severity of the hemorrhagic transformation that naturally accompanies the evolving infarct is the central safety issue. Hemorrhagic transformation consists of hemorrhagic infarction or parenchymal hematoma.'15,116 Hemorrhagic infarction refers to petechial or confluent petechial hemorrhage confined to the ischemic zone. Parenchymal hematoma is a homogeneous, discrete mass of blood (coagulum) that may extend to the ventricle and exert mass effect with shift of midline structures. It may lie within or outside the region of ischemia. The most clinically relevant presentation of fibrinolysis-associated hemorrhage is the development of clinical deterioration caused by hemor-

INTERVENTIONAL USE OF PAS IN CENTRAL NERVOUS SYSTEM DISEASES

547

rhagic infarction, parenchymal hematoma, or both, which may even lead to the patient’s demise. It is relevant to distinguish between neurologic deterioration caused by parenchymal hematoma and that caused by edema in association with hemorrhagic infarction (which would be otherwise silent), although the underlying mechanisms may be related.41 The radiographic distinction between severe hemorrhagic infarction and parenchymal hematoma is difficult in some cases. Hemorrhagic infarction is commonly observed in patients with carotid territory embolic stroke, occurring in 38% to 46% of patients.76,11*, 154 Parenchymal hematoma, which is most often ~ymptornatic,”~ seems to accompany acute carotid territory embolism more often in the setting of anticoagulant treatment.6, 57,82, 97 The suggestion that hemorrhagic transformation may result from arterial reperfusion is so far not supported by angiographic 40, Io5, Io6 Ogata et alllohave suggested that hemorrhage may occur from vascular sources other than the primary occluded artery 53 Experimental work, however, has indicated (e.g., collateral channels).52, that hemorrhage is associated with microvascular 69, 70 and may 59, 60, 64 be augmented by induced hyperten~ion.~~, Several factors contribute to thrombolysis-related hemorrhage in acute ischemic stroke. One prospective study of rt-PA (duteplase) indicated that extended time from symptom onset to PA exposure was associated with a significant increase in all hemorrhage types evident at 24 A post hoc analysis of two symptom-based studies of systemically administered rt-PA (alteplase) suggests that symptomatic hemorrhage was dependent on diastolic hypertension,S8 body mass,S8 age,S5 and signs of ischemic injury at baseline62in that setting. NEUROLOGIC STATUS AND ITS MEASUREMENT

Approaches and instruments for measuring neurologic outcome are in evolution, and their use varies geographically. Mortality has limited utility as an outcome in acute stroke trials because 1-year mortality generally does not exceed 15%, of which most is due to cardiovascular causes.128To date, large-scale mortality outcome trials of stroke treatments, similar to the International Stroke Trial (IST),140have not been developed for thrombolysis owing in part to (1) the need to assess neurologic status in a detailed way and (2) the contribution of hemorlgl rhage to mortality in rt-PA Stroke patients may display progressive improvement in the absence of treatment according to scoring instruments based on the neurologic examination (e.g., Scandinavian Stroke ScalelZ8).For PAS, the outcomes of recanalization frequency, regional blood flow, and measures of neurologic function and disability have been used. None of the neurologic scoring instruments (including the National Institutes of Health stroke scale (NIHSS),Zo,21, the Hemispheric Stroke Scale (HSS),lo7or modifications of specific scales152)used in acute ischemic stroke trials have been prospectively validated for long-term outcome,71although interobserver

548

DEL ZOPPO & SASAHARA

correlations for some scales have been published.90Prospective symptom-based, randomized, placebo-controlled trials of intravenous PAS have employed disability scores, described by the Rankin scalelZ1modified for death and the Barthel index?l as outcome markers. Data from the European Cooperative Acute Stroke Study (ECASS) suggests that the lack of benefit in functional outcome and neurologic recovery was due to a subgroup of patients with clinically significant cerebral injury who were at increased risk for hemorrhage or further deterioration after intravenous thrombolysis. Overall analysis suggests that when a subgroup of patients with early infarct signs, at high risk for poor outcome or hemorrhage, would have been excluded, 90-day disability outcome would have been favorably affected.35, Furthermore, defining the subgroup(s) represented by the excluded patients in advance of treatment is of major importance. The need to define subtle alterations on the initial computed tomography (CT) scans consistent with evolving ischemic injury that may place those patients at high risk for poor outcome has not been recognized for any series or trial of interventional PA delivery in acute ischemic stroke reported to date. Taken together, the ECASS and National Institutes of Neurological Diseases and Stroke (NINDS) studies indicate the enormous importance of patient selection to reduce the hemorrhagic risk that accompanies the use of PAS in stroke.62,141 It has been asserted that the interval from symptom onset to treatment to achieve clinical improvement varies individually." Collateral protection also varies individually. The two studies and their forebears4O.Io7, 153 indicate that improvement in outcome is feasible within a longer interval before treatment. Both studies suggest that at the current state of development, CT scans and neurologic scores at presentation do not completely identify those at risk for hemorrhage. Evidence of large hemispheric regions (>33%) of ischemic injury on entry CT scan, however, is associated with poor outcome. It is currently not possible to separate benefit from hemorrhagic risk in a given patient based on clinical presentation alone. Radiographic investigations are required. Carotid Artery Territory Ischemia

Clinical outcome is directly related to occlusion site in the MCA territory.lz6Specifically, 31.3% of patients (5 of 16) with MCA occlusions (M1 segment and M2 segment) and 29.4% of patients (5 of 17) with proximal M1 segment occlusions had fatal outcomes at 3 months, whereas the 3-month mortality among M3 branch occlusions was 14.3% (1 of 7 patients). In another study, M1 segment MCA occlusions were associated with a poor outcome in 87.5% of untreated patients.50In a population of stroke patients not selected by vascular diagnostic techniques, however, mortality may be substantially different. Substantial neurologic improvements in patients with carotid territory infarction were noted by Fieschi et a147when the baseline Canadian Neurological

INTERVENTIONAL USE OF PAS IN CENTRAL NERVOUS SYSTEM DISEASES

549

Scale score was 6.5 or greater (normal, 10.0).31Those observations and the relationship of subtle signs of ischemic injury on baseline CT scan to poor outcome suggest that neurologic outcome, symptomatic hemorrhage, and stroke-related mortality are related to the severity of the ischemic injury. In carotid territory stroke, the consequences of PA exposure are likely to depend on the severity of injury.

Vertebrobasilar Artery Territory Ischemia

The clinical outcome of brain stem infarction follows one of two 51,81, 158, 159 One is characterized by high mortality or severe di~ability.~, 24, 83 An 86% mortality was observed among 22 consecutive patients with vertebrobasilar artery occlusions treated with antiplatelet agents, anticoagulants, or both.63A separate, more benign course is associated with only minor or transient brain stem symptoms at 16, 18, 23, 46, 49, 114 The latter patients would not be considered pre~entation.~, candidates for PA treatment. In general, patients with milder deficits in the carotid artery or vertebrobasilar territories are more likely to fare better than those with severe deficits. Mortality or ultimate neurologic status is generally a poor indicator of the anatomic location of the occlusion. Although neurologic deficits reflect occlusion location, the clinical deficits do not invariably correlate. Disability outcomes are reasonable targets as outcome measures for treatment trials in acute ischemic stroke. Patients with moderate carotid artery territory or moderate to severe vertebrobasilar artery territory ischemic symptoms are taken as appropriate candidates for PA exposure.

profile^.^, 17, 24-26,

ACUTE THROMBOTIC AND THROMBOEMBOLIC STROKE

The primary advance in the application of PAS to ischemic stroke has come with acceptance that arterial recanalization must occur within the early minutes to hours of focal cerebral ischemia for neurologic recovery to be signifi~ant.~~ The effects of intra-arterial local delivery fibrinolysis in acute carotid territory ischemia on arterial recanalization, hemorrhagic transformation, and neurologic outcome have been addressed by many anecdotal (level IV and V) and phase I (level 111) doserate finding but only one phase I11 (level I) clinical trial. Although favorable clinical outcome associated with recanalization has been suggested by several studies, only one prospective placebo-controlled trial has been undertaken to prove this concept.38Acute vertebrobasilar ischemia has provided a less rigorously explored venue for thrombus lysis.

550

DEL ZOPPO & SASAHARA

PLASMINOGEN ACTIVATORS

Thrombolytic agents are PAS that convert the inactive zymogen to plasmin. The endogenous fibrinolytic system is comprised of plasminogen, PAS, and inhibitors of fibrinolysis. Tissue-type plasminogen activator (t-PA), single-chain urokinase plasminogen activator (scu-PA), and urokinase plasminogen activator (u-PA) are endogenous PAS.^, 8* 30, 147 Exogenous fibrinolysis is achieved by t-PA, u-PA, and scu-PA and by substances of exogenous origin, including streptokinase (SK), acylated plasminogen streptokinase activator complex (APSAC), staphylokinase, PAS of vampire bat origin, and other novel agents that generate plasmin.80,131, 146*147 The fibrin matrix of the thrombus offers a platform for plasminogen activation, whereas receptors for plasminogen on polymorphonuclear neutrophil leukocytes, platelets, and endothelial cells enhance local plasmin production.118Plasminogen is a single-chain 92-kD glycoprotein serine protease containing 791 amino acids that exists in two forms: gluplasminogen and lys-pla~minogen.~, 55 Both t-PA and u-PA catalyze the conversion of glu-plasminogen to lys-plasmin through either of two intermediates, glu-plasmin or lys-pla~minogen.~~~ The use of PAS in cerebrovascular disease is now confined to the acute setting. Presently, only rt-PA (alteplase) is licensed for clinical use in acute ischemic stroke and that by systemic delivery within 3 hours of symptom onset under strict 1imitati0ns.l~~ Hence, a substantial increase in the number of patients displaying no or minimal disability could be achieved among patients treated within 3 hours of symptom onset with rt-PA in this study. On this basis, alteplase received approval for clinical use in acute ischemic stroke in the United States by the Food and Drug Administration with strict limitations. Tissue-Type Plasminogen Activator

A single-chain 527 amino acid serine protease glycoprotein, t-PA is converted to the two-chain form by plasmin cleavage of the is01eu~~~ linkage.122, lz4 The catalytic efficiency of single-chain and twochain t-PA for in vitro conversion of plasminogen to plasmin is stimulated to similar activity in the presence of fibrin.119, lZo, lW The preferential cleavage of fibrin (in the presence of fibrin-bound plasminogen) over fibrinogen in vitro and in vivo suggests that both t-PA species have relative fibrin-selective properties.", 12* In humans, infusion studies of both t-PA species have demonstrated a half-life of 3 to 8 minutes, although the biologic half-life is believed to be somewhat longer. rt-PA has been prepared in single-chain (alteplase) and in two-chain (duteplase) form. Urokinase

High-molecular-weight u-PA (54 kD) is a fibrin-nonselective serine protease that converts plasminogen to plasmin directly by first-order

INTERVENTIONAL USE OF PAS IN CENTRAL NERVOUS SYSTEM DISEASES

551

kinetics.15,54, 137, 150 u-PA exists as a low-molecular-weight species (32 kDa), which is the current commercially available urokinase, derived from tissue cultures of human neonatal kidney cells.61Infused highmolecular-weight u-PA has a plasma half-life of 4 to 5 minutes, and lowmolecular-weight u-PA has a half-life of 12 to 13 minutes.

Single-Chain Urokinase Plasminogen Activator scu-PA is a 54-kD endogenous fibrin-selective proenzyme of u-PA that is unusual in generating plasmin at the thrombus s ~ r f a c e . ~89, The relationship of scu-PA to u-PA is complex. Cleavage or removal of lys15* of scu-PA produces the high-molecular-weight (54 kDa), two-chain u-PA, whereas further cleavages at lys135and produce low-molecular-weight (31 kD) U-PA.'~~ Both high-molecular-weight and low-molecular-weight species are enzymatically active in vivo.

Streptokinase SK, a 47-kD glycoprotein product of Streptococcus hemolyticus (group G), activates plasminogen to plasmin by complex kinetics. Active SK/ plasminogen and SK/plasmin species are generated. Free circulating plasmin and complexed SK/plasmin(ogen) degrade both fibrinogen and fibrin and inactivate prothrombin, factor V, and factor VIII,*9,27 thereby producing a systemic Zytic state similar to that produced by u-PA. Doserate adjustments with SK are difficult because of the nonstoichiometric generation of plasmin and, to a larger degree, the inactivation of an unknown quantity of infused SK by circulating antistreptococcal antibodies. Extreme hypoplasminogenemia may occur, limiting the activity of an SK infusion.

Acylated Plasminogen Streptokinase Activator Complex APSAC is an inactive complex of acylated human lys-plasminogen and streptokinase with fibrin-binding properties owing to the lys-plasminogen kringles. Plasmin is generated by streptokinase within the complex by hydrolytic activation of the acyl-protected, plasminogenactive The biologic activity of APSAC is believed to be longer than that of streptokinase,96,132 and the hypofibrinogenemia and inactivation of factors V and VIII is similar to that produced by SK. APSAC has been used in only a small number of stroke patients in preliminary studies.

552

DEI, ZOPPO & SASAHARA

Novel Thrombolytic Agents A number of PA constructs have been prepared with the intent to enhance thrombus lytic potency, shorten half-life, extend half-life, alter clearance, or take advantage of known synergistic actions. These constructs include single-site t-PA mutants, t-PA/scu-PA and t-PA/u-PA chimera,’17 u-PA/antifibrin monoclonal antibody conjugates,’25and scuPA deletion mutants.58Mutants of t-PA, including TNK, r-PA, and n-PA, have altered clearance and therefore different half-lives than rt-PA. None have so far been used in the clinical treatment of cerebrovascular disease.

DIRECT INTRA-ARTERIAL DELIVERY OF PLASMINOGEN ACTIVATORS Early difficulties with the local intra-arterial delivery of PAS in stroke revolved around dosage adjustments of the thrombolytic substances themselves and the delivery systems. Fibrinolysin, thrombolysis, and plasmin were replaced by SK and u-PA, which had greater stability and ease of use. Limitations of early studies included (1)uncertain dose rates and duration of PA infusion, which was not standardized or uniformly controlled; (2) simple delivery systems; (3) little information on the natural history of atherothromboembolic stroke; (4) the development of hemorrhagic transformation; and (5) the inability to exclude hemorrhage as a cause of stroke symptoms. Thus, the true relationship of vascular occlusion, recanalization, fibrinolytic agent, and neurologic outcome could not be evaluated. Progress in this area has come with the development of guidewire-directed catheter delivery systems and the application of radiographic techniques for evaluation of the extent of injury. Direct intra-arterial infusion of plasminogen activators (e.g., u-PA, rt-PA) within hours of the onset of focal cerebral ischemia requires navigation of a microcatheter into the occluded artery and placement of the tip into the thrombus. Although practice varies, directed infusion of several doses followed by frequent interval angiography may be req ~ i r e dPulse . ~ ~ delivery and mechanical disruption of the occlusion before clot lysis have been reported,’O but the efficacy and relative safety of these variations have not been evaluated prospectively. Carotid Territory Ischemia Studies of direct intra-arterial infusion of PAS have established the feasibility of arterial recanalization in acute carotid artery territory stroke patients (Table l).155, 157 Following the reports of single or small case series? 29, 98, loo, lo8,ls7 larger prospective open trials of regional or local infusion u-PA or SK have documented recanalization of acute carotid 63, 95, lol, lo4, artery territory or vertebrobasilar artery territory 0cc1usions.~~~ ’05, 14*, 157 Consideration of angiography-based series suggests that direct

wl wl W

1-24 1-24 0.8-7 2-504 1-24 4.0 <6.0

activator; rt-PA

=

-

1

-

9-72

A(T-0) (h)

1.0-4.0 1.o 0.2-0.5 <1 .o 0.2-0.5 2.0 2.0

0.2-0.5 0.5-7.0 0.5-1 .O

Duration (h)

R R IIR I IIR IIR IIR IIR I I

R

R

Infusion 3 1 1 3 18 2 10 12 24 29 15 2

N (100.0) (100.0) (100.0) (100.0) (90.0) (66.7) (45.5) (100.0) (60.0) (93.5) (57.7) (14.3)

(%)

Recanalization

3 1 0 3 16 1 18 9 27 25 13 9

nil 0 0 0 0 4 1 1 1 9 6

HI

13* 5*

0 0 0 0 0 1 3 2 4 0

PH

(“h)

(18.2) (25.0) (32.5) (0.0) (50.0)* (35.7)*

(20.0)

Hemorrhage

0.0 15.4 14.3

-

0 0 0 0 0.0 1 13.6 16.6

% With Deterioration

= hemorrhagic infarction; PH = parenchymal hematoma; SK = streptokinase; u-PA = urokinase plasminogen recombinant tissue plasminogen activator; rscu-PA = recombinant prourokinase; R = regional; I = interventional.

3 1 1 3 20 3 22 12 40 31 26 14

Patients

A(T-0) = lntefval from symptom onset to treatment; HI

+ PH.

F P T P SWu-Pa rt-PA U-PA SWU-PA U-PA rt-PAh-PA rscu-PA Placebo

Clarke and ClifftonZ9 Atkin et aI5 Meyer et alga Miyakawaqoo del Zoppo et aP6 del Z o ~ p o ~ ~ Mori et allos Theron et all4* Matsumoto and Satohg5 Zeumer et alls6 del Zoppo et a P

*HI

Agent

Reference

Treatment

Table 1. INTRA-ARTERIAL DELIVERY OF PLASMINOGEN ACTIVATORS IN THE CAROTID ARTERY TERRITORY

554

DEL ZOPPO & SASAHARA

intra-arterial deliveryz9produced a superior recanalization frequency to intravenous delivery,138although no direct comparison has been made to date. Arterial recanalization has been reported in 46% to 100% of patients with carotid territory focal ischemia who received a PA by direct arterial infusion. Among 125 patients treated locally with u-PA, SK, or rt-PA from four prospective open studies, 90 (72.0%) underwent complete or partial recanalization after intra-arterial infusion.36,95, Io5, 142 In general, patients in those trials were entered from 0.2 to 6.0 hours from symptom onset, although exceptionally some patients received the agent up to 24 hours after the initial symptoms.36Z e ~ m e r , del ' ~ ~Zoppo et a1,3'j and Mori et allMdemonstrated the feasibility of recanalization and the safety of the angiographic techniques as applied in the acute phase. In addition, del Zoppo et a136indicated the benign outcome of hemorrhagic infarction occurring during the period of thrombolysis, and Mori et allo4demonstrated that recanalization was associated with significant reduction in the infarction volume by CT scan. In these series, ICA occlusions were more resistant to recanalization than distal MCA o b ~ t r u c t i o n sIo5 , ~ an ~~~ observation also made in two angiographic studies of intravenous infulo7Others have confirmed that directed infusion sion rt-PA (d~teplase).~~, of u-PA or SK could contribute to early reperfusion of documented symptomatic carotid territory 0cc1usions.~~~ 142 The development of thrombus (fibrin)-selective PAS has not obviated the option of their direct intra-arterial delivery in the central nervous system. Here, thrombus selectivity would be irrelevant if regional delivery into the anterograde stagnant blood column is made because thrombus localization would be inefficient if it depended almost exclusively on diffusion. The first use of t-PA (melanoma-derived) in carotid territory occlusions by del Z o ~ p had o ~ a~ mixed outcome. Subsequently, Zeumer et described successful recanalization with rt-PA (alteplase) in the carotid artery and ophthalmic artery circulation^.^^ Zeumer et extended the experiments to vertebrobasilar territory occlusions. Twentynine of 31 (93.5%) patients with carotid artery territory occlusions displayed complete recanalization of the primary affected artery, resulting in only 19.4%hemorrhagic infarctions. No hemorrhage-related deterioration was observed. Similarly, Ohtaki et al"' reported recanalization of ICA, MCA, or basilar artery occlusions in 51 patients after direct superselective catheter delivery of u-PA or rt-PA within 10 hours of symptom onset. One fatal parenchymal hematoma occurred in a patient with an M1 MCA occlusion (3.9%), whereas asymptomatic hemorrhagic transformation occurred in 5 of 26 (19.2%)MCA patients and 2 of 13 (15.2%)ICA patients by 24 hours. This is representative of the large Japanese experience in the intensive application of PAS in acute ischemic stroke.lZ7 A number of small series supporting the feasibility of recanalization by intra-arterial u-PA or rt-PA have subsequently appeared.'O, 13, 28, 73, 79, 87, lo9,139 Reports combining intra-arterial thrombolysis with other vascular

INTERVENTIONAL USE OF PAS IN CENTRAL NERVOUS SYSTEM DISEASES

555

techniques have also appeared.I2,136 Among these, Higashida et a173 described recanalization in 37 of 45 (82.2%) acute cerebral arterial occlusions with intra-arterial u-PA and clinical improvement in 18 of 27 (66.7%) patients. Three treatment-related symptomatic hemorrhages and one arterial perforation occurred. Nine patients died within the followup period. Barnwell et allo reported recanalization in 10 of 13 (76.9%) patients treated for thromboembolic occlusions of the intracranial carotid artery or basilar artery territory. Clinical improvement was observed in nine patients within 48 hours. Among those, three suffered hemorrhagic infarction, and three died. By contrast, Jansen et a179reported successful recanalization in only 2 of 16 (12.5%) patients with thromboembolic occlusions of the intracranial ICA using either u-PA or rt-PA. Among those treated, eight patients suffered intracranial hemorrhage, and nine patients succumbed. Only one patient experienced a good clinical outcome. Technical feasibility has been confirmed by those studies, but apparent clinical outcome has varied considerably. Generally, hemorrhagic transformation occurred in 20.0% to 32.5% of treated patients in the four studies employing consistently similar 95, lo5, 14* excluding the report by Zeumer et al.I5'j selection Overall the incidence of parenchymal hematoma (mostly symptomatic) in 94 patients was 10.6% and hemorrhagic infarction was 14.9%. The most recent reports for the most part have supported the earlier experience, except that of Jansen et al.79Because carotid artery territory ischemia is associated with a significant incidence of hemorrhagic infarction and parenchymal hematoma, it is unclear whether the mean 11%parenchymal hematoma incidence associated with PAS would be different from placebo-treated patients with identical lesions. Similarly the relationship of hemorrhagic transformation and recanalization to overall outcome is uncertain in those series. Clinical outcome, recanalization, and hemorrhage frequency have been approached in one level I prospective placebo-controlled phase I1 trial. The ethical basis for conducting proper level I trials of an interventional procedure in acute ischemic stroke have been presented.37To this end, the Prolyse for Acute Cerebral Thromboembolism (PROACT) trial was designed to compare two doses of recombinant scu-PA with placebo in a prospective, double-blinded, dose-rate finding phase 1/11 format.3s The study randomized patients 2:l to recombinant scu-PA or placebo, delivered over 2 hours (with repositioning of the catheter). Recanalization was the principal outcome. Of 1314 patients screened, 105 underwent angiography, and 46 had complete occlusions of the M1 or M2 MCA. A significant increase in 2-hour recanalization was associated with 6 mg/kg recombinant scu-PA and heparin over placebo and heparin when the mode of delivery was controlled. Hemorrhagic transformation within 24 hours of treatment occurred in 11 (42.3%) patients in the recombinant scu-PA group compared with one (7.1%) patient in the placebo group (2P = .030). Hemorrhagic transformation causing neurologic deterioration within 24 hours of treatment occurred in four (15.4%) of the recombinant scu-PA UK-treated patients, and one (7.1%) placebo-

556

DEL ZOPPO & SASAHARA

treated patient (2P = .64). Both the frequency of recanalization and hemorrhagic transformation were directly dependent on heparin dose. Regarding the safety of the radiographic procedures, adverse clinical events followed angiography in five patients, including transient vasospasm of the catheterized cavernous internal carotid artery (neurologic deterioration was attributed to the signal stroke), a seizure during the screening angiogram with neurologic worsening and demise, and neurologic worsening after the 120-minute angiogram in each of three placebo patients. Among two patients who received recombinant scu-PA, one suffered acute worsening of chronic renal insufficiency owing to the radiocontrast agent, and a second was unable to handle oral secretions during the infusion, developed an aspiration pneumonia, but subsequently improved. Injection site hemorrhages occurred in 10 patients, one of which required transfusion. The study was underpowered to address clinical outcome adequately. Although there was a clear interaction between heparin and scu-PA in this study, the feasibility of undertaking this type of study was clearly shown. The relationship of the adverse events to the procedures and whether the number of events was excessive must await evaluation of larger treatment cohorts. Vertebrobasilar Territory Ischemia

The potential for poor outcome associated with vertebrobasilar ischemia has prompted a search for measures that may manage the underlying thrombotic cause (Table 2). Nenci et allosfirst reported successful complete recanalization without hemorrhage in four patients with vertebrobasilar ischemia treated within 6 to 96 hours of symptom onset with either SK or u-PA. A single-site retrospective comparison of clinical outcome and recanalization efficacy in 43 patients with vertebrobasilar ischemia who received either SK or u-PA with 22 patients who received conventional antiplatelet and anticoagulant therapy has been reported.63Of the 43 patients with technically successful interventional procedures, 14 of 19 (73.7%)who achieved complete recanalization survived, whereas only 4 of the 23 (17.4%)patients who received anticoagulants survived. A significant association between recanalization and survival and between recanalization and improved outcome has been suggested.63In the treated group, two patients had hemorrhagic infarction and two patients had parenchymal hematoma, and three patients deteriorated. So far, no prospective controlled study of sufficient power has yet reproduced that observation. reported Matsumoto and Sat0h,9~Mobius et al,'O' and Zeumer et recanalization in 40.0% of patients with vertebrobasilar thrombosis who ~ ~of , patients received u-PA by regional infusion95and 77.8%'07or ~ O O Y O '157 receiving u-PA/SK or u-PA by direct infusion. Of 18 patients who received either u-PA or SK in the study of Mobius et al,lo1 10 of 14 patients who displayed recanalization within the 2-hour therapeutic period had at worst moderate residual deficits, whereas all 4 patients

v

m m

SWU-PA SWU-PA u-PA SWU-PA u-PA rt-PNu-PA U-PA U-PA U-PA

Nenci et allm Hacke et aP3 Zeumer et all5’ Mobius et aPi Matsumoto and Satohg5 Zeumer et aP6 Becker et all4 Cross et a132 Wijdicks et alisl

9

4 43 7 18 10 28 12 20

Patients

-

<12 14-79 2-1 3

-

3-24

6-96 <24 4-48

A(T-0) (h)

<3.6

-

activator; rt-PA

=

recombinant tissue plasminogen activator; R = regional; I =

interventional.

=

I

IIR

I IIR

I I R

R I

Infusion 4 19 7 14 4 28 10 13 7

(100.0) (44.2) (100.0) (77.8) (40.0) (100.0) (83.0) (65.0) (77.8)

Recanalization, N (%)

26 10 17 8

g

6 14

39

4

nil

parenchymal hematoma; SK = streptokinase; u-PA

0.3110-44 <4/12-48 2 2 0.2-0.7 2

Duration (h)

A(T-0) = Interval from symptom onset to treatment; HI = hemorrhagic infarction; PH

Agent

Reference

Treatment

Table 2. INTRA-ARTERIAL DELIVERY OF PLASMINOGEN ACTIVATORS IN THE VERTEBROBASILAR ARTERY TERRITORY

=

-

2 3

0

0 2 0 0 1

PH

(14.3) (0.0) (10.0) (0.0) (16.7) (15.0) (0.0)

(9.3)

(0.0)

urokinase Plasminogen

1

-

0 2 1 0 0 2

HI

Hemorrhage

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who did not display recanalization died.'O* Similarly, three of four patients with basilar artery occlusion treated by Matsumoto and S a t ~ h ~ ~ who displayed recanalization had fair or good clinical outcome, whereas three of six patients who did not undergo recanalization had similar outcome. Those with progressive symptoms at outset seemed to fare worse than those with sudden onset of symptoms. Becker et all4 reported recanalization in 10 of 12 (83.3%) patients with direct infusion u-PA by a microcatheter embedded into the face of the arterial thrombus. Here an initial 1- to 2-hour infusion was followed by a prolonged low-dose infusion, intended to prevent rethrombosis. Of the patients who underwent recanalization, 60% succumbed because rethrombosis occurred in three patients, all of whom died. Coma and quadriparesis on presentation seemed to increase risk; all three patients with these conditions died. Two (16.7%)patients of this series suffered symptomatic and fatal intracerebral hemorrhage. It should be noted that atheroma-based thrombosis is generally treated with anticoagulants. Cross et a132demonstrated a somewhat lower frequency of recanalization with u-PA in 13 of 20 (65.0%)patients with vertebrobasilar thrombosis. Symptomatic hemorrhage complicated the outcome of three (15.0°/0) patients in this series. Wijdicks et al,lsl in an exploratory effort, demonstrated recanalization of acute basilar artery occlusion with u-PA in seven of nine (77.8%) patients leading to full recovery in five (two of whom presented with locked-in syndrome). Treatment was performed up to 12 hours in this series. Another report described experience with 16 patients with acute vertebrobasilar thromboembolism enrolled in a pilot study of intraarterial u-PA treatment.99In all 11 cases in which the microcatheter was placed into the thrombus itself, the initial attempt at recanalization was successful. Two patients with evidence of atherosclerosis, however, experienced reocclusion within 24 hours. In five cases in which technical difficulties forced placement of the catheter proximal to the occlusion, recanalization was achieved in only two. Clinically significant hemorrhage occurred in two patients who received 1 million IU u-PA. A patent artery significantly correlated with survival; 10 of 11 patients (90.9%) with patent arteries were still alive after 6 months, but 4 of the 5 (80.0%) with persistent occlusion had died. Nine of the 11 survivors (82.0%) achieved a good functional outcome; two were severely disabled. The ability of regional and local intra-arterial infusion of rt-PA (alteplase) to achieve recanalization has been the subject of a small number of reports.22,72* Io2 These are in concert with the larger series employing u-PA or SK. In general, however, the premise suggested by the anecdotal series noted previously must be confirmed by appropriately controlled studies of direct intra-arterial infusion of PAS. These and other reports indicate that early recanalization of symptomatic occluded arteries of the vertebrobasilar system is associated with improved survival. Reocclusion is more likely to occur when atherosclerosis complicates midbasilar flow and anticoagulants are not Time to treatment is relevant but is confounded by the variable symptom

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course associated with this disease. Coma and quadriparesis on presentation auger poorly, but anecdotal reports of recovery have appeared. The precise limitations of this approach have not been tested prospectively, however.63,99, 157 FEASIBILITY AND SAFETY CONSIDERATIONS OF DIRECT INTRA-ARTERIAL TECHNIQUES

Cerebral angiography is critical to document the occlusion site, correlate it with clinical symptoms, and evaluate objectively the recanalization efficacy of the proposed treatment, in addition to placement of the delivery catheters. The safety and efficacy of cerebral angiography have been evaluated. It is the standard to which all current imaging modalities are compared for eva1~ation.l~~ Mani et a192-94 reported experience with 5000 patients studied by conventional catheter cerebral angiography over a 6-year period at four medical centers. All patient records were analyzed for adverse events occurring before, during, and for 48 hours after the cerebral angiogram. A total morbidity of 1.4%, with an incidence of permanent complications of only 0.1%, and a mortality of only one patient (0.02%) were reported for that series. A number of reports have appeared from centers experienced in the use of microcatheter systems for intra-arterial delivery that give a view 65, 67, 74, 75, 86, 14* Halbach et aF6 of the safety of these techniq~es.~~, reported a 5-year experience of 1200 interventional endovascular procedures using microcatheter systems in the central nervous system. Technique-related complications caused by placement of the microcatheter into the targeted blood vessel included 15 perforations and dissections of intracerebral blood vessels (1.25%).Those consisted of perforation of a normal vessel in six cases, disruption of a dysplastic vessel or aneurysm in five cases, and fluid overinjection in four cases. There were two deaths and three long-term sequelae in this group, accounting for five (0.42%) permanent complications among the 1200 cases.66That report argues for the conduct of intra-arterial procedures in centers with significant experience. As denoted by the PROACT study, care must be taken in safety assessments to distinguish the consequences of focal ischemia and the PA from the interventional procedure. OTHER VENUES FOR DIRECT INFUSION THROMBOLYSIS Retinal Vascular Ischemia

The usefulness of PAS in retinal artery or retinal vein occlusion was examined by K ~ a a nPartial . ~ ~ to complete visual recovery was described even when retinal vein occlusion was treated with intravenous SK within 2 weeks of symptom onset. Freitag et a156have noted that partial recovery

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of form vision was possible in some patients with acute retinal artery occlusion treated up to 33 hours after symptom onset. That study confirmed a similar previous experience with microcatheter delivery of uPA.129Neither approach has been formally tested in prospective, placebocontrolled formats in a larger population, however. Dural Sinus Thrombosis Dural sinus thrombosis is associated variably with headache, altered mental status, focal neurologic deficits, seizures, and death. Management has varied from observation to aggressive treatment. The first report of local thrombus lysis with u-PA appeared in 1988I3Odescribing a healthy subject with a 24-hour history of headache progressing to coma. Thrombosis of the dural sinuses was diagnosed by CT and cerebral arteriography before placement of an infusion catheter in the parietal segment of the superior sagittal sinus. Continuous infusion of u-PA for 11 hours was required for evidence of thrombus dissolution, after which the patient’s level of alertness and function gradually improved. Separately, 13 patients with dural sinus thrombosis, 4 with symptoms for a month or longer, received u-PA by selective catheterization via the internal jugular vein, which was accessed via the femoral vein.77 Patency of the sinus was achieved in 12 of the 13 patients (92%), all of whom had good or excellent clinical outcome. Tsai et infused lower doses of u-PA directly into the occluded sinus of five patients, all of whom recovered completely, without any residual deficits. In contrast, Smith et treated seven patients with symptoms for 1 week to 6 months; u-PA infusions ranging from 88 to 244 hours were required, but all patients improved. Cerebellar Hematoma Local infusion of u-PA has been employed in intracranial disease to assist in the evacuation of cerebellar hematomas. Mohadjer et allo2 performed stereotactic puncture and fibrinolysis with urokinase in 14 patients with cerebellar hemorrhage. This procedure was performed 10 to 96 hours after the acute event. CONCLUSIONS Growing evidence supports the rigorous study of interventional techniques for the direct intra-arterial infusion of PAS in treatment for acute cerebrovascular ischemia in which thrombotic occlusion is documented. Appropriate prospective controlled trials are required to evaluate (1) the safety of the PA regimen and the delivery techniques, (2) the

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range of treatment windows in the carotid and vertebrobasilar territory, (3) applicable dose rates, and (4) the overall effect on disability outcome adjusted for mortality. Despite the growing use of this approach, it is evident that it remains experimental, in part because of unresolved safety concerns. It should be confined to usage under ethically acceptable protocols and study formats. Those venues should take into account the following observations: 1. Recanalization of carotid and vertebrobasilar territory occlusion is technically feasible within 3 to 6 hours of symptom onset. 2. Complete thrombotic occlusions of the cervical ICA are more resistant t o thrombolysis than occlusions of the stem and major branches of the MCA. 3. Direct infusion of PAS into the carotid artery territory is feasible, but the relative risk of hemorrhagic transformation and benefit of outcome have not been determined. 4. Rethrombosis may accompany recanalization of atheroma-based thrombotic occlusions of the basilar artery if appropriate anticoagulation is not undertaken. 5. An increased frequency of hemorrhagic transformation accompanies the use of fibrinolytic agents and is significantly increased by delayed intervention, diastolic hypertension, dose, and presence of severe ischemia on baseline CT scan.

As with the use of PAS in retinal vascular thrombosis, sinus venous thrombosis, and cerebellar hematoma formation, their use by direct intra-arterial infusion in symptomatic cerebral arterial thrombosis requires formal evaluation. ACKNOWLEDGMENT The authors are grateful for the expert preparation of this manuscript by Marcia Filbert.

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