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Systemic rtPA in Patients with
Acute Ischemic Stroke

Wolf-Dieter Heiss, MD

Max-Planck-Institut für neurologische Forschung, Köln, Germany

INTRODUCTION
   With an incidence between 150 and 300/100.000/year and a mortality between 32 and 164/100.000/year ischemic stroke is the leading cause of disability worldwide (Murray and Lopez, 1997) and an enormous burden to economy. Until recently, very little treatment to improve neurologic outcome could be offered and the attitude toward acute ischemic stroke was predominantly nihilistic.

   Despite improved understanding of the mechanisms leading to ischemic cell damage (Siesjö, 1992; Barone and Feuerstein, 1999; Dirnagl et al., 1999; Schulz et al., 1999) the search for agents that effectively prevent damage to the ischemic brain has been discouraging (Grotta, 1994). However, since all further molecular and biochemical alterations contributing to the cascade of ischemic damage are initiated by the disturbance in flow the restoration of sufficient perfusion must be the predominant aim in the treatment of acute ischemic stroke. This concept which was neglected in most studies with neuroprotective agents over many years is supported by the demonstration that in the largest proportion (~ 70 %) of the final infarct flow is critically decreased i.e. below the threshold for maintaining morphological integrity in the first hours after the attack (Heiss et al., 1999).

THE CONCEPT OF THE PENUMBRA
   Ischemic tissue is only amenable to therapy as long as the lack of blood supply did not lead to morphological destruction and only caused functional impairment.

   This tissue, termed penumbra by Astrup et al. (Astrup et al., 1981) is perfused at a level within the thresholds of functional impairment and morphologic integrity and has the capacity to recover if perfusion is improved. The extent of this tissue compartment of penumbra is dependent on residual flow and duration of flow disturbance (review in Heiss and Graf) (Heiss and Graf, 1994) (Figure 1). Its volume is large and involves even the center of ischemia immediately after onset of perfusional disturbance, and it becomes progressively smaller with time elapsed since the vascular attack (Figure 2). This concept as developed in animal experiments defines the penumbra as a dynamic process depending on residual perfusion and duration, with conversion into irreversible neurons propagating over time from the center of ischemia to the neighboring tissue (Figure 3). This concept explains the time window of therapeutic opportunity which is variable and ill-defined: it is very short for the core of ischemia and may extend to several hours in the moderately ischemic surrounding tissue (Figure 2). With functional neuroimaging modalities penumbral tissue can be identified in patients early after ischemic strokes.

Fig. 1: Diagram of cerebral blood flow (CBF) thresholds required for the preservation of function and morphology of brain tissue. The development of single cell necrosis and infarction is dependent on the duration of time for which CBF is impaired below a certain level. The solid line separates structurally damaged from functionally impaired but morphologically intact tissue (the "penumbra"), and the dashed line distinguishes viable from functionally impaired tissue.

Fig. 2: Diagram of ischemic area distinguishing between dense ischemia in the core and moderate ischemia in the penumbra.

Fig. 3: Reconstructed surface view of left hemispheric oxygen extraction fraction (OEF) in three cats after permanent or transient occlusion of the middle cerebral artery. Increased OEF indicates penumbra tissue, decreased OEF identifies irreversible tissue damage.Centrifugal conversion of penumbra into irreversible damage in permanent occlusion, reperfusion can only reverse penumbra and prevent damage as long as increased OEF indicates tissue viability.

DEMONSTRATION OF PENUMBRA IN EXPERIMENTAL STUDIES
   Pathophysiologic changes occurring during the early period after focal ischemia can be followed by multitracer positron emission tomography (PET) which provides quantitative maps of several important physiologic variables - including regional cerebral blood flow (rCBF), regional cerebral metabolic rate of oxygen (rCMRO2), regional oxygen extraction fraction (rOEF) and regional cerebral metabolic rate of glucose (rCMRglc). Changes in these physiologic variables were studied after occlusion of the middle cerebral artery (MCAO) in baboons (Tenjin et al., 1992; Pappata et al., 1993). In the cat, changes after MCAO are immediate and severe. Sequential studies of CBF, CMRO2, and CMRglc from a control before to the endpoint 24 h after MCA occlusion (Heiss et al., 1994) recorded an immediate decrease of CBF within the MCA territory to below 30% of control upon arterial occlusion. CMRO2 was less diminished and preserved at an intermediate level; consequently OEF was increased, indicating misery perfusion. This ischemic penumbra spread with time from the center to the borders of the MCA territory (Figure 3). In most instances, the misery perfusion condition was followed by a marked decrease in OEF, reflecting progressive impairment of metabolism and suggesting transition to necrosis spreading from the core to the periphery of the ischemic territory. The infarcts were more or less complete 18-24 h after MCA occlusion. Occasionally, spontaneous collateral reperfusion resolved the penumbra condition and the morphological integrity of the cortex was preserved.

   Reversible MCA occlusion was studied in cats by reopening the MCA after 30, 60, and 120 min (Heiss et al., 1997). All cats survived 30 min of MCA occlusion without developing infarcts. During 60 min of MCA occlusion, OEF remained elevated throughout the ischemic episode in animals surviving 24 h of reperfusion; reperfusion was efficient in preventing large infarcts involving cortical areas (Figure 3). In contrast, the initial OEF increase disappeared during 60 min of ischemia in those cats that died during the reperfusion period; extended post-ischemic hyperperfusion accompanied large reductions in CMRO2 and rCMRglc, large infarcts developed, and intracranial pressure increased fatally. These results highlight the importance of the severity of the ischemia in relation to its duration for the further course after reperfusion (Heiss and Rosner, 1983), and a comparison to clinical findings may be justified (Figures 4 and 5). Permanent MCA occlusion resembles the natural course after vascular occlusion, leading to large infarcts in most cases, with a chance of collateral reperfusion that may resolve the misery perfusion and improve the outcome. Reopening of the MCA resembles the (spontaneous) dissolution of vascular occlusions in transient ischemic attacks, spontaneous lysis of emboli within the tolerable time period, and therapeutic thrombolysis. In the cat experiments, reperfusion after 30 min of MCA occlusion led to a short lasting hyperperfusion period and to a fast normalization of flow and metabolism. This may be comparable to a transient ischemic attack. During longer lasting MCA occlusions, 2 patterns can be distinguished (Figure 3): (i) a decrease of the OEF during the MCA occlusion reflects fast irreversible damage of tissue (Figure 4), whereas (ii) a persistence of elevated OEF indicates preserved viability of tissue over the ischemic period (Figure 5). Forced reperfusion by reopening the MCA cannot salvage irreversibly damaged tissue, but may cause additional damage by inducing edema via leaking vascular endothelium. In such cases, the infarcts are large and animals die early due to increased intracranial pressure. These courses resemble the deleterious outcome of thrombolytic therapy which is initiated too late and thus can not prevent the development of large infarcts (Figures 4 and 5), resulting in additional edema and secondary hemorrhagic transformation.

Fig. 4: Left side: sequential PET images from an individual cat undergoing 60-min MCAO and reperfusion resulting in an unfavorable outcome. Images represent CBF, CMR2, and OEF before (control), immediately after and 30 min after MCAO, and after reperfusion. During the ischemic episode, CMRO2 deteriorated further and the initially increased OEF decreased already during ischemia. After reperfusion, pronounced hyperperfusion occurred in this particular cat, and final CMRglc showed major deficits. Right side: patient study demonstrating only partially successful reperfusion after thrombolysis (frontal part of ischemic focus), resulting, however, in pronounced hyperperfusion. Structural damage as determined by MRI occurred in this particular case in both nonreperfused and hyperperfused portions of the ischemic territory.

Fig. 5: Left side: sequential PET images from an individual cat undergoing 60-min MCAO and reperfusion resulting in a favorable outcome. Images represent CBF, CMRO2 and OEF before (control), immediately after and at the end of MCAO and after reperfusion. During the ischemic episode, CMRO2 did not deteriorate further and OEF remained increased. Hyperperfusion was not pronounced in this particular cat, and final CMRglc did not show major deficits. Right side: patient study demonstrating successful reperfusion after thrombolysis. Structural damage as determined by MRI did not occur in this particular case.

CONTROLLED MULTITRACER TRIALS WITH THROMBOLYSIS
   Cerebral angiography conducted soon after the onset of stroke demonstrates arterial occlusion in up to 80 percent of acute infarctions (Fieschi et al., 1989; del Zoppo et al., 1992). Thrombolytic recanalization of occluded arteries therefore may reduce the degree of injury to the brain if it is done before the process of infarction has been completed. Since intracerebral hemorrhage was a frequent major complication reported in early trials of thrombolytic therapy (Wardlaw et al., 1997) the use of recombinant human tissue plasminogen activator (rt-PA) for cerebral arterial thrombolysis required careful evaluation of both, the risks and the potential benefits in controlled randomized multitracer trials.

ECASS I
   In ECASS I, 620 patients were randomized and treated within 6 hours from the onset of symptoms (Hacke et al., 1995). The dose of rt-PA was 1.1 mg/kg body weight up to 100 mg. A bolus of 10 % of the total dose was injected intravenously within 1-2 min followed by the rest of the dose as an intravenous infusion lasting 1 hour. The primary predetermined endpoints were Barthel Index (BI) and modified Rankin Scale (mRS) at day 90. Patients who died received the worst score in BI and mRS. The occurrence of large parenchymatous hemorrhages was significantly more frequently in the rt-PA-treated patients (19.8% v. 6.5%). No significant difference was seen between rt-PA and placebo in the primary outcome events due to increased mortality of rt-PA-treated patients at day 90 compared with placebo-treated patients (22.4 vs 15.8%). If the results of ECASS I had been analyzed based on the NINDS methodology of dichotomized outcomes, ECASS I would have been a positive trial.

NINDS
   The NINDS rt-PA Stroke Study Group enrolled and treated 624 patients within 3 hours of the onset of symptoms, half of them within 90 min (The NINDS rt-PA Stroke Study Group, 1995). The dose of rt-PA was 0.9 mg/kg body weight (maximum 90 mg), 10% of which was given as a bolus followed by delivery of the remaining 90% as a constant infusion over a period of 60 min. It assessed the clinical outcome according to BI, mRS, Glasgow Outcome Scale and National Institute of Health Stroke Scale. In the NINDS trial, 11-13% more patients in the rt-PA arm reached an excellent functional outcome with no increase in mortality, although symptomatic hemorrhages were increased tenfold by thrombolysis (6.4 vs 0.6%). On the basis of the results, rt-PA was approved in the US for use within a 3-hour time window.

ECASS II
   In ECASS II, 800 patients were randomized and treated. The dose was the same as in the NINDS trial, 0.9 mg/kg , and ECASS II included a strict blood pressure control and a 6-hour time window (Hacke et al., 1998). The primary endpoint was the proportion of patients with favorable outcome (mRS 0-1). All investigators were trained to read baseline CTs. In ECASS I, 8.6% of patients had infarcts larger than one third of the MCA territory, while in ECASS II, such protocol violations only occurred in 4.6% of patients. Mortality of the ECASS II rt-PA arm was 10.3% and that of the placebo arm 10.7%, despite a 2.5-fold increase in symptomatic parenchymal hemorrhages after rt-PA therapy (8.8 vs 3.4%). ECASS II was powered to detect a 10% effect size in the primary endpoint based on the data from ECASS I and the NINDS trial. This primary outcome event was not reached, probably due to extremely good outcome in the placebo group (36.6% of the patients in the placebo group and 40.3% in the rt-PA group reached modified Rankin scale 0-1 at 3 months). However, a post hoc analysis using a more often used dichotomization for independent versus dead or dependent patients revealed a significant 8.3% difference favoring rt-PA therapy (54.3 vs 46.0%), which is equivalent to 83 per 1,000 fewer patients dead or disabled after thrombolysis.

   A recent follow-up study of the NINDS trial demonstrated a sustained benefit of rt-PA at 12 months (Kwiatkowski et al., 1999). Donnan (in Hacke et al., 1999) was the first to present a meta-analysis of the three trials, ECASS I, the NINDS trial and ECASS II. It revealed that thrombolysis decreases the risk of death and dependency. For each 1,000 patients treated within 3 hours, there will be 140 less dead or dependent and 90 less, if the treatment is given within 6 hours (Table 1). A recent Cochrane systematic review verified Donnan's analysis, and also revealed that it is possible to reduce the number of dead and disabled stroke patients with thrombolysis (Wardlaw et al., 2000). These data support the view that rt-PA should be part of the management of acute ischemic stroke within 3 hours, and probably beyond, in selected patients and experienced centers (The European Ad Hoc Consensus Group, 1996). It was also demonstrated that intra-arterial application of a thrombolytic agent (prourokinase) is efficient up to 6 h after the attack, if angiography reveals occlusion of a major vessel (Furlan et al., 1999). It was also suggested repeatedly (Kaste, 2001), that neuroprotective agents may prolong the time interval that the brain can tolerate ischemia before reperfusion and thereby extend the time window for thrombolysis.

EXPERIENCE WITH ROUTINE APPLICATION OF rtPA IN ACUTE ISCHEMIC STROKE
   Since its approval by the FDA in 1996 rtPA has been used safely and effectively in routine clinical practice in academic medical centers as well as in community hospitals, and guidelines have been developed to ensure safety in the use of rtPA for acute ischemic stroke (Adams et al., 1996). These guidelines restrict the routine use of rtPA to those patients who can be treated within 3 h of symptom onset and emphasize the importance of involving physicians with expertise in the diagnosis of stroke, in the interpretation of CT scans and in the ability to handle hemorrhagic complications. Up to now, 7 studies on routine use have been published (Chiu et al., 1998; Trouillas et al., 1998; Schmülling et al., 2000; Albers et al., 2000; Katzan et al., 2000; Wang et al., 2000; Chapman et al., 2000) and one large survey has been presented(Tanne et al., 2000) (Table 2). In order to increase the number of patients who can benefit from rtPA treatment a referral system must be organized to transfer appropriate cases in the early hours after ischemic stroke to the appropriate centers. Such referral systems were successfully set up for urban (Grond et al., 1998) as well as for rural environments(Davenport et al., 2000). With the exception of one study (Katzan et al., 2000) in which exclusion criteria were not carefully followed, all the published experience supports the beneficial effect of rtPA treatment (Hacke et al., 1999) but also stress the point that only a small portion (1-2%) of all patients with acute ischemic stroke are actually receiving this potentially effective therapy.

   The experience in our center, where more than 280 patients with acute ischemic stroke received rtPA intravenously within 3 h after symptom onset following the NINDS protocol, is given as an example of thrombolytic treatment in clinical routine. Based on a cooperative referral system involving 14 city hospitals and the emergency system patients with suspected acute ischemic stroke are admitted using age under 80, no severe impairment of consciousness and presentation within 3 h of symptom onset as simple selection criteria. Of these preselected cases 22% were receiving iv rtPA treatment within the time window (Grond et al., 1998). The outcomes of patients treated in Cologne were very similar to those of the patients in the NINDS trails, and this effect carries through also for the 150 patients followed up to 12 months after treatment (Schmülling et al., 2000). As demonstrated in the diagrams of Figure 6, the proportion of patients in the no or minimal disability group (m Rankin Scale 0 and 1) was comparable (42%9 to the NINDS cohort as well as the 3 h cohort of ECASS I and II after 3 months and to the NINDS cohort (Kwiatkowski et al., 1999) after 12 months (both 41%). The number of diseased patients (11% after 3 months, 15% after 12 months) was the lowest in the Cologne study, but this might be related to the exclusion of very severe cases from this treatment (median NIHSS score at inclusion in Cologne 11 - as in ECASS II - , but 14 for NINDS rtPA trial). Despite the application of heparin after thrombolysis in the majority of patients the rate of asymptomatic parenchymal hemorrhages (4%) was similar as in ECASS II, slightly lower than in the NINDS and distinctly lower than in the ECASS I treatment groups. Similar results were reported in surveys collecting data of routinely treated stroke patients from various centers (Chiu et al., 1998; Hacke et al., 1998; Albers, 1999; Tanne et al., 2000; Wang et al., 2000; Chapman et al., 2000).

Fig. 6: Modified Rankin Scale scores at 3 and 12 months in patients treated in Cologne compared with patients from the NINDS rtPA Stroke Trial placebo and treatment groups (3 and 12 months) and with the ECASS I and ECASS II 3 h rtPA cohorts (3 months).

EFFECTS OF THROMBOLYSIS ON THE PENUMBRA
   Several small treatment studies used effects on the penumbra, as assessed by functional imaging, as surrogate targets. An effect of the therapeutic intervention can therefore only be expected as long as penumbral tissue is present, and in most instances the compartment of penumbral tissue is rather small at the time of intervention (Heiss et al., 1999). Thrombolysis is still the only approved therapy for acute ischemic stroke, and its effect was demonstrated recently in several imaging studies, in which reperfusion to penumbral tissue was associated with improvement in neurological deficits. Previous SPECT observations on the combined effect of severity of initial hypoperfusion and extent of reperfusion on the final outcome (Sasaki et al., 1996; Ryu et al., 1999; Ueda et al., 1999) were supported by results in a small cohort selected from the National Institute of Neurological Disorders and Stroke (NINDS) study (Grotta and Alexandrov, 1998). In this double-blind controlled study, significantly greater reperfusion occurred in the recombinant tissue-type plasminogen activator-treated patients than in the placebo group.

   The volume of tissue salvaged by reperfusion was established in a study in which CBF, as determined by H215O-PET within 3 h of stroke onset, was compared with the volume of infarction determined on MRI 3 weeks after the ictus (Heiss et al., 1998). The percentage of initially critically ischemic voxels (i.e. with a flow below the threshold of 12 ) ml/100g/min that became reperfused at almost normal levels clearly predicted the degree of clinical improvement achieved within 3 weeks (Figure 7). Overall, only 22.7% of the grey matter that was initially perfused at rates below the conventional threshold of critical ischemia became necrotic after thrombolytic therapy in this small sample of 12 patients. That means, that a considerable portion of the critically hypoperfused tissue was probably salvaged by the reperfusion therapy (Figure 8). Another PET study in 11 patients (Heiss et al., 2000) indicated that hypoperfused tissue could benefit from reperfusion only as long as cortical flumazenil binding was not reduced to or below 3.4 times the mean uptake in white matter. This marker of neuronal integrity can therefore serve as an indicator for irreversibly damaged tissue that is not amenable to treatment.

Fig. 7: Scatter diagram relating improvement, from initial assessment to 3 weeks, of neurologic deficit (NIHSS) and percentage decrease in size on the day of acute thrombolytic treatment of gray matter region perfused at levels below threshold of dense ischemia in patient groups S and L. rho = 0.82, P < 0.01. Two observations hidden at value 0/0. o group S; group L

Fig. 8: Scatter diagram relating volume of infarcted gray matter according to late MRI and initial volume of gray matter perfused at levels below threshold of dense ischemia . Rho = 0.82, P < 0.001. Beside the line of identity, notice the regression line based on five cases with minimized infarcts. o group S; group L.

   CT perfusion imaging (Klotz and König, 1999; Segal et al., 1999) and Xenon enhanced CT (Rubin et al., 1999) were also used in an attempt to predict outcome after thrombolysis, but a refinement of CT for reliable identification of irreversible tissue damage during the first hours after onset of symptoms is required before these methods can be introduced into clinical routine (Koroshetz and Gonzales, 1999).

   Recently, the difference in the volumes of abnormality in PWI and DWI has been used as a surrogate marker of efficacy in stroke trials (Fisher and Albers, 1999; Saver et al., 1999). Two groups reported results of serial DW and PW imaging in patients undergoing intravenous thrombolysis. Inhibition of lesion growth was observed in patients experiencing reperfusion compared with patients with persistent perfusion deficits (Jansen et al., 1999; Schellinger et al., 2000).

   Normalization of PWI occurred in five out of six patients receiving recombinant tissue-type plasminogen activator, but only in one out of six patients in the control group (Marks et al., 1999). Increases in ADC, which were observed in ischemic zones of five patients with early reperfusion, were closely associated with the reperfusion seen after intravenous recombinant tissue-type plasminogen activator therapy. Similar effects were observed after intra-arterial thrombolytic therapy within 6 h of symptom onset (Kidwell et al., 2000). With recanalization proved by angiography, the volume of DWI lesions decreased from 23 cm3 at baseline to 10 cm3 early after lysis. This study demonstrated that perfusion deficits can be resolved and that DWI signatures of early ischemic injury can be reversed by prompt thrombolytic vessel recanalization. This means that the ischemic penumbra includes not only a region of diffusion/perfusion mismatch, but also portions of the volume of initial diffusion abnormality. The various techniques that permit identification of the penumbra (i.e. potentially salvageable tissue) might be applied to extend the window of therapeutic opportunity (Albers, 1999).

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2nd Virtual Congress of Cardiology

Dr. Florencio Garófalo
Steering Committee
President
Dr. Raúl Bretal
Scientific Committee
President
Dr. Armando Pacher
Technical Committee - CETIFAC
President
fgaro@fac.org.ar
fgaro@satlink.com
rbretal@fac.org.ar
rbretal@netverk.com.ar
apacher@fac.org.ar
apacher@satlink.com

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