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Neurology India
Medknow Publications on behalf of the Neurological Society of India
ISSN: 0028-3886 EISSN: 1998-4022
Vol. 50, Num. s1, 2002, pp. S50-S56

Neurology India, Vol. 50, (Suppl. 1), Dec, 2002, pp. S50-S56

Thrombolytic Therapy for Acute Ischemic Stroke: Issues and Answers

M. Moonis

Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Correspondence to : Dr. M. Moonis, Department of Neurology, University of Massachusetts Medical School, 55 Lake Avenue, Worcester, Massachusetts, USA.

Code Number: ni02162

Summary

Thrombolytic therapies have perhaps been the most important single development in the management of acute ischemic stroke. Results of the National Institute of Neurologic disorders and Stroke (NINDS) trial revealed a 30% greater chance of being disability free at three months if patients with acute ischemic stroke were treated with recombinant tissue plasminogen activator (rt-PA) within 3 hours of onset. These results have been validated in large community studies in the United States. The Prolyse in Acute Cerebral Thromboembolism (PROACT II) trial further demonstrated that patients with middle cerebral artery occlusion can be treated up to 6 hours of onset of stroke with intra-arterial Pro-urokinase. In spite of these results, community use of thrombolytic therapy remains dismally low. Increasing stroke awareness in the community, establishing primary to tertiary stroke centers and physician education are possible methods of increasing utilization of thrombolytic therapy.

Key words : Stroke, Thrombolysis.

Introduction

In the short span of a decade, acute stroke management has moved from an art (experience based) to a science (evidence based). Perhaps the most important advancement has been in the field of thrombolytic therapy. Initial attempts at thrombolysis with intravenous streptokinase were all unsuccessful. These included the Multi Center Acute Stroke Trial- Italy (MAST), Multicenter Acute Stroke Trial-Europe (MAST-E) and the Australian Stroke Trial (AST) that was stopped prematurely because of excessive hemorrhage in the treatment arm.1,2 Based on these trials; currently there is no place for streptokinase in the treatment of acute ischemic stroke.

Thrombolytic therapy with recombinant tissue plasminogen activator

The first trial of recombinant tissue plasminogen activator (rt-PA) in Europe, European Cooperative Acute Stroke Study (ECASS), was reported in 1995. The outcome of a Modified Rankin Scale Score (MRSS) of 0-1 was similar in the treated and untreated group. Six hundred and twenty patients were enrolled to be treated with rt-PA (1.1mg per kg) within 6 hours of onset of symptoms. Symptomatic intracranial hemorrhage (ICH) was seen in a very high percentage of patients; 19.8% vs 6.6 % in the placebo group. The study had several problems including protocol violations and use of a higher dose of rt-PA than later trials (1.1mg per kilogram body weight vs 0.9mg per kilogram body weight). The overall stroke severity was significantly higher in this study in comparison to the later studies.3 Following at the heels of ECASS came the National Institute of Neurological Disorders and Stroke (NINDS) trial, which was also a double blind placebo controlled study where patients with acute ischemic stroke were treated within 3 hours of stroke onset with intravenous rt-PA. A total of 624 patients were enrolled and 50 % of the patients were treated within 90 minutes of onset of stroke. Patients had mild to moderate strokes. A global outcome score of the National Institute of Health Stroke scale, Modified Rankin Scale Score, Glasgow Outcome Score and Barthel Index (NIHSS, MRSS, GOS, BI) was used to assess the outcome. The results demonstrated a 30% greater probability of being independent at 3 months in the patients treated with 0.9 mg per kilogram of rt-PA intravenously compared to placebo. The results were equally significant for cardioembolic, large vessel and small vessel (presumed lacunar) strokes. Compared to placebo there was a 5.8% greater incidence of symptomatic intracranial hemorrhage. The overall mortality rate was comparable at 3 months in both groups.4,5 A second European study ECASS II followed the NINDS where the dose of rt-PA was reduced to 0.9 mg per kg, but the time of treatment kept at 6 hours from stroke onset again revealed no improvement in the treated group compared to placebo. However, the incidence of intracranial bleeding was not significantly higher than the NINDS trial.6 The results of these studies have shown that treatment with intravenous rt-PA given within 3 hours of onset of an acute ischemic stroke is effective in improving outcome. The efficacy of treatment is time dependent and the earlier blood reflow is reestablished, the greater the chances of improvement. Intracranial hemorrhage tends to increase with elevated baseline blood pressure, stroke severity (NIHSS > 23), protocol violations (aspirin use prior to thrombolysis, greater than 1/3 middle cerebral artery territory hypo-attenuation on CT) and older age.7,8

Appendix 1, Appendix 2

However, if the protocol is carefully adhered to, the risk of bleeding in the elderly is perhaps not significantly greater than in younger patients. Double blind placebo controlled trials of other drugs for acute stroke have also shown promise. Ancrod is a fibrinogen depleting agent that was found effective. Five hundred patients were randomized to ancrod infused over 72 hours or placebo, after an ischemic stroke. The treatment window was 3 hours. The outcome measures of co-variate adjusted proportions of functional success were 42.2% vs 34.4%. The mortality in the 2 groups was similar. ICH was seen in 5.2% vs 2% respectively. Even though the trial is considered positive, it has not received Food and Drug Administration (FDA) approval so far. 9-13 Growing realization that large vessel thromboembolism is more effectively treated with intraarterial treatment led to the PROACT II trial.14-16 This trial included patients with angiographically proven middle cerebral artery occlusion (MCA) and were treated with intraarterial pro-urokinase or placebo within 6 hours of stroke onset. After screening, 478 patients were included in the trial. Of these 180 patients were randomized to be treated with active medication. The primary outcome measure of Modified Rankin Stroke Scale (MRSS) of <2 was achieved in 40% compared with 25% in the other group. Hemorrhage was seen in the treated group at a significantly higher rate. Patients receiving concomitant intravenous heparin had a significantly higher rare of bleeding. However, the overall mortality was comparable in the 2 groups. This study demonstrated that reperfusion even at 6 hours may be associated with a good outcome. The use of intraarterial pro-urokinase is not FDA approved at this time.14-16

Figure 1

Even though thrombolytic therapy is clearly effective in acute ischemic stroke treatment, less than 4% of patients are at present eligible for such treatment. The main reasons are poor understanding of stroke in the general population and lack of effective resources. Community phase 4 open labeled studies have been instructive. A nation wide study, the Standard Treatment with Alteplase to reverse Stroke (STARS) study, where pooled data from multiple centers was analyzed revealed 35% of treated patients had a MRSS of 0-1 (functionally independent) at 1 month and 43% had a MRSS of 0-2 (mild disability). The incidence of intracranial hemorrhage was low (3.3%). Patients with hypo-attenuation of greater than 1/3 the middle cerebral artery territory (2 patients) had a higher symptomatic conversion rate. The mean door to needle time was 96 minutes. Eighty six percent were treated within 180 minutes of stroke onset but only 4.1% received treatment within 90 minutes. Mean NIHSS was 14. The 30-day mortality rate was only 13%.17 Very similar results were seen from an individual center.18,19 In these studies, patients were primarily treated by neurologists. On the other hand, data from the Cleveland clinic where community physicians were responsible for treatment, the results were very different. Three thousand nine hundred and forty eight patients from 29 hospitals were included. Of these, 1.8% received rt-PA. Protocol violations were seen more often and the rate of intracranial hemorrhage was dramatically higher at 15.7% of which half were fatal.20 Our own experience with 23 consecutive patients treated with rt-PA within 3 hours revealed a more immediate improvement in functional outcome within 5±2 days after treatment.21 Results of a later retrospective case control study of 32 patient patients where a significant number were treated outside the 3-hour time window failed to show the same robust effect. Only posterior circulation strokes demonstrated a significant improvement.22,23 These community studies highlight several important points. Firstly, thrombolytic therapy is effective in treating acute ischemic strokes in the community setting (results of the NINDS trial are revalidated). Secondly, if the appropriate protocol is followed, the risk of intracranial hemorrhage is low.24 Thirdly, treatment by an organized team is clearly better than by physicians unfamiliar with stroke subtypes and thrombolytic therapy. The door to needle time is clearly important. Patients treated in the first 90 minutes of the NINDS study had better outcome in comparison to those treated in the 90-180 minute window.25 A similar trend was noticed in our study.22 Only 3 patients were treated within the 90 minute window, 17 patients were treated between 90-180 minutes and 12 patients > 180 minutes. Anterior circulation patients treated with rt-PA had significantly less infarct growth compared to controls (9.5cc vs 25.4cc p < 0.05). Functional outcome did not differ significantly between groups even though the treated group did show a trend towards significance. Posterior circulation strokes treated with rt-PA did show a significant improvement over the untreated controls, implying a differential ischemic variability.22

Although, thrombolytic therapy is effective in improving outcome, it remains underutilized. Lack of stroke awareness in the community, neurologists' concerns about possible intracranial hemorrhage and lack of organized protocols in a significant number of hospitals are some important factors limiting more widespread use.26

Can treatment be extended beyond the 3-hour window?

So far two major double blind placebo controlled trials of treatment with intravenous rt-PA have not demonstrated the efficacy of thrombolytic treatment in improving the outcome in patients treated beyond the 3-hour window. The European Acute Stroke Study (ECASS 11) failed to show a positive outcome of MRSS (0-1). However, in a post hoc analysis where MRSS of 0-2 was considered, there was a statistically significant benefit in the treated group. Were the outcome criteria too expectant? The Alteplase Thrombolysis for Non Interventional Therapy in Ischemic Stroke (ATLANTIS) was similar in design to the NINDS study with the exception that patients were treated within the 3-5 hour window. The primary outcome of MRSS (0-1) was similar in the treated and placebo group.27 A subsequent meta analysis of all thrombolytic trials revealed thrombolytic therapy to be effective in improving outcome at the risk of increased intra and extracranial hemorrhage. Using a dichotomized scale of MRSS of < or = to 2 versus > or = 3, there was a 37% relative chance of improvement. The higher rate of hemorrhage in the 3- 6 hour vs the 0-3 hour window (Odds ratios 3.23 vs 2.68) were not statistically significant.28 Differential ischemic tolerability may be a possible explanation. Posterior circulation strokes and anterior circulation strokes with good collateral circulations may benefit from treatment in the extended window. This was stressed in a recent study where the treatment was based on MRI evidence of a diffusion-perfusion mismatch evidence beyond 3 hours of onset of stroke. Nineteen patients with MRI diffusion-perfusion mismatch were treated with intravenous rt-PA. For comparison, 21 historical controls were chosen. The treated group had better recanalization at day 3 (87% vs 47%), significantly less lesional expansion (14 cc vs 56cc) and a significantly higher number of patients demonstrating an improvement in the NIHSS of greater than 7 points.29 Should all ischemic strokes seen beyond the 3-hour window be treated? The answer is obviously negative. Small vessel or lacunar strokes are usually associated with a good outcome regardless of the treatment. Even though the NINDS trial demonstrated a good outcome in the sub-group of patients with lacunar stroke treated with intravenous rt-PA, most physicians are reluctant to treat these patients since the risk of hemorrhage probably outweighs the small benefit from the treatment. Ideally, clinically suspected large vessel stroke should be evaluated with diffusion-perfusion MRI studies. Patients seen within the 3 hour time window without a diffusion perfusion mismatch are unlikely to benefit from any treatment (completed stroke) while patients with significant diffusion-perfusion mismatch would be expected to benefit from therapy. Since MRI is not readily available, it does limit the usefulness of this approach. In the future, perfusion CT and CT Angiography (CTA) may become an accepted alternate imaging modality to MRI.14

Combination therapies : Intravenous and intra-arterial therapy

Since intravenous therapy appears to be of limited value in recanalization of large vessel occlusion particularly complete internal carotid or middle cerebral main stem occlusions, attempts have been made to treat patients with intra-arterial thrombolysis. In itself this approach has limitations since a longer time period is required. Initial treatment with intravenous rt-PA (0.6 mg per kilogram) was followed by intra-arterial thrombolysis with rt-PA (maximum of 0.3 mg per kilogram) or pro-urokinase (up to 750,000 U) if the patient did not improve. Prior to intra-arterial treatment, MRI with diffusion -perfusion imaging was done and abnormal MRI was followed by an angiogram to document embolic occlusion. Forty-five patients treated by this approach had a favorable outcome and the risk of symptomatic intracranial hemorrhage was 4.4%, below the reported rate in the NINDS trial.30 These results are preliminary and the safety of this approach needs to be firmly established before it can become standard therapy.31 Even then, the application will be limited to centers where standard equipment and interventionists are available, limiting this to tertiary stroke centers.32

Ultrasound as an aid to thrombolysis

Transcranial Doppler studies have demonstrated 20KHz frequencies delivered through the temporal windows accelerate clot lysis in vivo and in vitro models. More recently data on patients with acute stroke monitored with TCD seem to agree with these earlier observations.33-37 If proven in further doubleblinded studies, TCD may become a useful ancillary tool to thrombolytic therapy.38,39

Conclusion

  1. Thrombolytic therapy for acute ischemic stroke within the 3-hour window is effective in improving outcome with a relative 30% greater chance of patients being disability free at 3 months after treatment. The results have been validated in phase 4 community studies. Faster door to needle times lead to earlier recanalization and better outcome. So far, less than 4% stroke patients have received such therapy. Stroke awareness in the community, written and well rehearsed thrombolytic protocols, and physicians experienced in various aspects of stroke management are necessary to extend the effective use of rt-PA to a larger group of patients.26
  2. The risk of symptomatic intracranial hemorrhage is directly proportional to stroke severity, radiological hypo-attenuation of >1/3 of the normalized middle cerebral arterial territory and inversely proportional to time to treatment (stroke to needle time).
  3. Protocol violations (treating patients with uncontrolled hypertension, treatment beyond the time window and by physicians inexperienced in stroke and thrombolytic therapy management) increase the chances of symptomatic hemorrhage.
  4. Therapy beyond the 3 hour window, combined intravenous and intraarterial thrombolysis, thrombolysis with ultrasound sonification appear to improve outcome but are applicable to selected group of patients and at present limited to specialized tertiary stroke center.
  5. Within defined geographical territories a hierarchical system of stroke care should be defined so that patients with ischemic stroke are quickly referred to specialized stroke centers to minimize delays and extend the use of thrombolytic therapy to larger patient population.40

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