ABSTRACT: Thrombolysis with intravenous tissue plasminogen activator (tPA), administered within 3 hours of symptom onset, is the only FDA-approved treatment for acute ischemic stroke. Recently, intra-arterial prourokinase was found to improve recanalization and clinical outcome when administered to select patients up to 6 hours after symptom onset. Combination intravenous/intra-arterial thrombolysis can compensate for the delays that are often associated with intra-arterial therapy (products of the paucity of qualified centers and the time required for angiography). Increased risk of hemorrhagic transformation is associated with all routes of thrombolytic administration. However, greater awareness of specific risk factors for hemorrhagic transformation-especially newer CT and MRI criteria-may enable physicians to select patients with an optimal chance of benefiting from thrombolytic therapy, and may also extend the therapeutic window. Despite the higher rate of hemorrhagic transformation, thrombolytic therapy has demonstrated a significant benefit in the treatment of patients with acute stroke.
Stroke is a major health problem worldwide. It ranks third after cardiovascular disease and cancer as a cause of death in adults, and first as a cause of permanent disability.1
Ischemic stroke accounts for about 84% of all strokes.2 The aim of acute therapy in this setting is to prevent or reverse acute ischemia. The 2 major approaches currently being studied are reperfusion and neuroprotection. Although reperfusion can be achieved by several methods, thrombolytic therapy is the one used most frequently. The efficacy and safety of neuroprotective agents have yet to be demonstrated in clinical trials.
Despite the proven effectiveness of thrombolysis in acute ischemic stroke, the threat of hemorrhagic transformation has hampered its use. Improved identification of patients at risk for bleeding may reduce the incidence of this complication.
Here I describe clinical, radiologic, and biochemical factors associated with an increased risk of hemorrhage. I also discuss the pros and cons of various routes of delivery of thrombolytics.
Thrombolysis has been used successfully for many years as an acute treatment of myocardial infarction. The first use of thrombolytic therapy for stroke dates to the 1960s.3 Since then, several randomized clinical trials (RCTs) have investigated the efficacy of thrombolysis in this setting, using a variety of agents. Table 1 summarizes the characteristics of the different agents that have been tried.
Streptokinase. Intravenous streptokinase was used initially. The Multicenter Acute Stroke Trial-Italy (MAST-I) was a non-placebo-controlled RCT of streptokinase and aspirin given either together or separately within 6 hours of symptom onset.4 The Multicenter Acute Stroke Trial-Europe (MAST-E) randomized patients with carotid territory stroke to treatment with either streptokinase or placebo within 6 hours of stroke onset.5 The Australian Streptokinase (ASK) trial was an RCT with a time window of 4 hours.6 All these trials were prematurely stopped because of a high rate of early death (mostly the result of hemorrhagic transformation) and because of lack of benefit. Overall in the streptokinase trials, there were 92 additional fatal hemorrhagic transformations per 1000 treated patients (odds ratio, 6.03; 95% confidence interval, 3.47 to 10.47).7 Based on the results of these trials, streptokinase is not indicated for the management of acute ischemic stroke.
Tissue plasminogen activator. Intravenous administration of tissue plasminogen activator (tPA) began to attract attention after the results of the European Cooperative Acute Stroke Study (ECASS) I and the National Institute of Neurological Disorders and Stroke (NINDS) trials were published in 1995.8,9 In the NINDS trial, there was an 11% to 13% increase in favorable outcomes among patients treated with tPA compared with those who received placebo.8 Two other RCTs have since been published: ECASS II in 199810 and Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) in 1999.11
All together, these trials randomized a total of 2657 patients to treatment with placebo or intravenous tPA, within 0 to 3 hours (NINDS), 3 to 5 hours (ATLANTIS), or 0 to 6 hours (ECASS I and II) of symptom onset. A novel aspect of the trials was the requirement of a baseline CT scan to exclude intracerebral hemorrhage. Except for the NINDS study, all had established CT exclusion criteria. The dose of tPA used in all of these trials except ECASS I was 0.9 mg/kg, to a maximum of 90 mg. The dose used in ECASS I was slightly higher, 1.1 mg/kg, to a maximum dose of 100 mg. In all 4 trials, 10% of the total dose was given as a bolus; the rest was infused over 1 hour. Table 2 summarizes the findings in the 4 RCTs of intravenous tPA.
To date, intravenous tPA, administered within 3 hours of symptom onset, is the only FDA-approved treatment of acute ischemic stroke.8 FDA approval was based primarily on the results of the NINDS trial.
A large phase 3 clinical trial demonstrated that intra-arterial administration of thrombolytics may improve clinical outcome in select patients up to 6 hours after symptom onset.12 The rationale for use of the intra-arterial route of administration is that a higher concentration of thrombolytic agent is delivered locally where it is needed, while the systemic concentration is minimized. Hence, local intra-arterial thrombolysis may result in better recanalization rates and may even help extend the therapeutic window.
Results of several case series on local thrombolysis in the carotid artery territory have been promising but not convincing.13 When the results of these case series are combined, complete clot lysis was achieved in 62 (36%) of 174 patients.13 The combined partial or complete recanalization rate for these patients was 75%.13
Only 2 RCTs have studied the efficacy of intra-arterial thrombolytics. The Prolyse in Acute Cerebral Thromboembolism (PROACT) I trial was a phase 2 RCT, in which recombinant prourokinase (rpro-UK) was compared with placebo in patients with angiographically proven proximal middle cerebral artery (MCA) occlusion.14 A total of 105 patients underwent angiography; 65 of these were excluded from randomization. Of the 40 treated patients, 26 received rpro-UK and 14 received placebo at a median of 5.5 hours after symptom onset.14 The recanalization rate was significantly higher in the rpro-UK group (57.7%, as opposed to 14.2% in the group that received placebo).
PROACT II was a multicenter open-label RCT. Its aim was to determine the clinical efficacy and safety of intra-arterial rpro-UK in patients with acute stroke caused by MCA occlusion and of less than 6 hours' duration.12 Of 12,323 patients screened in 54 centers, only 474 (4%) underwent angiography at a median of 4.5 hours after stroke onset. Only 121 patients who received rpro-UK and 59 control patients were included; 294 were excluded based on angiographic criteria.12 The recanalization rate was 66% in the rpro-UK group and 18% in the control group (P < .001). Table 2 summarizes the pertinent findings in the PROACT I and II trials.
Unfortunately, intra-arterial thrombolysis is not available in all US hospitals. In addition, there may be considerable time delay to angiography in the centers that do support this therapy. Hence, it is reasonable to combine intra-arterial and intravenous therapy to compensate for these drawbacks.15 In this approach, a patient may receive intravenous tPA in any hospital and then be immediately transferred to a stroke center for possible intra-arterial tPA therapy.
The Emergency Management of Stroke Bridging Trial is the only study to have tested the feasibility, efficacy, and safety of combined intravenous and intra-arterial tPA therapy for stroke within 3 hours of symptom onset.15 In this double-blind, phase 1 RCT, 35 patients were randomly assigned to an intravenous tPA/intra-arterial tPA group (17) or to a placebo/intra-arterial tPA group (18). Patients received 0.6 mg/kg of tPA, 60 mg maximum, with a 10% bolus administered over 1 minute and the remainder over the next 30 minutes. A clot was found in 22 of 34 patients. Although recanalization was better in the intravenous tPA/intra- arterial tPA group, no difference was noted in outcome. More deaths were reported in the intravenous tPA/intra-arterial tPA group; however, the number of patients in whom intracerebral hemorrhage occurred was similar in the 2 groups.15 Thus, the study demonstrated that the combination intravenous/intra-arterial approach is feasible and safe.15
RISK OF HEMORRHAGIC TRANSFORMATION
The main complication and limiting factor associated with thrombolytic therapy-whatever the route of administration-is the development of hemorrhagic transformation.12,16 The risk of this complication has prevented some physicians from treating qualified patients with tPA17 despite the proven efficacy of thrombolysis.8 Table 3 summarizes the current indications and contraindications for intravenous tPA administration.
Rates of hemorrhagic transformation following thrombolysis have varied widely, depending on the thrombolytic agent, route of administration, and time window allowed for the initiation of therapy. In trials of intravenous thrombolysis, the rates of symptomatic hemorrhage in treated patients have ranged from 6% to 19.8%.9-11,16,18 In the PROACT II trial, the only large RCT of the efficacy of intra-arterial thrombolysis, symptomatic hemorrhage occurred in 10% of treated patients.12
Historically, hemorrhagic transformations have usually been linked to violations of the treatment protocol. In ECASS I, the first trial to use CT exclusion criteria, there were 109 protocol violations (17.4%); of these, 66 (11%) were CT protocol violations (extensive ischemic changes on baseline CT).9
The mechanism of hemorrhagic transformation following cerebral ischemia is not clearly understood. However, several clinical, radiologic, biochemical, and hematologic factors- in addition to the contraindications listed in Table 3-have been associated with hemorrhagic transformation. Still, these predictors have not yet been fully established as contraindications for tPA therapy because of the lack of clinical evidence beyond that of retrospective studies (Table 4).These predictors include:
Clinical factors, such as severe baseline neurologic deficits (National Institutes of Health Stroke Scale score greater than 20), congestive heart failure, increased age, elevated baseline systolic pressure,8,18-21 cardioembolic stroke,22 and delayed administration of thrombolytic therapy.20,21
Biochemical and hematologic factors, such as aspirin use, low platelet count, and hyperglycemia.18,20,21,23,24
The first reported radiologic predictors of hemorrhagic transformation were early ischemic changes visible on pretreatment CT scans:
Blurring of the gray matter-white matter distinction.
Blurring of the putaminal border.
Advances in magnetic resonance (MR) technology have led to the identification of other possible predictors. These include:
Lower apparent diffusion coefficient (ADC) values.
Persistently delayed perfusion.
Volume of lesion on initial diffusion-weighted MRI scan.
Absolute number of voxels with an ADC value of 550 × 10−6 mm2 or less.21,25
In addition, the presence of silent microbleeds (detected by using T2* MR sequences) may be a marker for increased risk of hemorrhagic transformation. Recently, early parenchymal enhancement of the stroke lesion was also reported as a good predictor of this complication.26
Improved identification of patients at risk for bleeding may reduce the incidence of hemorrhagic transformation. In addition, optimal patient selection may help extend the time win- dow for administration of thrombolytic agents beyond 3 hours.
Despite the risk of hemorrhagic transformation,2 large meta-analyses have nonetheless demonstrated benefit for thrombolytic therapy in acute stroke.27,28 The first meta-analysis covered only the NINDS study and the 2 ECASS trials (total number of patients, 2044).27 The second meta-analysis included all 18 RCTs of thrombolysis in acute stroke (total number of patients, 5727).28 The trials in this meta-analysis tested urokinase, streptokinase, tPA, and rpro-UK. Two trials used intra- arterial administration; the rest used the intravenous route. Table 5 summarizes the findings of both of these meta-analyses. The authors concluded that the significant increase in early death and hemorrhagic transformation are offset by the significant reduction of disability in survivors. n
1. Stroke-1989. Recommendations on stroke prevention, diagnosis, and therapy. Report of the WHO Task Force on Stroke and other Cerebrovascular Disorders. Stroke. 1989;20:1407-1431.
2. Mohr JP, Caplan LR, Melski JW, et al. The Har-vard Cooperative Stroke Registry: a prospective reg-
istry. Neurology. 1978;28:754-762.
3. Meyer JS, Gilroy J, Barnhart MI, Johnson JF. Therapeutic thrombolysis in cerebral thromboembolism: double-blind evaluation of intravenous plasmin therapy in carotid and middle cerebral arterial occlusion. Neurology. 1963;13:927-937.
4. Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Multicentre Acute Stroke Trial-Italy (MAST-I) Group. Lancet. 1995;346:1509-1514.
5. Thrombolytic therapy with streptokinase in acute ischemic stroke. The Multicenter Acute Stroke Trial-Europe Study Group. N Engl J Med. 1996;335: 145-150.
6. Donnan GA, Davis SM, Chambers BR, et al. Streptokinase for acute ischemic stroke with relationship to time of administration: Australian Streptokinase (ASK) Trial Study Group. JAMA. 1996;276: 961-966.
7. Wardlaw JM, del Zoppo G, Yamaguchi T. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev. 2000;(2):CD000213.
8. Tissue plasminogen activator for acute ischemic
stroke. The National Institute of Neurological Disor-
ders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333:1581-1587.
9. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The Euro-
pean Cooperative Acute Stroke Study (ECASS). JAMA. 1995;274:1017-1025.
10. Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet. 1998;352:1245-1251.
11. Clark WM, Wissman S, Albers GW, et al. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: a randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA. 1999;282:2019-2026.
12. Furlan A, Higashida R, Wechsler L, et al. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA. 1999;282:2003-2011.
13. Schellinger PD, Fiebach JB, Mohr A, et al. Thrombolytic therapy for ischemic stroke-a review, II: intra-arterial thrombolysis, vertebrobasilar stroke, phase IV trials, and stroke imaging. Crit Care Med. 2001;29:1819-1825.
14. del Zoppo GJ, Higashida RT, Furlan AJ, et al. PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT In-
vestigators. Prolyse in Acute Cerebral Thromboembolism. Stroke. 1998;29:4-11.
15. Lewandowski CA, Frankel M, Tomsick TA, et al. Combined intravenous and intra-arterial r-TPA versus intra-arterial therapy of acute ischemic stroke: Emergency Management of Stroke (EMS) Bridging Trial. Stroke. 1999;30:2598-2605.
16. Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. The NINDS t-PA Stroke Study Group. Stroke. 1997;28:2109-1218.
17. Alberts MJ. tPA in acute ischemic stroke: United States experience and issues for the future. Neurology. 1998;51(suppl 3):S53-S55.
18. Jaillard A, Cornu C, Durieux A, et al. Hemor-
rhagic transformation in acute ischemic stroke. The MAST-E study. MAST-E Group. Stroke. 1999;30: 1326-1332.
19. Larrue V, von Kummer RR, Muller A, Bluhmki E. Risk factors for severe hemorrhagic transformation in ischemic stroke patients treated with recombinant tissue plasminogen activator: a secondary analysis of the European-Australasian Acute Stroke Study (ECASS II). Stroke. 2001;32:438-441.
20. Kidwell CS, Saver JL, Carneado J, et al. Predictors of hemorrhagic transformation in patients receiving intraarterial thrombolysis. Stroke. 2002;33: 717-724.
21. Selim M, Fink JN, Kumar S, et al. Predictors of hemorrhagic transformation after intravenous recombinant tissue plasminogen activator: prognostic value of the initial apparent diffusion coefficient and diffusion-weighted lesion volume. Stroke. 2002;33: 2047-2052.
22. Okada Y, Yamaguchi T, Minematsu K, et al. Hemorrhagic transformation in cerebral embolism. Stroke. 1989;20:598-603.
23. Broderick JP, Hagen T, Brott T, et al. Hyperglycemia and hemorrhagic transformation of cerebral infarcts. Stroke. 1995;26:484-487.
24. Kase CS, Furlan AJ, Wechsler LR, et al. Cerebral hemorrhage after intra-arterial thrombolysis for ischemic stroke: the PROACT II trial. Neurology. 2001;57:1603-1610.
25. Tong DC, Adami A, Moseley ME, et al. Prediction of hemorrhagic transformation following acute stroke: role of diffusion- and perfusion-weighted magnetic resonance imaging. Arch Neurol. 2001;58: 587-593.
26. Vo KD, Santiago F, Lin W, et al. MR imaging enhancement patterns as predictors of hemorrhagic transformation in acute ischemic stroke. AJNR. 2003;24:674-679.
27. Hacke W, Brott T, Caplan L, et al. Thrombolysis in acute ischemic stroke: controlled trials and clinical experience. Neurology. 1999;53(suppl 4):S3-S14.
28. Wardlaw JM, Zoppo G, Yamaguchi T, Berge E. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev. 2003;(3):CD000213.