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2314 Part XII: Hemostasis and Thrombosis Chapter 135: Fibrinolysis and Thrombolysis 2315

30 percent improvement in clinical outcomes at 3 months and the ben- examined benefits and risks of streptokinase treatment with or without
efit persisted at 12 months, despite a 10-fold increase in early symp- aspirin in patients with acute ischemic stroke who presented within
tomatic intracranial hemorrhage. At 3 months, there was no difference 6 hours of symptom onset. An interim analysis resulted in early ter-
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in mortality between the groups. This study formed the basis of the mination because streptokinase treatment was associated with a 2.7-fold
approval by the FDA of intravenous t-PA for stroke in 1996. increase in fatality at 10 days among patients receiving both streptokinase
Early randomized trials of IV t-PA did not show clear benefit for and aspirin. In the Multicenter Acute Stroke Trial-Europe (MAST-E)
patients treated beyond 3 hours after stroke onset. In the European trial, the mortality rate at 10 days was higher in patients who received
Cooperative Acute Stroke Study (ECASS) Study, subjects with moderate streptokinase (34.0 percent) compared with placebo (18.2 percent, p
to severe symptoms were randomized to placebo or t-PA within 6 hours <0.02) primarily because of hemorrhagic transformation of infarcts. 352
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of symptom onset ; results showed no significant difference in either
the primary end point of functional status at 90 days or in 30-day mor- Tenecteplase Therapy
tality. In the ECASS II, in which patients were randomized and stratified Tenecteplase is a genetically modified and genetically engineered
for presentation up to 3 hours after symptom onset or between 3 and recombinant t-PA; it has a higher fibrin specificity and greater resis-
6 hours, there was no significant benefit of thrombolytic therapy using tance to inactivation by its endogenous inhibitor (PAI-1) compared to
the primary end point of functional capacity of 90 days. The Alteplase native t-PA. In a phase IIB study, there were no significant differences
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Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke in intracranial bleeding or other serious adverse events in patients
(ATLANTIS) Study evaluated the safety of recombinant t-PA (rt-PA) in receiving alteplase versus tenecteplase. However, the two tenecteplase
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a double-blind, placebo controlled study with administration of drug groups had greater reperfusion (p = 0.004) and clinical improvement
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between 3 and 5 hours after symptom onset, and the primary end (p <0.001) at 24 hours compared with the alteplase group. The study
point of excellent neurological recovery was observed in 32 percent of outcome supports ongoing phase II–III trials of tenecteplase ver-
placebo and 34 percent of rt-PA–treated patients. Early symptomatic sus alteplase in the time window that is currently approved for stroke
intracranial hemorrhage occurred in 1.1 percent of control and 7.0 per- thrombolysis (NCT01472926 and NCT01949948).
cent of rt-PA–treated patients. There was a nonsignificant trend toward
increased mortality with rt-PA treatment at 90 days (6.9 percent vs. 11.0 Intraarterial Thrombolysis
percent, p = 0.09). A meta-analysis pooling data from NINDS, ATLAN- Intraarterial administration allows delivery of a high concentration of
TIS, and ECASS II patients who received either alteplase or placebo a Plg activator in proximity to the thrombus, more accurate anatomic
within 6 hours showed that the odds of a favorable 3-month outcome diagnosis, the ability to observe the course of recanalization, and lower
decreased as the interval from stroke onset to the start of alteplase treat- total doses of drug that might reduce intracranial hemorrhage. On the
ment increased. Furthermore, the study alluded to the potential bene- other hand, this approach requires specialized facilities and experienced
fit of extending the treatment window to 4.5 hours with favorable but personnel to perform arteriography and selective catheterization, which
decreasing odds ratio for alteplase treatment beyond 3 hours. 344 may delay treatment. Several small open-label trials observed a high
The benefit of IV t-PA for treatment beyond the 3-hour window rate of recanalization and apparent clinical benefit with intraarterial
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was established by the ECASS III trial. This study showed that IV therapy using urokinase, streptokinase or t-PA, but hemorrhagic trans-
t-PA treatment initiated at 3 to 4.5 hours after ischemic stroke onset formation was a frequent problem. 327,331,334,337,354–360
led to a modest improvement in the 3-month outcome. More patients The Prolyse in Acute Cerebral Thromboembolism (PROACT)
had a favorable outcome with t-PA than with placebo (52.4 percent vs. and PROACT II trials evaluated recombinant human prourokinase by
45.2 percent; odds ratio: 1.34; 95 percent CI 1.02 to 1.76). While the catheter-directed intraarterial administration. 361,362 In the PROACT
incidence of intracranial hemorrhage was higher with t-PA treatment trial, a significantly higher recanalization rate was observed with
(2.4 percent vs. 0.2 percent; p = 0.008), there was no difference in mor- prourokinase treatment with no increase in intracranial hemorrhage.
tality between the two groups. This led to the larger PROACT II trial, which revealed a significantly
The effect of alteplase given beyond 3 hours after stroke on infarct higher recanalization rate with prourokinase (66 percent vs. 18 percent,
growth and reperfusion was studied in the Echoplanar Imaging Throm- p <0.001), and superior functional improvement at 90 days. 363,364
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bolytic Evaluation Trial (EPITHET) trial. Alteplase was shown to Symptomatic intracranial hemorrhage occurred in 10 percent of
be significantly associated with increased reperfusion in patients who patients treated with prourokinase and 2 percent of controls. Although
had mismatch at baseline (p = 0.001), better neurologic outcome promising, these results did not lead to FDA approval of intraarterial
(p <0.0001), and better functional outcome (p = 0.010). The observa- prourokinase for treatment of stroke.
tional Safe Implementation of Treatment in Stroke International Stroke A third study, the Middle Cerebral Artery Embolism Local
Thrombolysis Register (SITS-ISTR) study further supported the safety Fibrinolytic Intervention Trial (MELT), was underpowered because
of administering IV t-PA between 3 and 4.5 hours after acute ische- of premature study closure. A favorable, but not statistically signifi-
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mic stroke. 347,348 Compared to patients treated within less than 3 hours cant, outcome at 90 days was more likely with intraarterial urokinase
(n = 11,865), those treated at 3 to 4.5 hours (n = 664) had similar rates compared with placebo. The proportion of patients with an excel-
of independence, symptomatic intracranial hemorrhage, and mortal- lent functional outcome was significantly better in the intraarterial
ity. An updated pooled analysis of ECASS, ATLANTIS, NINDS, and urokinase group (42 percent vs. 23 percent, p = 0.045). Intracerebral
EPITHET trials continues to demonstrate that patients with ischemic hemorrhage within 24 hours of treatment occurred in 9 percent and
stroke, selected by clinical symptoms and CT, benefit from intravenous 2 percent, respectively (p = 0.206). This study suggested that intraarte-
alteplase when treated no later than 4.5 hours. 349 rial fibrinolysis has the potential to increase the likelihood of excellent
functional outcome in appropriate clinical settings.
Streptokinase Therapy Overall, these studies show that treatment of acute stroke with
Streptokinase has been evaluated in three large stroke trials. The Aus- thrombolytic therapy can lead to recanalization of the occluded artery
tralian Streptokinase (ASK) study showed an increase in death rate at and improvement in clinical outcomes. The need for early treatment,
90 days in streptokinase- treated patients, and the study was prematurely which improves outcome, is currently the single largest limitation
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terminated. The Multicentre Acute Stroke Trial–Italy (MAST-I) study to greater application of thrombolytic therapy for stroke, and less

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