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

recent years due to control of risk factors, but total numbers are increas- irreversible necrosis is shorter, the risk and consequences of bleeding are
ing as a consequence of aging of the population. Although aspirin and greater, and there is more variability in the thrombo(embolic) occluding
anticoagulants may be useful in prevention, thrombolytic therapy is the lesion. Further, the occlusive platelet-fibrin thrombus that precipitates a
only available intervention during the acute stage. myocardial infarction is quite small, whereas the occlusive lesion caus-
The appropriate use of thrombolytic therapy for stroke is based ing ischemic stroke may be a large in situ thrombus, small platelet-fibrin
on an understanding of its pathogenesis. Ischemic stroke is most com- embolus, or large embolus of varying age and composition originating
monly caused by rupture of an atherosclerotic plaque within a large from the left atrium. Thrombolysis has had a smaller impact for stroke
or medium-sized artery in the neck or cranium. In addition, transient than it has for myocardial infarction, based largely on these differences.
ischemic attacks (TIAs) and strokes involving small arteries can result
from embolization of platelet-fibrin thrombi that form on atheroscle- Early Thrombolytic Studies
rotic vessels in the neck and ascending aorta, or from embolization of The current therapeutic approach began with small, open-label stud-
thrombi that form in the heart in association with atrial fibrillation, ies that used intravenous or intraarterial streptokinase, urokinase, and
valve dysfunction, artificial valves, or endocardial thrombi. Up to t-PA to determine dose, recanalization rate, hemorrhagic potential, and
30 percent of strokes have no defined etiology. clinical predictors of response. 324–339 These studies demonstrated that
Current approaches to thrombolytic therapy for stroke are based on recanalization could be achieved, that early treatment was essential,
imaging to define the etiology, results of clinical trials, and the experience and that the rate of intracranial hemorrhage and hemorrhagic trans-
with thrombolysis for acute myocardial infarction. Modern computed formation within the ischemic area was high. Phase II studies defined
tomography (CT) imaging and magnetic resonance imaging (MRI) can the optimum dosage and time window for intravenous t-PA and served
identify ischemic areas and localize areas of hemorrhage quite early. as the basis for larger phase III trials that led to the current t-PA-based
Additionally, arteriography can identify obstructed vessels and follow approach to thrombolytic therapy for stroke (Table 135–5). At present,
the course of recanalization during thrombolytic therapy. Clinical stud- the only FDA-approved therapy for acute stroke is intravenous alteplase
ies have generally followed the successful designs used for myocardial (recombinant t-PA) given within 3 hours of symptom onset.
infarction that demonstrated the critical pathologic role of the occluded
vessel, the importance of early recanalization in preserving myocardium, Tissue Plasminogen Activator Therapy
and the impressive decrease in morbidity and mortality resulting from The National Institute of Neurological Disorders and Stroke (NINDS)
early reperfusion. They have also characterized the bleeding risk. Study was a two-part randomized, double-blind, placebo-controlled
The experience with thrombolytic treatment for stroke also high- study to test whether t-PA improved clinical outcome at 24 hours and
340
lights important differences from myocardial infarction. The arterial 3 months. All patients were treated within 3 hours of symptom onset
anatomy of the brain is more complex, the time from onset of ischemia to with a total dose of 0.9 mg/kg of t-PA. The combined results showed a

TABLE 135–5. Major Fibrinolytic Therapy Trials in Stroke
Study No. of Patients Time Drug Thrombolytic Dose* † Main Efficacy Result
NINDS 624 ≤3 h t-PA, IV 0.9 mg/kg Reduced disability at 3 months
ECASS I 620 ≤6 h t-PA, IV 1.1 mg/kg No significant difference
ECASS II 800 ≤6 h t-PA, IV 0.9 mg/kg No significant difference
ECASS III 821 3–4.5 h t-PA, IV 0.9 mg/kg Improved outcome at 3 months
ATLANTIS 613 ≤6 h ‡ t-PA, IV 0.9 mg/kg No significant difference
SITS-ISTR # 11,865 vs. 664 ≤3 vs. 3–4.5 h t-PA, IV 0.9 mg/kg No significant difference
ASK 340 ≤4 h SK, IV 1.5 million units Increased morbidity and mortality
MAST-I 622 ≤6 h SK, IV ¶ 1.5 million units Increased mortality
MAST-II 310 ≤6 h SK, IV § 1.5 million units Increased mortality
||
PROACT II 180 ≤6 h pro-UK, IA 9 mg Improved 3-month outcome
MELT 114 ≤6 h u-PA, IA variable ’ No significant difference in favorable
outcome; significant difference in
excellent functional outcome

ASK, Australian Streptokinase; ATLANTIS, Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke; ECASS, European
Cooperative Acute Stroke Study; IA, intraarterial; MAST, Multicentre Acute Stroke Trial; MELT, The Middle Cerebral Artery Embolism Local
Fibrinolytic Intervention Trial; NINDS, National Institute of Neurological Disorders and Stroke; Pro-UK, pro-urokinase; PROACT II, Prolyse in
Acute Cerebral Thromboembolism II; SITS-ISTR, Safe Implementation of Treatments in Stroke—International Stroke Thrombolysis Registry; SK,
streptokinase; t-PA, tissue-type plasminogen activator; u-PA, urokinase plasminogen activator.
*All placebo controlled.
† All given over 1 h except PROACT II, which was 2 h.
‡ 547/613 within 3–5 h.
# Observational study without placebo arm.
¶ 2 × 2 factorial design with acetylsalicylic acid (ASA) 300 mg/day.
§ Acetylsalicylic acid (ASA) 100 mg/day.
|| Pro-UK and placebo group also received heparin.
< Mean doses of u-PA in patients with good and poor outcome were 555,000 IU and 789,000 IU.

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