Clinical Review & Education
Review
Progress in Intravenous Thrombolytic Therapy for Acute Stroke Randolph S. Marshall, MD, MS
IMPORTANCE Intravenous recombinant tissue plasminogen activator (alteplase) was
approved by the US Food and Drug Administration in 1996 for the treatment of acute ischemic stroke. Nearly 20 years later, it remains the only approved treatment, despite limitations in both efficacy and safety. With a growing capacity for stroke treatment worldwide, physicians need to understand where we have come from and what the future of stroke treatment might be. OBJECTIVE To present a historical prospective as well as current trends in thrombolytic therapy, focusing on characteristics of drugs that have worked and clinical trials that are moving the field forward. EVIDENCE REVIEW Sources are published pivotal clinical trials; seminal articles on physiology, pharmacology, and neuroimanging; and listings from clinical trial registries. FINDINGS The slow progress in thrombolysis for acute stroke has been multifactorial. A focus on extending the time window for alteplase beyond 4.5 hours has encumbered substantial resources in the field for many years, yet these efforts have been largely unsuccessful. New drug development has also been slow. Several drugs have failed in clinical trials and currently only tenecteplase remains to be tested as a potential alternative to alteplase. The parallel pursuit for catheter-based interventional revascularization in acute stroke, which appears to be successful, has shifted emphasis away from pharmacologically based studies. CONCLUSIONS AND RELEVANCE Although the field of acute thrombolysis has been making
progress slowly for many years, advances in neuroimaging and new clinical trials that combine thrombolytics with other pharmacological and interventional techniques are beginning to gain momentum once again. The emergence of new approaches based largely on combination therapy strategies has reset a course to advance thrombolytic treatment for acute stroke and promises to improve outcomes in acute stroke in the near future. JAMA Neurol. doi:10.1001/jamaneurol.2015.0835 Published online June 1, 2015.
I
ntravenous (IV) recombinant tissue plasminogen activator (rtPA; alteplase) was approved by the US Food and Drug Administration in 1996 for the treatment of acute ischemic stroke. Now, nearly 20 years after completion of the pivotal National Institute of Neurological Disorders and Stroke (NINDS) trial,1 we are in essentially the same place with regard to IV thrombolysis. No new drugs have been approved for acute stroke and the time window for alteplase remains at 3 hours in the United States, widened marginally to 4.5 hours in Europe. Compare this with the explosion of endovascular device development in the last decade and the fastpaced emergence of pharmacotherapeutics for secondary stroke prevention, such as new antiplatelets, novel anticoagulants, and statins. There is an inexplicable stagnation in the field of IV thrombolysis. Why has the progress been so slow? Did we serendipitously arrive at the final ideal drug, dose, and time window in 1995? Alteplase provides benefits but it has limitations both in efficacy and safety.
Author Affiliation: Department of Neurology, New York-Presbyterian/ Columbia University Medical Center, New York. Corresponding Author: Randolph S. Marshall, MD, MS, Department of Neurology, New York-Presbyterian/ Columbia University Medical Center, 710 W 168th St, New York, NY 10032 ([email protected]). Section Editor: David E. Pleasure, MD.
Why have alternatives been so slow to emerge? Is there insufficient science? Insufficient funding? Too much inertia in this arena compared with the promise of greater advances elsewhere? This review traces the development of IV thrombolysis to date, considers the shortcomings of alteplase, and examines alternative thrombolytic approaches currently in the pipeline, including the role of neuroimaging and the possibility of combination therapies.
Historical Perspective The concept of thrombolysis emerged in 1933 with the discovery by Tillett and Garner2 that certain strains of Streptococcus could dissolve fibrin clots. In the 1950s, Tillett and Garner2 put this concept to practical use in a study using streptokinase (SK) in the treatment of patients with intravascular thrombi. A second naturally occurring
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thrombolytic substance was discovered in the 1940s, when human urine was demonstrated to have thrombolytic properties. The isolation of this agent termed urokinase offered another option for thrombolysis. The first reported use of thrombolysis for acute stroke occurred in 1958, when Sussman and Fitch3 treated 3 patients with fibrinolysin (plasmin) with IV injections for 4 to 6 days who showed some clinical improvement. Although this was a far cry from today’s double-blind randomized clinical trials, the Sussman and Fitch study3 launched a drive to refine the use of thrombolysis for acute ischemic stroke. Not surprisingly, early SK and urokinase trials were plagued by intracranial hemorrhage and high mortality. The main problem was a lack of pretreatment imaging to determine whether neurological deficit was caused by ischemia or hemorrhage. Therefore, this treatment approach was abandoned for many years. It was not until the emergence of computed tomography (CT) scanning that a reasonable attempt to test this pharmacotherapy could be reconsidered. It was not until the 1980s that the first clinical trials began to emerge in pursuit of the heretofore untreatable condition of acute ischemic stroke. In 1986, Fujishima et al4 used urokinase vs urokinase plus dextran sulfate to treat 143 patients with acute stroke, reporting improvement in 74% of patients who received urokinase alone and 84% of patients who received the combination. However, there was no control arm to test the thrombolytic agent compared with the placebo and no blinding of assessments, standardization of outcomes, or standard protocol for imaging. Other trials in that period had similar shortcomings. A common characteristic of the thrombolytic trials of the 1980s was the administration of low-dose thrombolysis given across several days and started several days after stroke onset. Soon to follow was an increased interest in early high-dose administration and, in particular, SK for acute ischemic stroke. The Multicenter Acute Stroke Trial Italy (MAST-I) and Multicenter Acute Stroke Trial Europe (MAST-E) tested this agent in 2 large multicenter trials.5,6 However, high intracranial hemorrhage rates occurred, leading to the abandonment of SK for acute stroke. A better drug was needed. The interest in tPA for dissolving intravascular thrombi started with treatment of myocardial infarction. Initially, the naturally occurring thrombolytic was used but the availability of this tissue-derived glycoprotein was extremely limited and difficult to produce. It was not until the recombinant form rtPA (alteplase) was created using a Chinese hamster ovary cell line to clone the gene that the capacity for widespread use was realized. The genetic modification technique involved in refining rtPA revolutionized the commercial production of many different drugs and has become a multibillion dollar worldwide operation. The first major phase 3 clinical trial using rtPA was a cardiac trial, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I), which randomized more than 40 000 patients with acute myocardial infarctionandshowedsuperiorityofIValteplaseplusheparincomparedwith SK for thrombolysis of coronary arteries. The first trial of rtPA for acute stroke was conducted in the late 1980s, comparing alteplase with urokinase in 364 patients.7 This trial showed no difference in stroke outcomes between treatment groups. The NINDS then sponsored the seminal trials of IV alteplase, beginning with dose-finding pilot studies in the 3-hour time window.8,9 The establishment of the treatment protocol with 0.9 mg/kg, giving 10% as an initial bolus and the remaining 90% across 1 hour, was tested in the pivotal phase 3 trial.1 This study had 2 parts, the first (n = 291) assessed clinical improvement within 24 hours as measured by an imE2
provement of 4 points or more on the National Institutes of Health Stroke Scale (NIHSS), and the second (n = 333) measured functional outcome at 3 months, using the modified Rankin Scale, NIHSS, Barthel Index, Glasgow Outcome Scale, and a global measure combining all 4 of these measures. The first part was negative for the 24-hour outcome but the second was positive, demonstrating that those treated with IV rtPA were 30% more likely to achieve better functional outcomes than those treated with placebo (global odds ratio for a favorable outcome = 1.7; 95% CI, 1.2-2.6; P = .008). The result from part 2 was validated in a post hoc analysis of the patients from part 1 and remained positive across subgroups of age, stroke subtype, stroke severity, and the use of aspirin before the stroke. Symptomatic intracranial hemorrhage occurred in 6.4% of those treated with rtPA (much lower than the >10% rate with SK and urokinase) vs 0.6% in those receiving the placebo. Despite the difference in symptomatic intracranial hemorrhage rate, mortality was nearly identical, 17% in the rtPA group and 21% in the placebo group (P = .30). The result of this trial published in 1995 was a major breakthrough in the management of acute ischemic stroke and led to the US Food and Drug Administration approval of this drug in 1996. The use of IV rtPA according to the NINDS trial dosing regimen has remained the mainstay of acute stroke treatment for the ensuing 19 years (Figure 1).
IV rtPA: Intrinsic Properties and Alternative Drugs The approval of IV alteplase revolutionized acute stroke treatment worldwide; however, it had important limitations. The efficacy and safety of thrombolytic agents are dependent on several key characteristics, including specificity for the intravascular clot, the drug’s half-life, the secondary inhibition of plasminogen activation, the drug’s effects on the blood-brain barrier (BBB), and its effects on lipid processing. These important properties are key to understanding potential advances in the field. Thrombolytic drugs lyse clots in the vascular bed by activating plasminogen, which catalyzes its conversion to plasmin, the lytic molecule that breaks down the clot in situ. Intravascular thrombi are composed of fibrin monomers that are cross-linked through lysine side chains. The binding of thrombolytic agents to these lysine cross links gives them specificity for the clot. Plasminogen also has a high affinity for the lysine side chains; therefore, there is a high concentration of plasminogen at the clot site. Once plasminogen is converted to plasmin, it breaks the thrombus into fibrin degradation products. Fibrin specificity is the most important pharmacological property that determines safety. The higher the fibrin selectivity, the greater the specificity for thrombolysis at the clot site; therefore, the less risk of systemic hemorrhage. Urokinase and SK have low-fibrin selectivity, accounting in part for higher hemorrhage rates in clinical trials. Alteplase has a higher fibrin selectivity than urokinase and SK but some of the newer thrombolytic agents, such as tenecteplase and desmoteplase, have an even higher fibrin selectivity and, thus, have the potential for higher efficacy and lower morbidity in acute ischemic stroke. A second property of thrombolytic agents is the drug’s halflife. The half-life of alteplase is 4 to 8 minutes, resulting in the need to deliver the drug as a bolus followed by an infusion, as delineated in the US Food and Drug Administration–approved alteplase administration protocol. Tenecteplase has a half-life of 11 to 20 minutes and desmoteplase has a half-life of 138 minutes, which means that throm-
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Progress in Intravenous Thrombolytic Therapy for Acute Stroke
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Figure 1. History of Thrombolysis 1933
1940
1986
Streptokinase discovered
1991 1995 1996
2009
Mass production of recombinant tissue plasminogen activator Urokinase discovered
First urokinase trial
2015
Desmoteplase trials fail
US Food and Drug Administration approves recombinant tissue plasminogen activator for stroke
Combination trials
Phase 3 tenecteplase trials
National Institute of Neurological Disorders and Stroke tissue plasminogen activator trial Urokinase and streptokinase trials fail
Timeline showing the history of intravenous thrombolysis.
Table 1. Properties of Thrombolytic Agents Agent
Fibrin Selectivity
PAI-1 Inhibition
Half-life, min
BBB Opening
HDL-C Level Lowering
Alteplase
Moderate
Streptokinase
Negligible
High
4-8
Moderate
Moderate
Negligible
6
Unknown
Urokinase
Negligible
High
Unknown
15
Unknown
Unknown
Desmoteplase
Very high
Unknown
138
Negligible
Unknown
Tenecteplase
High
Low
Unknown
Low
11-20
bolysis may be achieved with a bolus injection alone for these agents, making administration easier, particularly if the IV treatment is to be followed up with endovascular intervention. A third important property is the secondary induction of type I plasminogen activator inhibitor, which results in a paradoxical counteraction of the thrombolytic effect once the drug reaches the clot. While urokinase and alteplase have this property, desmoteplase and tenecteplase do not, making them potentially more effective as thrombolytic agents. A fourth property of alteplase is its effect on the BBB. This effect is thought to be mediated by the upregulation of matrix metalloproteinases in endothelial cells. Using an in vitro model of the BBB, it has been shown that under ischemic conditions in the presence of plasminogen, alteplase degrades the BBB; however, in a direct comparison in an in vitro model, desmoteplase did not.10 The breakdown of the BBB after administration of an agent that breaks up clots would be a crucial factor in determining the safety of acute thrombolysis, including the development of poststroke edema and the hemorrhagic conversion of an ischemic infarct. In the absence of an agent that does not have this effect, one proposed approach to mediate the matrix metalloproteinase effects is the use of ρ kinase inhibitors at the time of thrombolysis administration.11 A fifth property of thrombolytic agents is their effect on apolipoprotein A-I, the main protein component of high-density lipoprotein cholesterol levels. Degredation of this protective element of the lipid family was tested in 38 patients with myocardial infarction, 19 patients receiving standard cardiac doses of alteplase and 19 patients receiving treatment with tenecteplase.12 Although both agents caused plasmin-mediated proteolysis of apolipoprotein A-I, those
Abbreviations: BBB, blood-brain barrier; HDL-C, high-density lipoprotein cholesterol; PAI-1, type I tissue plasminogen activator.
treated with tenecteplase had a lesser effect at least in the short term, potentially preserving the atheroprotective effects of high-density lipoprotein cholesterol levels. There may be a neurotoxic effect of alteplase via its interaction with the N-methyl-D-aspartate receptor.13 Overall, the shortcomings of alteplase have generated an examination of alternative thrombolytic agents in an attempt to improve the drug’s efficacy and safety profile (Table 1). Desmoteplase is an orthologue of human tPA derived from the saliva of the common vampire bat, Desmodus rotundus. Its main plasminogin activator has a 72% homologue with human tPA. 14 Desmoteplase is much more fibrin selective than alteplase, has a much longer half-life, and has no known effect on the BBB. Two small phase 2 clinical trials using demoteplase demonstrated good reperfusion and suggested increased efficacy compared with the placebo.15,16 However, the first phase 3 trial, DIAS (Desmoteplase In Acute Stroke) 2, which randomized 193 patients to desmoteplase vs placebo at 3 to 9 hours after stroke, was negative.17 The protocol used magnetic resonance (MR) or CT perfusion to identify patients with brain tissue at risk, regardless of time poststroke, for as long as 9 hours. Limitations included a small study sample and lack of standardization of imaging selection criteria. The following 2 additional phase 3 trials have finished: DIAS 3, which started in 2009 in Europe, Australia, and Asia and has no results published to date, and DIAS 4, which started in 2011 in the United States and was terminated owing to the result of DIAS 3 being unlikely to reach its primary endpoint with the current protocol (https://clinicaltrials.gov). Tenecteplase, a third-generation rtPA, represents a targeted genetic upgrade to improve thrombolytic safety and efficacy. Three
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Figure 2. Protein Substitutions to Make Tenecteplase Kringle 2 200 S C L P W N S E M I V H C W T P L L L K K A A I I Q N S F A G A W H R D K K P T R 250 G V H H G S Y D R L A T R R P T I A S 300 Y N W 125 D P Q A E A G N R A Q K P Y S G R R S F E L Y P D P C L R A A G C I S F G Y D R N S A L G 325 E R F P G N L V C K Q Q S F H G P G F 275 R I P H N I G K 225 A C L Y L F S H G L G L I H G W Q C C 150 S L P N A Q N S S D A H S T D D R S Y P N T S P K V C G L R Q R C Y N T S C L W W I I E Q N C A C S S L T P A C V V G Y S G T R E R C S E C C V R S F V A 175 L E T S F K G A G K Y S S P Y D E Y C T S D R P S Q E A V A K I G A S V T S W T G R Y R L D E 400 P E L Q E G T Q Q L P D W T E C E L S G Y 100 K D G L 375 F I 350 K E Epidermal C C L G D N L C E H G K V E M R V growth factor domain A T A E K Y P C Q C L I L I A F G E V 75 V V D P L H N G S F S W L R K G R C D P H P Q I Y F D E G F V 25 T H I N S Y E D S D D F L S Q S G S E 425 F 500 G D R W G Q G L R C Y T S Y Q 475 G C S L L N I K 50 Q C C K C T S Q V Q A M S R R A H D L E P G S L W Y D A P Q V V L I Q Y H V H N A S L T R E K R N C G L H T N K D L D D Y R A T C Fibronectin E V M R Q P G V N C T 450 G S N Q K D P M D V finger T W 525 R A T Y V G R C R P C N G I Protease domain S Q V S Y S
G A
Kringle 1
COOH
NH2
specific alterations to the alteplase molecule, a tetra-alanine substitution in the protease domain and 2 other single amino acid substitutions in the kringle 1 lysine-binding domain, resulted in a longer half-life, greater binding affinity for fibrin, and better resistance to inactivation by the endogenous inhibitor type I plasminogen activator inhibitor (Figure 2). These properties have made tenecteplase a potentially more effective and safer thrombolytic drug than alteplase. Two prospective randomized open-label blinded endpoint (PROBE design) clinical trials have either been completed or are now underway to test tenecteplase compared with alteplase for acute ischemic stroke. The first was a small phase 2B open-label blinded outcome trial completed in 2011, randomizing 75 patients to receive 0.1 mg/kg of IV tenecteplase or 0.25 mg/kg of IV tenecteplase as a single bolus vs a standard dose of IV alteplase in a 1 to 1 to 1 randomization scheme in a 6-hour window.18 Coprimary endpoints were the proportion of the CT perfusion deficit that was reperfused at 24 hours and clinical improvement at 24 hours on the NIHSS. Secondary endpoints included the proportion of patients recanalized at 24 hours and a 90-day modified Rankin Scale. The study results were positive for both primary endpoints (greater reperfusion, P = .004; and better NIHSS at 24 hours, P < .001) despite the small number of participants randomized. The study also established the dose of 0.25 mg/kg as superior to the 0.1 mg/kg dose in efficacy, with no significant decrement in safety. The symptomatic hemorrhage rate in the alteplase group in this study was 12%, nearly double the 6.4% reported in the original NINDS alteplase trial. The following secondary endpoints were also positive: infarct growth at 24 hours and 90 days, complete or partial recanalization at 24 hours, E4
Red circles designate the locations where protein substitutions were made to change the properties of alteplase to make tenecteplase.
major neurological improvement (NIHSS reduction of ⱖ8) at 24 hours, and excellent or good recovery at 90 days. A phase 3 trial is planned to follow up this phase 2 effort, the TASTE (Tenecteplase vs Alteplase for Stroke Thrombolysis Evaluation) trial, which will test IV tenecteplase vs alteplase in the zero- to 4.5-hour window. A second phase 3 tenectoplase trial, the NOR-TEST (Norwegian Teneteplase Stroke Trial) aims to randomize 954 patients to identify a 9% or more difference in excellent outcome for IV tenecteplase at a dose of 0.4 mg/kg vs a standard dose of IV alteplase.19 This study will also use a zero- to 4.5-hour window but, uniquely, will include those who present within 4.5 hours of awakening with stroke symptoms and for those in whom endovascular embolectomy is planned within a 6-hour window. The primary outcome measure for this study will be clinical only, a modified Rankin Scale score at 90 days, with secondary endpoints of 24-hour improvement in NIHSS and recanalization at 24 to 26 hours. A list of registered ongoing clinical trials using IV thrombolytics is represented in Table 2.
Brain Imaging and the Limits of the Thrombolysis Window Testing the limits of a safe and effective treatment window for thrombolysis has been a recurrent challenge since the original NINDS trials showed efficacy within a 3-hour window. Many clinical trials have taken the challenge, including the ATLANTIS (Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke) trial,20 EPITHET (Echoplanar Imaging Thrombolysis Evaluation Trial),21 and
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Table 2. Active Thrombolysis Trials Trial Registry Identification
Study Name
Drug/Intervention
Sponsor
Location
Study Phase
NCT02072226
PRISMS
Alteplase for mild stroke
Genentech
United States
3
Clinical (90-d mRS)
NCT01282242
MR WITNESS
Alteplase for wake-up stroke
NINDS
United States
2
Safety (ICH rate)
NCT01525290
WAKE-UP
Alteplase for wake-up stroke
University of Hamberg-Eppendorf
Europe
3
Clinical (90-d mRS)
NCT01643902
SAIL-ON
Alteplase for wake-up stroke
Genentech
United States
2
Safety (ICH rate)
NCT02002325
THAWS
0.6 mg Alteplase for wake-up stroke
National Cerebral and Cardiovascular Center
Japan
3
Clinical (90-d mRS)
NCT00887328
EXTEND
Alteplase in 3- to 9-h window
NSRI, Australia
Australia
3
Clinical (90-d mRS)
NCT01123161
ICTuS2/3
Alteplase + hypothermia
NINDS
United States
3-2
Clinical (90-d mRS)
NCT02222714
RHAPSODY
Alteplase + activated protein C
NINDS, ZZ Biotech
United States
2
Safety (dose-limiting toxicity)
NCT01464788
ARTSS-2
Alteplase + argatroban
NINDS
United States
2B
NCT01977456
CLEAR-FDR
Alteplase + eptifibatide
NINDS
United States
2
Safety (ICH rate)
NCT02189928
RESCUE-BRAIN
Alteplase + per-conditioning
Unité de Recherche Clinique Paris Ouest
France
2-1
Imaging (infarct growth)
NCT01098981
CLOTBUST-ER
Alteplase + ultrasound
Cerevast Therapeutics
United States
3
Clinical (90-d mRS)
NCT01678495
Sonothrombolysis Potentiated by Microbubbles for Acute Ischemic Stroke
Alteplase + ultrasound with microbubble
l'Hospital de la Sata Creu I Sant Pau
Spain
2
Imaging (recanalization)
NCT02338466
DIVA
Alteplase + tenecteplase
Centre Hosp Univers de Fort-de-France
France
2
Clinical (90-d mRS)
ACTRN12613000243718
TASTE
Tenecteplase in 4.5-h window
National Health and Medical Research Council
New Zealand
3
Clinical (90-d mRS)
NCT02180204
TALISMAN
Tenecteplase in 3to 4.5-h window
The Ohio State University
United States
2B
NCT01472926
ATTEST
Tenecteplase in 4.5-h window
NHS Greater Glasgow and Clyde
Scotland
2
Imaging (penumbra reversal)
NCT02101606
TAIS
Tenecteplase in 4.5to 12-h window
University of Alberta
Canada
2
Safety (ICH rate)
NCT01949948
NOR-TEST
Tenecteplase in 4.5-h window
Research Council of Norway
Norway
3
Clinical (90-d mRS)
NCT02150785
AASIST
Streptokinase
University of Alberta
Asia/Africa
2
Safety (ICH rate)
Primary Outcome
Clinical (90-d mRS)
Safety (ICH rate)
Abbreviations: AASIST, Asia Africa Streptokinase Trial; ARTSS-2, Argatroban With Tissue Plasminogen Activator for Acute Stroke; ATTEST, Aleteplase-Tenecteplase Trial Evaluation for Stroke Thrombolysis; CLEAR-FDR, Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue Plasminogen Activator in Acute Ischemic Stroke Full-dose Regimen; CLOTBUST-ER, Combined Lysis of Thrombus With Ultrasound and Systemic Tissue Plasminogen Activator for Emergent Revascularization in Acute Ischemic Stroke; DIVA, Superiority of Recombinant Tissue Plasminogen Activator Tenecteplase in Comparison With Recombinant Tissue Plasminogen Activator Only in Proximal Middle Cerebral Artery Occlusion; EXTEND, Extending the Time for Thrombolysis in Emergency Neurological Deficits; ICH, intracranial hemorrhage; ICTu2/3, The Intravascular Cooling in the Treatment of Stroke 2/3 Trial; mRS, modified Rankin Scale; MR WITNESS, A Study of Intravenous Thrombolysis With Alteplase in Magnetic
Resonance Imaging–selected Patients; NHS, National Health Service; NINDS, National Institute of Neurological Disorders and Stroke; NOR-TEST, Norweigian Tenecteplase Stroke Trial; NSRI, Nutritional Science Research Institute; PRISMS, A Study of the Efficacy and Safety of Activase (Alteplase) in Patients With Mild Stroke; RESCUE-BRAIN, Remote Ischemic Conditioning in Acute Brain Infarction Study; RHAPSODY, Safety Evaluation of 3K3A-APC in Ischemic Stroke; SAIL-ON, Safety of Intravenous Thrombolytics in Stroke on Awakening; TAIS, Penumbral-Based Novel Thrombolytic Therapy in Acute Ischemic Stroke; TALISMAN, Tenecteplase vs Alteplase in Ischemic Stroke Management; TASTE, Tenecteplase vs Alteplase for Stroke Thrombolysis Evaluation; THAWS, Thrombolysis for Acute Wake-up and Unclear-onset Stroke With Alteplase at 0.6 mg/kg; WAKE-UP, Efficacy and Safety of Magnetic Resonance Imaging–based Thrombolysis in Wake-up Stroke.
ECASS (European Cooperative Acute Stroke Studies) 1 to 3. Although ATLANTIS and EPITHET showed no benefit in a 6-hour window using the NINDS trial dosing regimen, the ECASS studies culminating with ECASS 3 were positive. This European-only study randomized 821 patients with acute ischemic stroke to receive IV alteplase vs placebo in the 3- to 4.5-hour window.22 The decision to examine rtPA efficacy in the 3- to 4.5-hour time window was based on a meta-analysis showing decreasing marginal benefit with rtPA between 3 and 6 hours, with almost no benefit vs the risk at 6 hours.23 The ECASS 3 trial used the modified Rankin Scale score of zero to 1 at 3 months as the primary outcome measure and showed efficacy compared with the placebo in this outcome (odds ratio, 1.34; 95% CI, 1.02-1.76; P = .04) as well as with the combined outcomes
that were used in the NINDS 3-hour trial. The European Medical Agency subsequently approved IV rtPA for acute stroke in the 3- to 4.5-hour window in 2011, limiting the use to those younger than 80 years as was required in the trial. Despite the American Heart Association concurring with the extended time window in revised guidelines, the US Food and Drug Administration failed to approve alteplase in the extended time window, leaving the United States with IV rtPA in the zero- to 3-hour time window as the only approved treatment for acute ischemic stroke. A major effort during the nearly 20 years since the NINDS Alteplase trial has been an attempt to show the potential for an extended time window for thrombolysis. The charge has been led by neuroimaging. Tissue response to acute loss of blood flow in the brain
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Progress in Intravenous Thrombolytic Therapy for Acute Stroke
is dependent on the following 3 main variables: absolute reduction in blood flow, volume of tissue affected, and duration of the ischemia. With 50 cm3/100 g per min as a mean cerebral blood flow, as cerebral perfusion decreases to about 40 cm3/100 g per min, protein synthesis is inhibited and denaturing occurs, anaerobic glycolysis begins at about 30 cm3/100 g per min, glucose metabolism declines and ion transients appear at about 20 cm3/100 g per min, electrical failure occurs at about 18 cm3/100 g per min, and membrane failure occurs at 10 to 12 cm3/100 g per min. Blood flow in the ischemic core is 6 to 10 cm3/100 g per min. The so-called ischemic penumbra, defined as the region around the infarct core that is reversibly damaged by ischemia, is thought to be the zone that has an upper threshold of electrical failure and a lower threshold of energy and ion pump (membrane) failure.24 This tissue at risk has the following 2 possible fates: incorporation into the infarct core if no reperfusion occurs or a return to normal function if the area is reperfused in time. The idea behind imaging strategies was that if it were possible to assess the physiological state of brain tissue at a given time after the onset of ischemia, then the timing of treatment with thrombolysis could be guided by the tissue clock rather than the time clock, even if the time since stroke onset was beyond 3 to 4.5 hours.25 Distinguishing the ischemic core from the penumbra or from a state of benign oligemia in which hypoperfused tissue never becomes incorporated into the ischemic core has been the holy grail of imageguided treatment of acute ischemic stroke. While the preclinical models of the penumbra used tissue probes and single-cell recording to determine the state of the cell membranes and metabolic state, such techniques are not possible in a clinical setting. The best noninvasive measure of the physiological state is positron emission tomography. Benign oligemia can be distinguished from more significant hemodynamic failure by characterizing zones of decreased flow with or without increased oxygen extraction fraction. A more significant hemodynamic failure termed stage 2 failure or misery perfusion can be distinguished from metabolic failure by measuring metabolic rate of oxygen directly. Positron emissiontomographyhasalsobeenusedtomeasureneuronalviabilitywith flumazenil labeled with radioactive carbon 11, which reflects the state of functioning benzodiazepine receptors.26 However, positron emission tomography has proven to be too expensive and too invasive and is not practical for use in short-term stroke treatment. Thus, the emergence of so-called mismatch imaging using MR perfusion and CT perfusion (CTP) has driven the quest for assessing tissue state in the last 2 decades and has been incorporated into several clinical trials. The diffusion-weighted imaging/perfusion-weighted imaging signal of MR and the CTP/cerebral blood volume signal of CT in the acute stroke period are used to delineate the ischemic core vs penumbra. These techniques are far removed from distinguishing electrical failure from membrane failure in a hypoperfused area, yet the advantages of MR perfusion and CTP techniques include a greater spatial resolution and wider clinical availability compared with positron emission tomography, particularly with CT scanning, which is required in every primary stroke center. Magnetic resonance has the additional advantage of being able to well define the ischemic core in the first hours after stroke onset. The challenge of these techniques has been standardization, whether imaging parameters are to be able to accurately represent the penumbra, particularly when the perfusion imaging takes place in later time windows. A penumbra has been reported as late as 48 hours27 but its implications for revascularization treatment are not E6
clear. Even the ischemic core, defined by the diffusion-weighted imaging, is not a static entity and may shrink or disappear in the first few hours after the ischemic insult. Several thrombolytic clinical trials have attempted to use MR or CT imaging to guide treatment or predict outcomes in acute ischemic stroke. For MR or CT perfusion, a penumbra is defined as a region outside the ischemic core where there is a delayed time to arrival of a bolus of contrast material. The time to maximum contrast concentration referred to as time to peak or Tmax has ranged from 2 to 6 seconds in various studies. Generally, a mismatch is considered significant if the penumbra is at least 20% of the ischemic core volume. One recommended threshold for the penumbra is a time to peak of 6 seconds, which is thought to be sensitive enough to include significant hypoperfusion and restrictive enough to exclude benign oligemia. In general, both the presence of a penumbra and reversal of a penumbra seem to correlate with improved clinical outcomes.28,29 The 2 desmoteplase early-phase trials (DIAS and DEDAS [Dose Escalation of Desmoteplase for Acute Ischemic Stroke]) used MR perfusion for treatment selection and showed promising results. Treating patients with stroke with diffusion-weighted imaging/perfusion-weighted imaging mismatch in the 3- to 9-hour time window had good reperfusion of mismatch areas and good clinical outcomes. However, the phase 3 randomized double-blind DIAS-2 trial failed to show clinical improvement, which was thought in part to be owing to less stringent time-to-peak criteria, resulting in the inclusion of patients in the later time windows with benign oligemia rather than tissue at risk. The phase 2B tenecteplase trial mentioned earlier used a CT/CTP mismatch criterion both for patient selection and as a primary outcome measure. The 2 other phase 3 tenecteplase trials, TASTE and NOR-TEST, will use CTP for selection criteria but within a standard 4.5-hour window. In addition to perfusion imaging, CT angiography and MR angiography are being used to assess the presence of pial collaterals as a predictors of better stroke outcomes and greater likelihood of treatment efficacy.30 For the most part, attempts to extend the time window for IV thrombolysisusingimagingcriteriahavebeenunsuccessfullargelyowing to the failure of accurately defining the penumbra at later points. Because the predominance of preclinical and clinical evidence suggests that 6 hours is the hard stop for reversible ischemia, the benefit of hemodynamic imaging in acute stroke may be to define those most likely to have tissue recovery within a more limited time window or to assist when the time of stroke onset is unknown. Further refinement of imaging techniques to better define the penumbra are required to bring hemodynamic imaging into the clinical arena.
Conclusions Although the extension of the time window may continue to be sought after, a clear unmet need is the improvement of the efficacy and safety of IV thrombolysis within a standard time window. The recently initiated trials of tenecteplase may further this goal and ultimately provide safer and more effective thrombolytic treatment. Continued attempts to improve fibrin specificity and reduce other detrimental effects inherent with alteplase are warranted. Basic pharmacology should be charged with generating what could be termed thenexteplase with rationally implemented modifications similar to what was done with tenecteplase. A promising second focus would be to maxi-
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Progress in Intravenous Thrombolytic Therapy for Acute Stroke
mize the effects of IV thrombolysis in combination with other acute stroke treatments, including mechanical clot retrieval. With the recent publication of the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) study along with the SWIFT PRIME (Solitaire FR as Primary Treatment for Acute Ischemic Stroke),31 the ESCAPE (Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke)32 and EXTEND-IA (Extending the Time for Thrombolysis in Emergency Neurological Deficits Intra-Arterial) trials,33 which were stopped early based on positive interim analyses, it appears that endovascuARTICLE INFORMATION Accepted for Publication: February 23, 2015. Published Online: June 1, 2015. doi:10.1001/jamaneurol.2015.0835. Conflict of Interest Disclosures: None reported. REFERENCES 1. Tissue plasminogen activator for acute ischemic stroke: the National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333(24):1581-1587. 2. Tillett WS, Garner RL. The fibrinolytic activity of hemolytic streptococci. J Exp Med. 1933;58(4):485502. 3. Sussman BJ, Fitch TS. Thrombolysis with fibrinolysin in cerebral arterial occlusion. J Am Med Assoc. 1958;167(14):1705-1709. 4. Fujishima M, Omae T, Tanaka K, Iino K, Matsuo O, Mihara H. Controlled trial of combined urokinase and dextran sulfate therapy in patients with acute cerebral infarction. Angiology. 1986;37(7):487-498.
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lar thrombectomy in combination with IV thrombolysis has greater efficacy than IV thrombolysis alone when alteplase is used as the medical agent.34 Further work testing tenecteplase or other future IV thrombolytics compared with IV/intra-arterial combination therapy is needed. In addition, approaches combining IV thrombolysis with othertreatmentsincludetheGIIb-IIainhibitors,sonothrombolysis,and combined thrombolysis and neuroprotection, with hypothermia or other neuroprotective approaches. The field of IV thrombolysis has been stagnant for so long and may finally be gaining momentum as the field of acute stroke treatment continues to push forward.
proteolysis by alteplase and tenecteplase. Biochem Pharmacol. 2013;85(4):525-530. 13. Micieli G, Marcheselli S, Tosi PA. Safety and efficacy of alteplase in the treatment of acute ischemic stroke. Vasc Health Risk Manag. 2009;5 (1):397-409. 14. Bringmann P, Gruber D, Liese A, et al. Structural features mediating fibrin selectivity of vampire bat plasminogen activators. J Biol Chem. 1995;270(43): 25596-25603. 15. Hacke W, Albers G, Al-Rawi Y, et al; DIAS Study Group. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke. 2005;36(1):66-73. 16. Furlan AJ, Eyding D, Albers GW, et al; DEDAS Investigators. Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke. 2006;37(5):1227-1231.
5. Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke: the Multicentre Acute Stroke Trial Italy (MAST-I) group. Lancet. 1995;346 (8989):1509-1514.
17. Hacke W, Furlan AJ, Al-Rawi Y, et al. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2009;8 (2):141-150.
6. Thrombolytic therapy with streptokinase in acute ischemic stroke: the Multicenter Acute Stroke Trial Europe study group. N Engl J Med. 1996;335 (3):145-150.
18. Parsons M, Spratt N, Bivard A, et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N Engl J Med. 2012;366 (12):1099-1107.
7. Terashi A, Kobayashi Y, Katayama Y, Inamura K, Kazama M, Abe T. Clinical effects and basic studies of thrombolytic therapy on cerebral thrombosis. Semin Thromb Hemost. 1990;16(3):236-241.
19. Logallo N, Kvistad CE, Nacu A, et al. The Norwegian Tenecteplase Stroke Trial (NOR-TEST): randomised controlled trial of tenecteplase vs. alteplase in acute ischaemic stroke. BMC Neurol. 2014;14:106.
8. Brott TG, Haley EC Jr, Levy DE, et al. Urgent therapy for stroke, part I: pilot study of tissue plasminogen activator administered within 90 minutes. Stroke. 1992;23(5):632-640. 9. Haley EC Jr, Levy DE, Brott TG, et al. Urgent therapy for stroke, part II: pilot study of tissue plasminogen activator administered 91-180 minutes from onset. Stroke. 1992;23(5):641-645. 10. Freeman R, Niego B, Croucher DR, Pedersen LO, Medcalf RL. t-PA, but not desmoteplase, induces plasmin-dependent opening of a blood-brain barrier model under normoxic and ischaemic conditions. Brain Res. 2014;1565:63-73. 11. Wang L, Fan W, Cai P, et al. Recombinant ADAMTS13 reduces tissue plasminogen activator-induced hemorrhage after stroke in mice. Ann Neurol. 2013;73(2):189-198. 12. Gomaraschi M, Ossoli A, Vitali C, et al. Off-target effects of thrombolytic drugs: apolipoprotein A-I
20. Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. 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(21): 2019-2026. 21. De Silva DA, Fink JN, Christensen S, et al; Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) Investigators. Assessing reperfusion and recanalization as markers of clinical outcomes after intravenous thrombolysis in the echoplanar imaging thrombolytic evaluation trial (EPITHET). Stroke. 2009;40(8):2872-2874. 22. Hacke W, Kaste M, Bluhmki E, et al; ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359(13):1317-1329.
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23. Hacke W, Donnan G, Fieschi C, et al; ATLANTIS Trials Investigators; ECASS Trials Investigators; NINDS rt-PA Study Group Investigators. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. 2004;363(9411):768-774. 24. Astrup J, Siesjö BK, Symon L. Thresholds in cerebral ischemia: the ischemic penumbra. Stroke. 1981;12(6):723-725. 25. Davis SM, Donnan GA, Butcher KS, Parsons M. Selection of thrombolytic therapy beyond 3 hours using magnetic resonance imaging. Curr Opin Neurol. 2005;18(1):47-52. 26. Heiss WD, Sobesky J, Smekal Uv, et al. Probability of cortical infarction predicted by flumazenil binding and diffusion-weighted imaging signal intensity: a comparative positron emission tomography/magnetic resonance imaging study in early ischemic stroke. Stroke. 2004;35(8):1892-1898. 27. Ma H, Wright P, Allport L, et al. Salvage of the PWI/DWI mismatch up to 48 h from stroke onset leads to favorable clinical outcome. Int J Stroke. 2014. 28. Kidwell CS, Jahan R, Gornbein J, et al; MR RESCUE Investigators. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med. 2013;368(10):914-923. 29. Markus R, Reutens DC, Kazui S, et al. Hypoxic tissue in ischaemic stroke: persistence and clinical consequences of spontaneous survival. Brain. 2004;127(Pt 6):1427-1436. 30. Liebeskind DS, Sanossian N. How well do blood flow imaging and collaterals on angiography predict brain at risk? Neurology. 2012;79(13)(suppl 1):S105S109. 31. Saver JL, Goyal M, Bonafe A, et al; SWIFT PRIME Investigators. Solitaire with the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke (SWIFT PRIME) trial: protocol for a randomized, controlled, multicenter study comparing the Solitaire revascularization device with IV tPA with IV tPA alone in acute ischemic stroke. Int J Stroke. 2015;10(3):439-448. 32. Goyal M, Demchuk AM, Menon BK, et al; ESCAPE Trial Investigators. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372(11):10191030. 33. Campbell BC, Mitchell PJ, Kleinig TJ, et al; EXTEND-IA Investigators. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 2015;372(11):1009-1018. 34. Berkhemer OA, Fransen PS, Beumer D, et al; MR CLEAN Investigators. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372(1):11-20.
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Review
Progress in Intravenous Thrombolytic Therapy for Acute Stroke Randolph S. Marshall, MD, MS
IMPORTANCE Intravenous recombinant tissue plasminogen activator (alteplase) was
approved by the US Food and Drug Administration in 1996 for the treatment of acute ischemic stroke. Nearly 20 years later, it remains the only approved treatment, despite limitations in both efficacy and safety. With a growing capacity for stroke treatment worldwide, physicians need to understand where we have come from and what the future of stroke treatment might be. OBJECTIVE To present a historical prospective as well as current trends in thrombolytic therapy, focusing on characteristics of drugs that have worked and clinical trials that are moving the field forward. EVIDENCE REVIEW Sources are published pivotal clinical trials; seminal articles on physiology, pharmacology, and neuroimanging; and listings from clinical trial registries. FINDINGS The slow progress in thrombolysis for acute stroke has been multifactorial. A focus on extending the time window for alteplase beyond 4.5 hours has encumbered substantial resources in the field for many years, yet these efforts have been largely unsuccessful. New drug development has also been slow. Several drugs have failed in clinical trials and currently only tenecteplase remains to be tested as a potential alternative to alteplase. The parallel pursuit for catheter-based interventional revascularization in acute stroke, which appears to be successful, has shifted emphasis away from pharmacologically based studies. CONCLUSIONS AND RELEVANCE Although the field of acute thrombolysis has been making
progress slowly for many years, advances in neuroimaging and new clinical trials that combine thrombolytics with other pharmacological and interventional techniques are beginning to gain momentum once again. The emergence of new approaches based largely on combination therapy strategies has reset a course to advance thrombolytic treatment for acute stroke and promises to improve outcomes in acute stroke in the near future. JAMA Neurol. doi:10.1001/jamaneurol.2015.0835 Published online June 1, 2015.
I
ntravenous (IV) recombinant tissue plasminogen activator (rtPA; alteplase) was approved by the US Food and Drug Administration in 1996 for the treatment of acute ischemic stroke. Now, nearly 20 years after completion of the pivotal National Institute of Neurological Disorders and Stroke (NINDS) trial,1 we are in essentially the same place with regard to IV thrombolysis. No new drugs have been approved for acute stroke and the time window for alteplase remains at 3 hours in the United States, widened marginally to 4.5 hours in Europe. Compare this with the explosion of endovascular device development in the last decade and the fastpaced emergence of pharmacotherapeutics for secondary stroke prevention, such as new antiplatelets, novel anticoagulants, and statins. There is an inexplicable stagnation in the field of IV thrombolysis. Why has the progress been so slow? Did we serendipitously arrive at the final ideal drug, dose, and time window in 1995? Alteplase provides benefits but it has limitations both in efficacy and safety.
Author Affiliation: Department of Neurology, New York-Presbyterian/ Columbia University Medical Center, New York. Corresponding Author: Randolph S. Marshall, MD, MS, Department of Neurology, New York-Presbyterian/ Columbia University Medical Center, 710 W 168th St, New York, NY 10032 ([email protected]). Section Editor: David E. Pleasure, MD.
Why have alternatives been so slow to emerge? Is there insufficient science? Insufficient funding? Too much inertia in this arena compared with the promise of greater advances elsewhere? This review traces the development of IV thrombolysis to date, considers the shortcomings of alteplase, and examines alternative thrombolytic approaches currently in the pipeline, including the role of neuroimaging and the possibility of combination therapies.
Historical Perspective The concept of thrombolysis emerged in 1933 with the discovery by Tillett and Garner2 that certain strains of Streptococcus could dissolve fibrin clots. In the 1950s, Tillett and Garner2 put this concept to practical use in a study using streptokinase (SK) in the treatment of patients with intravascular thrombi. A second naturally occurring
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Progress in Intravenous Thrombolytic Therapy for Acute Stroke
thrombolytic substance was discovered in the 1940s, when human urine was demonstrated to have thrombolytic properties. The isolation of this agent termed urokinase offered another option for thrombolysis. The first reported use of thrombolysis for acute stroke occurred in 1958, when Sussman and Fitch3 treated 3 patients with fibrinolysin (plasmin) with IV injections for 4 to 6 days who showed some clinical improvement. Although this was a far cry from today’s double-blind randomized clinical trials, the Sussman and Fitch study3 launched a drive to refine the use of thrombolysis for acute ischemic stroke. Not surprisingly, early SK and urokinase trials were plagued by intracranial hemorrhage and high mortality. The main problem was a lack of pretreatment imaging to determine whether neurological deficit was caused by ischemia or hemorrhage. Therefore, this treatment approach was abandoned for many years. It was not until the emergence of computed tomography (CT) scanning that a reasonable attempt to test this pharmacotherapy could be reconsidered. It was not until the 1980s that the first clinical trials began to emerge in pursuit of the heretofore untreatable condition of acute ischemic stroke. In 1986, Fujishima et al4 used urokinase vs urokinase plus dextran sulfate to treat 143 patients with acute stroke, reporting improvement in 74% of patients who received urokinase alone and 84% of patients who received the combination. However, there was no control arm to test the thrombolytic agent compared with the placebo and no blinding of assessments, standardization of outcomes, or standard protocol for imaging. Other trials in that period had similar shortcomings. A common characteristic of the thrombolytic trials of the 1980s was the administration of low-dose thrombolysis given across several days and started several days after stroke onset. Soon to follow was an increased interest in early high-dose administration and, in particular, SK for acute ischemic stroke. The Multicenter Acute Stroke Trial Italy (MAST-I) and Multicenter Acute Stroke Trial Europe (MAST-E) tested this agent in 2 large multicenter trials.5,6 However, high intracranial hemorrhage rates occurred, leading to the abandonment of SK for acute stroke. A better drug was needed. The interest in tPA for dissolving intravascular thrombi started with treatment of myocardial infarction. Initially, the naturally occurring thrombolytic was used but the availability of this tissue-derived glycoprotein was extremely limited and difficult to produce. It was not until the recombinant form rtPA (alteplase) was created using a Chinese hamster ovary cell line to clone the gene that the capacity for widespread use was realized. The genetic modification technique involved in refining rtPA revolutionized the commercial production of many different drugs and has become a multibillion dollar worldwide operation. The first major phase 3 clinical trial using rtPA was a cardiac trial, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I), which randomized more than 40 000 patients with acute myocardial infarctionandshowedsuperiorityofIValteplaseplusheparincomparedwith SK for thrombolysis of coronary arteries. The first trial of rtPA for acute stroke was conducted in the late 1980s, comparing alteplase with urokinase in 364 patients.7 This trial showed no difference in stroke outcomes between treatment groups. The NINDS then sponsored the seminal trials of IV alteplase, beginning with dose-finding pilot studies in the 3-hour time window.8,9 The establishment of the treatment protocol with 0.9 mg/kg, giving 10% as an initial bolus and the remaining 90% across 1 hour, was tested in the pivotal phase 3 trial.1 This study had 2 parts, the first (n = 291) assessed clinical improvement within 24 hours as measured by an imE2
provement of 4 points or more on the National Institutes of Health Stroke Scale (NIHSS), and the second (n = 333) measured functional outcome at 3 months, using the modified Rankin Scale, NIHSS, Barthel Index, Glasgow Outcome Scale, and a global measure combining all 4 of these measures. The first part was negative for the 24-hour outcome but the second was positive, demonstrating that those treated with IV rtPA were 30% more likely to achieve better functional outcomes than those treated with placebo (global odds ratio for a favorable outcome = 1.7; 95% CI, 1.2-2.6; P = .008). The result from part 2 was validated in a post hoc analysis of the patients from part 1 and remained positive across subgroups of age, stroke subtype, stroke severity, and the use of aspirin before the stroke. Symptomatic intracranial hemorrhage occurred in 6.4% of those treated with rtPA (much lower than the >10% rate with SK and urokinase) vs 0.6% in those receiving the placebo. Despite the difference in symptomatic intracranial hemorrhage rate, mortality was nearly identical, 17% in the rtPA group and 21% in the placebo group (P = .30). The result of this trial published in 1995 was a major breakthrough in the management of acute ischemic stroke and led to the US Food and Drug Administration approval of this drug in 1996. The use of IV rtPA according to the NINDS trial dosing regimen has remained the mainstay of acute stroke treatment for the ensuing 19 years (Figure 1).
IV rtPA: Intrinsic Properties and Alternative Drugs The approval of IV alteplase revolutionized acute stroke treatment worldwide; however, it had important limitations. The efficacy and safety of thrombolytic agents are dependent on several key characteristics, including specificity for the intravascular clot, the drug’s half-life, the secondary inhibition of plasminogen activation, the drug’s effects on the blood-brain barrier (BBB), and its effects on lipid processing. These important properties are key to understanding potential advances in the field. Thrombolytic drugs lyse clots in the vascular bed by activating plasminogen, which catalyzes its conversion to plasmin, the lytic molecule that breaks down the clot in situ. Intravascular thrombi are composed of fibrin monomers that are cross-linked through lysine side chains. The binding of thrombolytic agents to these lysine cross links gives them specificity for the clot. Plasminogen also has a high affinity for the lysine side chains; therefore, there is a high concentration of plasminogen at the clot site. Once plasminogen is converted to plasmin, it breaks the thrombus into fibrin degradation products. Fibrin specificity is the most important pharmacological property that determines safety. The higher the fibrin selectivity, the greater the specificity for thrombolysis at the clot site; therefore, the less risk of systemic hemorrhage. Urokinase and SK have low-fibrin selectivity, accounting in part for higher hemorrhage rates in clinical trials. Alteplase has a higher fibrin selectivity than urokinase and SK but some of the newer thrombolytic agents, such as tenecteplase and desmoteplase, have an even higher fibrin selectivity and, thus, have the potential for higher efficacy and lower morbidity in acute ischemic stroke. A second property of thrombolytic agents is the drug’s halflife. The half-life of alteplase is 4 to 8 minutes, resulting in the need to deliver the drug as a bolus followed by an infusion, as delineated in the US Food and Drug Administration–approved alteplase administration protocol. Tenecteplase has a half-life of 11 to 20 minutes and desmoteplase has a half-life of 138 minutes, which means that throm-
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Figure 1. History of Thrombolysis 1933
1940
1986
Streptokinase discovered
1991 1995 1996
2009
Mass production of recombinant tissue plasminogen activator Urokinase discovered
First urokinase trial
2015
Desmoteplase trials fail
US Food and Drug Administration approves recombinant tissue plasminogen activator for stroke
Combination trials
Phase 3 tenecteplase trials
National Institute of Neurological Disorders and Stroke tissue plasminogen activator trial Urokinase and streptokinase trials fail
Timeline showing the history of intravenous thrombolysis.
Table 1. Properties of Thrombolytic Agents Agent
Fibrin Selectivity
PAI-1 Inhibition
Half-life, min
BBB Opening
HDL-C Level Lowering
Alteplase
Moderate
Streptokinase
Negligible
High
4-8
Moderate
Moderate
Negligible
6
Unknown
Urokinase
Negligible
High
Unknown
15
Unknown
Unknown
Desmoteplase
Very high
Unknown
138
Negligible
Unknown
Tenecteplase
High
Low
Unknown
Low
11-20
bolysis may be achieved with a bolus injection alone for these agents, making administration easier, particularly if the IV treatment is to be followed up with endovascular intervention. A third important property is the secondary induction of type I plasminogen activator inhibitor, which results in a paradoxical counteraction of the thrombolytic effect once the drug reaches the clot. While urokinase and alteplase have this property, desmoteplase and tenecteplase do not, making them potentially more effective as thrombolytic agents. A fourth property of alteplase is its effect on the BBB. This effect is thought to be mediated by the upregulation of matrix metalloproteinases in endothelial cells. Using an in vitro model of the BBB, it has been shown that under ischemic conditions in the presence of plasminogen, alteplase degrades the BBB; however, in a direct comparison in an in vitro model, desmoteplase did not.10 The breakdown of the BBB after administration of an agent that breaks up clots would be a crucial factor in determining the safety of acute thrombolysis, including the development of poststroke edema and the hemorrhagic conversion of an ischemic infarct. In the absence of an agent that does not have this effect, one proposed approach to mediate the matrix metalloproteinase effects is the use of ρ kinase inhibitors at the time of thrombolysis administration.11 A fifth property of thrombolytic agents is their effect on apolipoprotein A-I, the main protein component of high-density lipoprotein cholesterol levels. Degredation of this protective element of the lipid family was tested in 38 patients with myocardial infarction, 19 patients receiving standard cardiac doses of alteplase and 19 patients receiving treatment with tenecteplase.12 Although both agents caused plasmin-mediated proteolysis of apolipoprotein A-I, those
Abbreviations: BBB, blood-brain barrier; HDL-C, high-density lipoprotein cholesterol; PAI-1, type I tissue plasminogen activator.
treated with tenecteplase had a lesser effect at least in the short term, potentially preserving the atheroprotective effects of high-density lipoprotein cholesterol levels. There may be a neurotoxic effect of alteplase via its interaction with the N-methyl-D-aspartate receptor.13 Overall, the shortcomings of alteplase have generated an examination of alternative thrombolytic agents in an attempt to improve the drug’s efficacy and safety profile (Table 1). Desmoteplase is an orthologue of human tPA derived from the saliva of the common vampire bat, Desmodus rotundus. Its main plasminogin activator has a 72% homologue with human tPA. 14 Desmoteplase is much more fibrin selective than alteplase, has a much longer half-life, and has no known effect on the BBB. Two small phase 2 clinical trials using demoteplase demonstrated good reperfusion and suggested increased efficacy compared with the placebo.15,16 However, the first phase 3 trial, DIAS (Desmoteplase In Acute Stroke) 2, which randomized 193 patients to desmoteplase vs placebo at 3 to 9 hours after stroke, was negative.17 The protocol used magnetic resonance (MR) or CT perfusion to identify patients with brain tissue at risk, regardless of time poststroke, for as long as 9 hours. Limitations included a small study sample and lack of standardization of imaging selection criteria. The following 2 additional phase 3 trials have finished: DIAS 3, which started in 2009 in Europe, Australia, and Asia and has no results published to date, and DIAS 4, which started in 2011 in the United States and was terminated owing to the result of DIAS 3 being unlikely to reach its primary endpoint with the current protocol (https://clinicaltrials.gov). Tenecteplase, a third-generation rtPA, represents a targeted genetic upgrade to improve thrombolytic safety and efficacy. Three
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Progress in Intravenous Thrombolytic Therapy for Acute Stroke
Figure 2. Protein Substitutions to Make Tenecteplase Kringle 2 200 S C L P W N S E M I V H C W T P L L L K K A A I I Q N S F A G A W H R D K K P T R 250 G V H H G S Y D R L A T R R P T I A S 300 Y N W 125 D P Q A E A G N R A Q K P Y S G R R S F E L Y P D P C L R A A G C I S F G Y D R N S A L G 325 E R F P G N L V C K Q Q S F H G P G F 275 R I P H N I G K 225 A C L Y L F S H G L G L I H G W Q C C 150 S L P N A Q N S S D A H S T D D R S Y P N T S P K V C G L R Q R C Y N T S C L W W I I E Q N C A C S S L T P A C V V G Y S G T R E R C S E C C V R S F V A 175 L E T S F K G A G K Y S S P Y D E Y C T S D R P S Q E A V A K I G A S V T S W T G R Y R L D E 400 P E L Q E G T Q Q L P D W T E C E L S G Y 100 K D G L 375 F I 350 K E Epidermal C C L G D N L C E H G K V E M R V growth factor domain A T A E K Y P C Q C L I L I A F G E V 75 V V D P L H N G S F S W L R K G R C D P H P Q I Y F D E G F V 25 T H I N S Y E D S D D F L S Q S G S E 425 F 500 G D R W G Q G L R C Y T S Y Q 475 G C S L L N I K 50 Q C C K C T S Q V Q A M S R R A H D L E P G S L W Y D A P Q V V L I Q Y H V H N A S L T R E K R N C G L H T N K D L D D Y R A T C Fibronectin E V M R Q P G V N C T 450 G S N Q K D P M D V finger T W 525 R A T Y V G R C R P C N G I Protease domain S Q V S Y S
G A
Kringle 1
COOH
NH2
specific alterations to the alteplase molecule, a tetra-alanine substitution in the protease domain and 2 other single amino acid substitutions in the kringle 1 lysine-binding domain, resulted in a longer half-life, greater binding affinity for fibrin, and better resistance to inactivation by the endogenous inhibitor type I plasminogen activator inhibitor (Figure 2). These properties have made tenecteplase a potentially more effective and safer thrombolytic drug than alteplase. Two prospective randomized open-label blinded endpoint (PROBE design) clinical trials have either been completed or are now underway to test tenecteplase compared with alteplase for acute ischemic stroke. The first was a small phase 2B open-label blinded outcome trial completed in 2011, randomizing 75 patients to receive 0.1 mg/kg of IV tenecteplase or 0.25 mg/kg of IV tenecteplase as a single bolus vs a standard dose of IV alteplase in a 1 to 1 to 1 randomization scheme in a 6-hour window.18 Coprimary endpoints were the proportion of the CT perfusion deficit that was reperfused at 24 hours and clinical improvement at 24 hours on the NIHSS. Secondary endpoints included the proportion of patients recanalized at 24 hours and a 90-day modified Rankin Scale. The study results were positive for both primary endpoints (greater reperfusion, P = .004; and better NIHSS at 24 hours, P < .001) despite the small number of participants randomized. The study also established the dose of 0.25 mg/kg as superior to the 0.1 mg/kg dose in efficacy, with no significant decrement in safety. The symptomatic hemorrhage rate in the alteplase group in this study was 12%, nearly double the 6.4% reported in the original NINDS alteplase trial. The following secondary endpoints were also positive: infarct growth at 24 hours and 90 days, complete or partial recanalization at 24 hours, E4
Red circles designate the locations where protein substitutions were made to change the properties of alteplase to make tenecteplase.
major neurological improvement (NIHSS reduction of ⱖ8) at 24 hours, and excellent or good recovery at 90 days. A phase 3 trial is planned to follow up this phase 2 effort, the TASTE (Tenecteplase vs Alteplase for Stroke Thrombolysis Evaluation) trial, which will test IV tenecteplase vs alteplase in the zero- to 4.5-hour window. A second phase 3 tenectoplase trial, the NOR-TEST (Norwegian Teneteplase Stroke Trial) aims to randomize 954 patients to identify a 9% or more difference in excellent outcome for IV tenecteplase at a dose of 0.4 mg/kg vs a standard dose of IV alteplase.19 This study will also use a zero- to 4.5-hour window but, uniquely, will include those who present within 4.5 hours of awakening with stroke symptoms and for those in whom endovascular embolectomy is planned within a 6-hour window. The primary outcome measure for this study will be clinical only, a modified Rankin Scale score at 90 days, with secondary endpoints of 24-hour improvement in NIHSS and recanalization at 24 to 26 hours. A list of registered ongoing clinical trials using IV thrombolytics is represented in Table 2.
Brain Imaging and the Limits of the Thrombolysis Window Testing the limits of a safe and effective treatment window for thrombolysis has been a recurrent challenge since the original NINDS trials showed efficacy within a 3-hour window. Many clinical trials have taken the challenge, including the ATLANTIS (Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke) trial,20 EPITHET (Echoplanar Imaging Thrombolysis Evaluation Trial),21 and
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Table 2. Active Thrombolysis Trials Trial Registry Identification
Study Name
Drug/Intervention
Sponsor
Location
Study Phase
NCT02072226
PRISMS
Alteplase for mild stroke
Genentech
United States
3
Clinical (90-d mRS)
NCT01282242
MR WITNESS
Alteplase for wake-up stroke
NINDS
United States
2
Safety (ICH rate)
NCT01525290
WAKE-UP
Alteplase for wake-up stroke
University of Hamberg-Eppendorf
Europe
3
Clinical (90-d mRS)
NCT01643902
SAIL-ON
Alteplase for wake-up stroke
Genentech
United States
2
Safety (ICH rate)
NCT02002325
THAWS
0.6 mg Alteplase for wake-up stroke
National Cerebral and Cardiovascular Center
Japan
3
Clinical (90-d mRS)
NCT00887328
EXTEND
Alteplase in 3- to 9-h window
NSRI, Australia
Australia
3
Clinical (90-d mRS)
NCT01123161
ICTuS2/3
Alteplase + hypothermia
NINDS
United States
3-2
Clinical (90-d mRS)
NCT02222714
RHAPSODY
Alteplase + activated protein C
NINDS, ZZ Biotech
United States
2
Safety (dose-limiting toxicity)
NCT01464788
ARTSS-2
Alteplase + argatroban
NINDS
United States
2B
NCT01977456
CLEAR-FDR
Alteplase + eptifibatide
NINDS
United States
2
Safety (ICH rate)
NCT02189928
RESCUE-BRAIN
Alteplase + per-conditioning
Unité de Recherche Clinique Paris Ouest
France
2-1
Imaging (infarct growth)
NCT01098981
CLOTBUST-ER
Alteplase + ultrasound
Cerevast Therapeutics
United States
3
Clinical (90-d mRS)
NCT01678495
Sonothrombolysis Potentiated by Microbubbles for Acute Ischemic Stroke
Alteplase + ultrasound with microbubble
l'Hospital de la Sata Creu I Sant Pau
Spain
2
Imaging (recanalization)
NCT02338466
DIVA
Alteplase + tenecteplase
Centre Hosp Univers de Fort-de-France
France
2
Clinical (90-d mRS)
ACTRN12613000243718
TASTE
Tenecteplase in 4.5-h window
National Health and Medical Research Council
New Zealand
3
Clinical (90-d mRS)
NCT02180204
TALISMAN
Tenecteplase in 3to 4.5-h window
The Ohio State University
United States
2B
NCT01472926
ATTEST
Tenecteplase in 4.5-h window
NHS Greater Glasgow and Clyde
Scotland
2
Imaging (penumbra reversal)
NCT02101606
TAIS
Tenecteplase in 4.5to 12-h window
University of Alberta
Canada
2
Safety (ICH rate)
NCT01949948
NOR-TEST
Tenecteplase in 4.5-h window
Research Council of Norway
Norway
3
Clinical (90-d mRS)
NCT02150785
AASIST
Streptokinase
University of Alberta
Asia/Africa
2
Safety (ICH rate)
Primary Outcome
Clinical (90-d mRS)
Safety (ICH rate)
Abbreviations: AASIST, Asia Africa Streptokinase Trial; ARTSS-2, Argatroban With Tissue Plasminogen Activator for Acute Stroke; ATTEST, Aleteplase-Tenecteplase Trial Evaluation for Stroke Thrombolysis; CLEAR-FDR, Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue Plasminogen Activator in Acute Ischemic Stroke Full-dose Regimen; CLOTBUST-ER, Combined Lysis of Thrombus With Ultrasound and Systemic Tissue Plasminogen Activator for Emergent Revascularization in Acute Ischemic Stroke; DIVA, Superiority of Recombinant Tissue Plasminogen Activator Tenecteplase in Comparison With Recombinant Tissue Plasminogen Activator Only in Proximal Middle Cerebral Artery Occlusion; EXTEND, Extending the Time for Thrombolysis in Emergency Neurological Deficits; ICH, intracranial hemorrhage; ICTu2/3, The Intravascular Cooling in the Treatment of Stroke 2/3 Trial; mRS, modified Rankin Scale; MR WITNESS, A Study of Intravenous Thrombolysis With Alteplase in Magnetic
Resonance Imaging–selected Patients; NHS, National Health Service; NINDS, National Institute of Neurological Disorders and Stroke; NOR-TEST, Norweigian Tenecteplase Stroke Trial; NSRI, Nutritional Science Research Institute; PRISMS, A Study of the Efficacy and Safety of Activase (Alteplase) in Patients With Mild Stroke; RESCUE-BRAIN, Remote Ischemic Conditioning in Acute Brain Infarction Study; RHAPSODY, Safety Evaluation of 3K3A-APC in Ischemic Stroke; SAIL-ON, Safety of Intravenous Thrombolytics in Stroke on Awakening; TAIS, Penumbral-Based Novel Thrombolytic Therapy in Acute Ischemic Stroke; TALISMAN, Tenecteplase vs Alteplase in Ischemic Stroke Management; TASTE, Tenecteplase vs Alteplase for Stroke Thrombolysis Evaluation; THAWS, Thrombolysis for Acute Wake-up and Unclear-onset Stroke With Alteplase at 0.6 mg/kg; WAKE-UP, Efficacy and Safety of Magnetic Resonance Imaging–based Thrombolysis in Wake-up Stroke.
ECASS (European Cooperative Acute Stroke Studies) 1 to 3. Although ATLANTIS and EPITHET showed no benefit in a 6-hour window using the NINDS trial dosing regimen, the ECASS studies culminating with ECASS 3 were positive. This European-only study randomized 821 patients with acute ischemic stroke to receive IV alteplase vs placebo in the 3- to 4.5-hour window.22 The decision to examine rtPA efficacy in the 3- to 4.5-hour time window was based on a meta-analysis showing decreasing marginal benefit with rtPA between 3 and 6 hours, with almost no benefit vs the risk at 6 hours.23 The ECASS 3 trial used the modified Rankin Scale score of zero to 1 at 3 months as the primary outcome measure and showed efficacy compared with the placebo in this outcome (odds ratio, 1.34; 95% CI, 1.02-1.76; P = .04) as well as with the combined outcomes
that were used in the NINDS 3-hour trial. The European Medical Agency subsequently approved IV rtPA for acute stroke in the 3- to 4.5-hour window in 2011, limiting the use to those younger than 80 years as was required in the trial. Despite the American Heart Association concurring with the extended time window in revised guidelines, the US Food and Drug Administration failed to approve alteplase in the extended time window, leaving the United States with IV rtPA in the zero- to 3-hour time window as the only approved treatment for acute ischemic stroke. A major effort during the nearly 20 years since the NINDS Alteplase trial has been an attempt to show the potential for an extended time window for thrombolysis. The charge has been led by neuroimaging. Tissue response to acute loss of blood flow in the brain
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Progress in Intravenous Thrombolytic Therapy for Acute Stroke
is dependent on the following 3 main variables: absolute reduction in blood flow, volume of tissue affected, and duration of the ischemia. With 50 cm3/100 g per min as a mean cerebral blood flow, as cerebral perfusion decreases to about 40 cm3/100 g per min, protein synthesis is inhibited and denaturing occurs, anaerobic glycolysis begins at about 30 cm3/100 g per min, glucose metabolism declines and ion transients appear at about 20 cm3/100 g per min, electrical failure occurs at about 18 cm3/100 g per min, and membrane failure occurs at 10 to 12 cm3/100 g per min. Blood flow in the ischemic core is 6 to 10 cm3/100 g per min. The so-called ischemic penumbra, defined as the region around the infarct core that is reversibly damaged by ischemia, is thought to be the zone that has an upper threshold of electrical failure and a lower threshold of energy and ion pump (membrane) failure.24 This tissue at risk has the following 2 possible fates: incorporation into the infarct core if no reperfusion occurs or a return to normal function if the area is reperfused in time. The idea behind imaging strategies was that if it were possible to assess the physiological state of brain tissue at a given time after the onset of ischemia, then the timing of treatment with thrombolysis could be guided by the tissue clock rather than the time clock, even if the time since stroke onset was beyond 3 to 4.5 hours.25 Distinguishing the ischemic core from the penumbra or from a state of benign oligemia in which hypoperfused tissue never becomes incorporated into the ischemic core has been the holy grail of imageguided treatment of acute ischemic stroke. While the preclinical models of the penumbra used tissue probes and single-cell recording to determine the state of the cell membranes and metabolic state, such techniques are not possible in a clinical setting. The best noninvasive measure of the physiological state is positron emission tomography. Benign oligemia can be distinguished from more significant hemodynamic failure by characterizing zones of decreased flow with or without increased oxygen extraction fraction. A more significant hemodynamic failure termed stage 2 failure or misery perfusion can be distinguished from metabolic failure by measuring metabolic rate of oxygen directly. Positron emissiontomographyhasalsobeenusedtomeasureneuronalviabilitywith flumazenil labeled with radioactive carbon 11, which reflects the state of functioning benzodiazepine receptors.26 However, positron emission tomography has proven to be too expensive and too invasive and is not practical for use in short-term stroke treatment. Thus, the emergence of so-called mismatch imaging using MR perfusion and CT perfusion (CTP) has driven the quest for assessing tissue state in the last 2 decades and has been incorporated into several clinical trials. The diffusion-weighted imaging/perfusion-weighted imaging signal of MR and the CTP/cerebral blood volume signal of CT in the acute stroke period are used to delineate the ischemic core vs penumbra. These techniques are far removed from distinguishing electrical failure from membrane failure in a hypoperfused area, yet the advantages of MR perfusion and CTP techniques include a greater spatial resolution and wider clinical availability compared with positron emission tomography, particularly with CT scanning, which is required in every primary stroke center. Magnetic resonance has the additional advantage of being able to well define the ischemic core in the first hours after stroke onset. The challenge of these techniques has been standardization, whether imaging parameters are to be able to accurately represent the penumbra, particularly when the perfusion imaging takes place in later time windows. A penumbra has been reported as late as 48 hours27 but its implications for revascularization treatment are not E6
clear. Even the ischemic core, defined by the diffusion-weighted imaging, is not a static entity and may shrink or disappear in the first few hours after the ischemic insult. Several thrombolytic clinical trials have attempted to use MR or CT imaging to guide treatment or predict outcomes in acute ischemic stroke. For MR or CT perfusion, a penumbra is defined as a region outside the ischemic core where there is a delayed time to arrival of a bolus of contrast material. The time to maximum contrast concentration referred to as time to peak or Tmax has ranged from 2 to 6 seconds in various studies. Generally, a mismatch is considered significant if the penumbra is at least 20% of the ischemic core volume. One recommended threshold for the penumbra is a time to peak of 6 seconds, which is thought to be sensitive enough to include significant hypoperfusion and restrictive enough to exclude benign oligemia. In general, both the presence of a penumbra and reversal of a penumbra seem to correlate with improved clinical outcomes.28,29 The 2 desmoteplase early-phase trials (DIAS and DEDAS [Dose Escalation of Desmoteplase for Acute Ischemic Stroke]) used MR perfusion for treatment selection and showed promising results. Treating patients with stroke with diffusion-weighted imaging/perfusion-weighted imaging mismatch in the 3- to 9-hour time window had good reperfusion of mismatch areas and good clinical outcomes. However, the phase 3 randomized double-blind DIAS-2 trial failed to show clinical improvement, which was thought in part to be owing to less stringent time-to-peak criteria, resulting in the inclusion of patients in the later time windows with benign oligemia rather than tissue at risk. The phase 2B tenecteplase trial mentioned earlier used a CT/CTP mismatch criterion both for patient selection and as a primary outcome measure. The 2 other phase 3 tenecteplase trials, TASTE and NOR-TEST, will use CTP for selection criteria but within a standard 4.5-hour window. In addition to perfusion imaging, CT angiography and MR angiography are being used to assess the presence of pial collaterals as a predictors of better stroke outcomes and greater likelihood of treatment efficacy.30 For the most part, attempts to extend the time window for IV thrombolysisusingimagingcriteriahavebeenunsuccessfullargelyowing to the failure of accurately defining the penumbra at later points. Because the predominance of preclinical and clinical evidence suggests that 6 hours is the hard stop for reversible ischemia, the benefit of hemodynamic imaging in acute stroke may be to define those most likely to have tissue recovery within a more limited time window or to assist when the time of stroke onset is unknown. Further refinement of imaging techniques to better define the penumbra are required to bring hemodynamic imaging into the clinical arena.
Conclusions Although the extension of the time window may continue to be sought after, a clear unmet need is the improvement of the efficacy and safety of IV thrombolysis within a standard time window. The recently initiated trials of tenecteplase may further this goal and ultimately provide safer and more effective thrombolytic treatment. Continued attempts to improve fibrin specificity and reduce other detrimental effects inherent with alteplase are warranted. Basic pharmacology should be charged with generating what could be termed thenexteplase with rationally implemented modifications similar to what was done with tenecteplase. A promising second focus would be to maxi-
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mize the effects of IV thrombolysis in combination with other acute stroke treatments, including mechanical clot retrieval. With the recent publication of the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) study along with the SWIFT PRIME (Solitaire FR as Primary Treatment for Acute Ischemic Stroke),31 the ESCAPE (Endovascular Treatment for Small Core and Proximal Occlusion Ischemic Stroke)32 and EXTEND-IA (Extending the Time for Thrombolysis in Emergency Neurological Deficits Intra-Arterial) trials,33 which were stopped early based on positive interim analyses, it appears that endovascuARTICLE INFORMATION Accepted for Publication: February 23, 2015. Published Online: June 1, 2015. doi:10.1001/jamaneurol.2015.0835. Conflict of Interest Disclosures: None reported. REFERENCES 1. Tissue plasminogen activator for acute ischemic stroke: the National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333(24):1581-1587. 2. Tillett WS, Garner RL. The fibrinolytic activity of hemolytic streptococci. J Exp Med. 1933;58(4):485502. 3. Sussman BJ, Fitch TS. Thrombolysis with fibrinolysin in cerebral arterial occlusion. J Am Med Assoc. 1958;167(14):1705-1709. 4. Fujishima M, Omae T, Tanaka K, Iino K, Matsuo O, Mihara H. Controlled trial of combined urokinase and dextran sulfate therapy in patients with acute cerebral infarction. Angiology. 1986;37(7):487-498.
Review Clinical Review & Education
lar thrombectomy in combination with IV thrombolysis has greater efficacy than IV thrombolysis alone when alteplase is used as the medical agent.34 Further work testing tenecteplase or other future IV thrombolytics compared with IV/intra-arterial combination therapy is needed. In addition, approaches combining IV thrombolysis with othertreatmentsincludetheGIIb-IIainhibitors,sonothrombolysis,and combined thrombolysis and neuroprotection, with hypothermia or other neuroprotective approaches. The field of IV thrombolysis has been stagnant for so long and may finally be gaining momentum as the field of acute stroke treatment continues to push forward.
proteolysis by alteplase and tenecteplase. Biochem Pharmacol. 2013;85(4):525-530. 13. Micieli G, Marcheselli S, Tosi PA. Safety and efficacy of alteplase in the treatment of acute ischemic stroke. Vasc Health Risk Manag. 2009;5 (1):397-409. 14. Bringmann P, Gruber D, Liese A, et al. Structural features mediating fibrin selectivity of vampire bat plasminogen activators. J Biol Chem. 1995;270(43): 25596-25603. 15. Hacke W, Albers G, Al-Rawi Y, et al; DIAS Study Group. The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke. 2005;36(1):66-73. 16. Furlan AJ, Eyding D, Albers GW, et al; DEDAS Investigators. Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke. 2006;37(5):1227-1231.
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17. Hacke W, Furlan AJ, Al-Rawi Y, et al. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2009;8 (2):141-150.
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19. Logallo N, Kvistad CE, Nacu A, et al. The Norwegian Tenecteplase Stroke Trial (NOR-TEST): randomised controlled trial of tenecteplase vs. alteplase in acute ischaemic stroke. BMC Neurol. 2014;14:106.
8. Brott TG, Haley EC Jr, Levy DE, et al. Urgent therapy for stroke, part I: pilot study of tissue plasminogen activator administered within 90 minutes. Stroke. 1992;23(5):632-640. 9. Haley EC Jr, Levy DE, Brott TG, et al. Urgent therapy for stroke, part II: pilot study of tissue plasminogen activator administered 91-180 minutes from onset. Stroke. 1992;23(5):641-645. 10. Freeman R, Niego B, Croucher DR, Pedersen LO, Medcalf RL. t-PA, but not desmoteplase, induces plasmin-dependent opening of a blood-brain barrier model under normoxic and ischaemic conditions. Brain Res. 2014;1565:63-73. 11. Wang L, Fan W, Cai P, et al. Recombinant ADAMTS13 reduces tissue plasminogen activator-induced hemorrhage after stroke in mice. Ann Neurol. 2013;73(2):189-198. 12. Gomaraschi M, Ossoli A, Vitali C, et al. Off-target effects of thrombolytic drugs: apolipoprotein A-I
20. Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. 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(21): 2019-2026. 21. De Silva DA, Fink JN, Christensen S, et al; Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) Investigators. Assessing reperfusion and recanalization as markers of clinical outcomes after intravenous thrombolysis in the echoplanar imaging thrombolytic evaluation trial (EPITHET). Stroke. 2009;40(8):2872-2874. 22. Hacke W, Kaste M, Bluhmki E, et al; ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359(13):1317-1329.
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23. Hacke W, Donnan G, Fieschi C, et al; ATLANTIS Trials Investigators; ECASS Trials Investigators; NINDS rt-PA Study Group Investigators. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. 2004;363(9411):768-774. 24. Astrup J, Siesjö BK, Symon L. Thresholds in cerebral ischemia: the ischemic penumbra. Stroke. 1981;12(6):723-725. 25. Davis SM, Donnan GA, Butcher KS, Parsons M. Selection of thrombolytic therapy beyond 3 hours using magnetic resonance imaging. Curr Opin Neurol. 2005;18(1):47-52. 26. Heiss WD, Sobesky J, Smekal Uv, et al. Probability of cortical infarction predicted by flumazenil binding and diffusion-weighted imaging signal intensity: a comparative positron emission tomography/magnetic resonance imaging study in early ischemic stroke. Stroke. 2004;35(8):1892-1898. 27. Ma H, Wright P, Allport L, et al. Salvage of the PWI/DWI mismatch up to 48 h from stroke onset leads to favorable clinical outcome. Int J Stroke. 2014. 28. Kidwell CS, Jahan R, Gornbein J, et al; MR RESCUE Investigators. A trial of imaging selection and endovascular treatment for ischemic stroke. N Engl J Med. 2013;368(10):914-923. 29. Markus R, Reutens DC, Kazui S, et al. Hypoxic tissue in ischaemic stroke: persistence and clinical consequences of spontaneous survival. Brain. 2004;127(Pt 6):1427-1436. 30. Liebeskind DS, Sanossian N. How well do blood flow imaging and collaterals on angiography predict brain at risk? Neurology. 2012;79(13)(suppl 1):S105S109. 31. Saver JL, Goyal M, Bonafe A, et al; SWIFT PRIME Investigators. Solitaire with the Intention for Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke (SWIFT PRIME) trial: protocol for a randomized, controlled, multicenter study comparing the Solitaire revascularization device with IV tPA with IV tPA alone in acute ischemic stroke. Int J Stroke. 2015;10(3):439-448. 32. Goyal M, Demchuk AM, Menon BK, et al; ESCAPE Trial Investigators. Randomized assessment of rapid endovascular treatment of ischemic stroke. N Engl J Med. 2015;372(11):10191030. 33. Campbell BC, Mitchell PJ, Kleinig TJ, et al; EXTEND-IA Investigators. Endovascular therapy for ischemic stroke with perfusion-imaging selection. N Engl J Med. 2015;372(11):1009-1018. 34. Berkhemer OA, Fransen PS, Beumer D, et al; MR CLEAN Investigators. A randomized trial of intraarterial treatment for acute ischemic stroke. N Engl J Med. 2015;372(1):11-20.
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