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Advances in Thrombolytics for Treatment of Acute Ischemic Stroke

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Advances in Thrombolytics for Treatment of Acute Ischemic Stroke Advances in thrombolytics for treatment of acute ischemic stroke Jawad F. Kirmani, MD ABSTRACT Ammar Alkawi, MD Over the past 50 years, thrombolytic agents have been devised with the aim of recanalizing Spozhmy Panezai, MD occluded coronary vessels, and later on, applied in the setting of acute ischemic stroke. Pharma- Martin Gizzi, MD, PhD cologic agents have generally targeted the plasminogen–plasmin transformation, facilitating the natural process of fibrinolysis. Newer agents with varying degrees of fibrin selectivity and phar- macologic half-life have influenced both recanalization rates and hemorrhagic complications, in- Correspondence & reprint requests to Dr. Kirmani: side and outside the CNS. Intra-arterial (IA) administration of fibrinolytic agents increases delivery [email protected] of the drug to the thrombus at a higher concentration with smaller quantities and therefore lowers systemic exposure. Mechanical thrombus disruption or extraction allows for drug delivery to a greater surface area of the thrombus. Delays associated with IA therapy may worsen the risk/ benefit ratio of thrombolysis; therefore, combinations of IA-IV treatments have been studied. To date, there are no direct comparative trials to show that endovascular administration is more efficacious or carries a lower risk of hemorrhagic complications than IV tissue plasminogen acti- vator. Neurology® 2012;79 (Suppl 1):S119–S125 GLOSSARY AIS ϭ acute ischemic stroke; DIAS ϭ Desmoteplase in Acute Ischemic Stroke Trial; ECASS ϭ European Cooperative Acute Stroke Studies; FDA ϭ US Food and Drug Administration; IA ϭ intra-arterial; ICH ϭ intracerebral hemorrhage; MCA ϭ middle cerebral artery; MMPs ϭ matrix metalloproteinases; MRA ϭ magnetic resonance angiography; NIHSS ϭ NIH Stroke Scale; NINDS ϭ National Institute of Neurological Disorders and Stroke; PROACT ϭ Prolyse in Acute Cerebral Thromboembolism; rtPA ϭ recom- binant tissue plasminogen activator; TIMI ϭ thrombolysis in myocardial ischemia; tPA ϭ tissue plasminogen activator. Stroke is the fourth leading cause of death in the United States and is a major cause of disability worldwide.1–3 Over the past 20 years, many advances in the treatment of stroke have been directed at better prevention and acute intervention in an effort to improve clinical outcomes and decrease associated mortality. Most of the acute interventions target the salvageable isch- emic penumbra. This is best achieved by IV or intra-arterial (IA) thrombolysis. Ongoing development of thrombolytic agents has produced 4 generations of drugs based on fibrin specificity and pharmacologic half-life. In addition, interventional mechanical devices can en- hance the performance of thrombolytic agents. THROMBOLYTICS Vessel occlusion, caused by a blood clot, interrupts cerebral blood flow and results in an acute ischemic stroke (AIS). Most commonly, the clot comprises a mesh of fibrin and platelets. The resultant cerebral infarct has a core lesion containing dead tissue and a surrounding viable ischemic penumbra. The ischemic penumbra is a region of hypoperfused and dysfunctional cerebral tissue, which may be salvageable. The stability and size of the penumbra are dependent mainly on the collateral blood supply.4 Rapid restora- tion of blood flow through dissolution of the obstructing clot allows recovery of the penumbra. Thrombolytic agents aim at disrupting the fibrin-rich clot that is created in response to injury of the endothelium.5 By activating plasminogen, the administration of thrombolytics leads to an increased produc- tion of plasmin, which dissolves the fibrin bonds in the clot (figure 1). When IV thrombolysis occurs, rapid local and systemic complications may be minimized. However, this time constraint is one of the major limitations of thrombolytic use, and penumbral imaging becomes of paramount significance in triaging AIS From the New Jersey Neurological Institute, JFK Neuroscience Institute, Edison. Go to Neurology.org for full disclosures. Disclosures deemed relevant by the authors, if any, are provided at the end of this article. © 2012 American Academy of Neurology S119 several days after stroke onset and, as a result, had Figure 1 The specificity for bound plasmin increases and systemic effects decrease as thrombolytics progress from first generation to fourth high rates of ICH. In 1980, the NIH consensus rec- ommended that thrombolysis of acute cerebrovascu- lar disorders be contraindicated,10 thus limiting its use in treatment of AIS. Second generation. Alteplase is a protease that is thought to exert a neurotoxic effect on the brain pa- renchyma when it crosses the blood–brain barrier. It also amplifies calcium currents through the NMDA receptor leading to neuroexcitotoxicity and cell death.11,12 Alteplase directly activates matrix metallo- proteinases (MMPs), which have been found to play a role in blood–brain barrier breakdown and neuro- nal injury in a stroke. Because these proteases may increase the risk of ICH and cerebral edema, early administration of the drug prior to natural MMP activation is ideal. The second-generation thrombolytics include re- combinant tissue plasminogen activator (rtPA), also known as alteplase, and prourokinase. These agents First, streptokinase and urokinase; second, alteplase and prourokinase; third/fourth, rete- plase, tenecteplase, monteplase, desmoteplase, and lanoteplase (t-PA ϭ tissue plasmino- are more fibrin-selective and have been studied ex- gen activator; PAI-1 ϭ plasminogen activator inhibitor 1). tensively in ischemic stroke.13–16 The National Insti- tute of Neurological Disorders and Stroke (NINDS) tissue plasminogen activator (tPA) trial was the first patients for thrombolytic therapy, which is addressed study to demonstrate efficacy of alteplase in patients elsewhere in the supplement. with AIS. The efficacy was based on administering First generation. Streptokinase and urokinase are the tPA, 0.9 mg/kg IV, given within 3 hours of symptom first generation of thrombolytics. Although they are onset.16 On the basis of the results of this study, the effective in clot lysis, they are not fibrin-specific. US Food and Drug Administration (FDA) approved Streptokinase is the oldest thrombolytic agent. It IV alteplase for treatment of AIS. Patients who re- is naturally produced by bacteria and was isolated ceived treatment within the first 90 minutes had a and manufactured in the 1950s.6 Streptokinase is more favorable outcome at 3 months than patients known to have immunogenic properties that may re- who were treated after 90 minutes.17 duce its effectiveness or induce an allergic reaction.7 The European Cooperative Acute Stroke Studies Early trials of streptokinase as a treatment for AIS (ECASS I, II, and II) looked at the efficacy of IV had poor outcomes and were all terminated early be- alteplase within 6 hours of symptom onset. These cause of increased mortality related to the develop- studies did not show significant improvement in ment of intracerebral hemorrhage (ICH) after neurologic outcomes at 3 months in comparison treatment.8 During these early trials, investigators with placebo. ECASS I used a dose of 1.1 mg/kg, a were unable to recruit patients within the first few higher dose than the NINDS rtPA study, which led hours of symptom onset, and many patients were en- to a higher incidence of ICH (19.8%).13 A lower rolled days later. This delay, among other factors, con- dose of 0.9 mg/kg was used in ECASS II, and a lower tributed to the increased incidence of hemorrhages.8 ICH rate (8%) was observed, as well as a trend to- More trials using streptokinase were conducted in ward better outcome.14 The ATLANTIS study began the late 1980s and early 1990s. These included the as an investigation of alteplase used within 6 hours of Australian Streptokinase Trial (AST), the Multi- symptom onset. Because of safety concerns, the time center Acute Stroke Trial (MAST), and the Multi- window was shortened to 5 hours.15 A pooled analy- center Acute Stroke Trial in Italy (MAST-I).7,9 In sis of the ATLANTIS, ECASS, and NINDS trials these trials, IV streptokinase was administered within showed beneficial effects of IV alteplase up to 4.5 4 to 6 hours of symptom onset. The results failed to hours after symptom onset. There was no significant show clear benefit and led to abandonment of its use benefit when it was given between 4.5 to 6 hours.18 in the treatment of AIS. ECASS III showed that although overall symptom- Urokinase was developed and studied in the atic ICH was higher in treated patients, the rate was 1970s. In the early 1980s, 3 trials tested IV urokinase not higher in patients treated within the approved in AIS. Again, these trials recruited patients up to 3-hour window and was not associated with in- S120 Neurology 79 (Suppl 1) September 25, 2012 creased mortality. The results were significant across plasma, allowing for single or repeated bolus injec- multiple endpoints and showed efficacy of treatment tions, as opposed to the continuous infusion required despite an increased rate of hemorrhage within 3 to with the first- and second-generation thrombolytics. 4.5 hours of symptom onset.19 There is evidence They have higher fibrin specificity and lower or no from MRI protocols and several studies that IV neurotoxicity, which may in turn lead to lower hem- thrombolysis beyond 3 hours in selected patients can orrhagic complications.5,12 be effective.20,21 Staphylokinase is a highly fibrin-selective agent. It Prourokinase is a proenzyme precursor of uroki- has a low affinity for plasminogen that is free or nase. When activated by fibrin-associated plasmin, 2 bound to intact fibrin, but it binds strongly to plas- single-chain prourokinase units bind at the surface of min and to plasminogen that is bound to partially the thrombus to form an active 2-chain urokinase degraded fibrin.28 This feature enables it to concen- molecule.22 The thrombolytic effect is enhanced by trate on the surface of a lysing thrombus. The heparin, possibly through neutralization of thrombin staphylokinase-plasmin complex is rapidly inhibited 23,24 ␣ or by stimulating tPA from the endothelium.
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