Trial thrombolytic

Comparisons between the different intra-arterial thrombolysis trials and between intraarterial thrombolysis and intravenous thrombolysis is hampered by differences in methodology and type of thrombolytic therapy. In addition, within the intra-arterial thrombolysis trials, thrombolytic deUvery has varied between regional into a parent vessel of the thrombosed vessel, local into the affected artery and into the thrombus itself, or combinations of these methods. In addition, the infusion process has been variable, ranging from continuous to pulsed infusion. Some studies have allowed physical clot dispersion using the tip of the microcatheter while this was prohibited in others, for instance in the PROACT trials. 

Several clinical trials have been conducted with streptokinase adrninistered either intravenously or by direct infusion into a catheterized coronary artery. The results from 33 randomized trials conducted between 1959 and 1984 have been examined (75), and show a significant decrease in mortaUty rate (15.4%) in enzyme-treated patients vs matched controls (19.2%). These results correlate well with an ItaUan study encompassing 11,806 patients (76), in which the overall reduction in mortaUty was 19% in the streptokinase-treated group, ie, 1.5 million units adrninistered intravenously, compared with placebo-treated controls. The trial also shows that a delay in the initiation of treatment over six hours after the onset of symptoms nullifies any benefit from this type of thrombolytic therapy. Conversely, patients treated within one hour from the onset of symptoms had a remarkable decrease in mortaUty (47%). The benefits of streptokinase therapy, especially in the latter group of patients, was stiU evident in a one-year foUow-up (77). In addition to reducing mortahty rate, there was an improvement in left ventricular function and a reduction in the size of infarction. Thus early treatment with streptokinase is essential. 

Anistreplase has a considerably longer a half-life than streptokinase, ie, 90 min compared to 20 min (87,88). Moreover, it does not require prolonged infusion to achieve its thrombolytic effects. Anistreplase was found to be highly effective after a single intravenous dose of 30 units over a 5-min period compared to a 60-min infusion of 1.5 million units of streptokinase (89—94). In direct comparative studies, anistreplase was as effective as intracoronary (95,96) and intravenously (96—100) adrninistered streptokinase. In a randomized, double-blind, placebo-controUed study (AIMS trial) with 1004 patients given this modified enzyme, the 30-day mortaUty rate was 12.2% for patients receiving placebo, compared to 6.4% for patients who received 30 units of anistreplase intravenously within six hours of the onset of symptoms (101). 

Compared to streptokinase, urokinase has been less extensively studied because of its high cost, ie, about 10 times that of a comparable treatment with streptokinase. In addition to the indications described for streptokinase, urokinase is indicated for use in patients with prior streptokinase treatment, or prior Streptococcal infection. Urokinase is commonly used at a loading dose of 4400 units /kg, with a maintenance intravenous infusion dose of 4400 units/kg/h for thromboses other than acute myocardial infarction. In the latter case, a much larger dose, ie, 0.5—2.0 million units/h or a bolus dose of 1.0 million units followed by a 60-min infusion with 1.0 million units, has been found optimal (106). An intracoronary dose of 2000 units/min for two hours was used in one comparative study with intracoronary streptokinase (107). In this study, urokinase exhibited efficacy equivalent to streptokinase with fewer side effects. Other studies with intracoronary urokinase have adrninistered doses ranging from 2,000 to 24,000 units/min with a reperfusion efficacy of 60—89% (108—112). In another urokinase trial, 2.0 million units were adrninistered intravenously, resulting in a thrombolytic efficacy of 60% (113). Effectiveness in terms of reduction in mortaUty rate has not been deterrnined because of the small number of patients studied. 

This section will review the phase III clinical trials of IV thrombolytic agents for acute ischemic stroke, organized by the type of agent and the time window from stroke onset to study drug delivery (Table 3.1). The 1995 National Institute of Neurological Disorders and Stroke (NINDS) rt-PA trial is presented first because it showed that IV rt-PA, given within 3 hours of stroke onset, reduced stroke-related disability. This trial was the basis for the United States Food and Drug Administration (FDA) approval for rt-PA for use in acute ischemic stroke. 

The Stroke-Thrombolytic Predictive Instrument (Stroke-TPI) has recently been developed in order to provide patient-specific estimates of the probability of a more favorable outcome with rt-PA, and has been proposed as a decision-making aid to patient selection for rt-PA." The estimates from this tool should, however, be treated with caution. The prediction rule is dependent on post hoc mathematical modeling, uses clinical trial data from subjects randomized beyond 3 hours who are not rt-PA-eligible according to FDA labeling and current best practice, and has not been externally validated. It is, therefore, not appropriate to exclude patients from rt-PA treatment based solely on Stroke-TPI predictions. 

Clark WM, Albers GW, Madden KR Hamilton S. The rtPA (alteplase) 0- to 6-hour acute stroke trial, part a (a0276g) results of a double-bhnd, placebo-controlled, multicenter study. Thrombolytic Therapy in Acute Ischemic Stroke Study Investigators. Stroke. 2000 31 811-816. 

Thrombolytic therapy with streptokinase in acute ischemic stroke. The Multicenter Acute Stroke Trial-Europe study group. N Engl J Med. 1996 335 145-150. 

No direct comparison trials have been reported between the different thrombolytic agents in acute ischemic stroke. In a retrospective review of the results for acute stroke lAT performed at our center, we have found significantly higher rates of recanalization and good clinical outcome in the era in which lA UK was used versus the era in which UK was not available and lAT with rt-PA was the primary treatment. Conversely, in another retrospective study, Eckert et al. found no major difference between the recanalization rates of UK and rt-PA. 

More recently, thrombolytic therapy was reported in 106 patients as part of the TEMPiS system in Bavaria, Germany. The network consists of two comprehensive and 12 regional centers connected by around-the-clock telemedicine support for stroke care. In the first year following intervention, the number of patients treated with rt-PA increased to 86 patients (2% of all patients admitted with stroke), compared to 10 patients treated in the year preceding intervention. The rate of symptomatic hemorrhage was 8.5%, similar to the NINDS trial. " ... 

In patients with acute PE, the use of thrombolytics provides short-term benefits such as restoring pulmonary artery patency and hemodynamic stability.8,26 A recent meta-analysis of nine small randomized clinical trials showed a slightly lower risk... 

Alteplase (rt-PA Activase) is an IV thrombolytic (fibrinolytic) that was approved for acute stroke treatment in 1996 based on the results of the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Trial.10 The current American Stroke Association guidelines include alteplase as the only Food and Drug Administration (FDA) approved acute treatment for ischemic stroke and strongly encourage early diagnosis and treatment of appropriate patients.11... 

Streptokinase is not indicated for use in acute ischemic stroke treatment. Three large randomized controlled trials evaluating streptokinase were stopped early due to a high incidence of hemorrhage in the streptokinase-treated patients.14-16 At the present time, there is no indication for the use of streptokinase or thrombolytics other than alteplase in the acute treatment of ischemic stroke. 

Intra-arterial thrombolytics may improve outcomes in selected patients with acute ischemic stroke due to large-vessel occlusion. Patients in the Prolyse in Acute Cerebral Thromboembolism II (PROACT II) trial were given 9 mg prourokinase (r-pro UK)... 

Genentech was founded in 1976 by scientist Herbert Boyer and the venture capitalist Robert Swanson. Headquartered in San Francisco, it employs almost 5000 staff worldwide and has 10 protein-based products on the market. These include hGHs (Nutropin, Chapter 11), the anti-body-based products Herceptin and Rituxan (Chapter 13) and the thrombolytic agents Ac-tivase and TNKase (Chapter 12). The company also has 20 or so products in clinical trials. In 2004, it generated some US 4.6 billion in revenues. 

Concomitant use with thrombolytic therapy Clinical trials in HIT patients have provided only limited information on the combined use of lepirudin and thrombolytic agents. The following dosage regimen of lepirudin was used in 9 HIT patients in the studies who presented with TECs at baseline and were started on both lepirudin and thrombolytic therapy (alteplase, urokinase, or streptokinase). 

Hematological agents In clinical trials in patients undergoing PTCA/PCI, coadministration of bivalirudin with heparin, warfarin, thrombolytics, or GPIIb/llla inhibitors was associated with increased risks of major bleeding events compared with patients not receiving these concomitant medications. There is no experience with coadministration of bivalirudin and plasma expanders such as dextran. 

The paradigm shift in 1980 on the causation of acute myocardial infarction to acute coronary occlusion by a thrombus created the rationale for thrombolytic therapy of this common lethal disease. At that time—and for the first time-intravenous thrombolytic therapy for acute myocardial infarction in the European Cooperative Study Group trial was found to reduce mortality significantly. Later studies, with thousands of patients in each trial, provided enough statistical power for the 20% reduction in mortality to be considered statistically significant. Although the standard of care in areas with adequate facilities and experience in percutaneous coronary intervention (PCI) now favors catheterization and placement of a stent, thrombolytic therapy is still very important where PCI is not readily available. 

The proper selection of patients for thrombolytic therapy is critical. The diagnosis of acute myocardial infarction is made clinically and is confirmed by electrocardiography. Patients with ST-segment elevation and bundle branch block on electrocardiography have the best outcomes. All trials to date show the greatest benefit for thrombolytic therapy when it is given early, within 6 hours after symptomatic onset of acute myocardial infarction. 

---