Use Of rt-PA Research Articles

Bleeding complications associated with the use of rt-PA versus r-PA for peripheral arterial and venous thromboembolic occlusions

This article analyzes the early experience with alteplase (rt-PA) and reteplase (r-PA) to identify noteworthy differences in bleeding and to determine correlations with dosage, concomitant anticoagulation, and duration of infusion. A retrospective review of the medical records was unavailable for the initial 82 patients who were treated with either rt-PA (44) or r-PA (38) for peripheral arterial or venous occlusions after urokinase therapy. Successful recanalization was achieved in 31 44 (70%) of the patients treated with rt-PA and in 34 38 (89%) of the patients treated with r-PA. Significant bleeding was documented in 20 44 (45%) of the rt-PA-treated patients (including 14 transfusions) versus 3 38 (8%) of the r-PA-treated patients (3 transfusions). Concomitant anticoagulation with either preceding warfarin (international normalized ratio > 1.1) or a bolus of heparin at the outset of the infusion was associated with significant bleeding in 13 17 (76%) of the rt-PA-treated patients (including 9 transfusions) versus 0 17 in the r-PA-treated patients. No significant correlation between either mean dose or total dose and bleeding was shown for either drug. Early experience indicates that r-PA is at least as effective as rt-PA for the thrombolysis of peripheral arterial and venous occlusions. It also appears that r-PA is less likely than rt-PA to be associated with significant bleeding during such infusions, especially if the patient is concomitantly anticoagulated.

Bleeding complications associated with the use of rt-PA versus r-PA for peripheral arterial and venous thromboembolic occlusions

Bleeding complications associated with the use of rt-PA versus r-PA for peripheral arterial and venous thromboembolic occlusions

Protocol violations in community-based rTPA stroke treatment are associated with symptomatic intracerebral hemorrhage.

Recombinant tissue plasminogen activator (rTPA) is an established treatment for acute ischemic stroke. The rate and type of protocol violations in rTPA use and their effect on patient outcomes in this setting are not well understood. The objective of this study was to examine associations between protocol violations and outcomes in community-based rTPA use. We reviewed medical records of stroke patients treated with rTPA in 10 acute-care hospitals in Indianapolis from July 1996 to February 1998 and assessed complications and outcome. Retrospective National Institute of Health Stroke Scale (on admission and discharge), Canadian Neurological Scale, and length of hospital stay were calculated. Appropriate use of rTPA was determined by the National Institute of Neurological Disorders and Stroke (NINDS) protocol. Fifty patients (mean age, 66 years; 76% white; 56% men) were treated by general neurologists (70%), stroke neurologists (24%), or emergency physicians (6%). Mean times to hospital arrival, brain CT, and start of rTPA infusion were 44, 86, and 141 minutes, respectively. In-hospital mortality rate was 10% (4 intracerebral hemorrhage [ICH], 1 cardiogenic shock). Complications were more frequent among patients with protocol violations (n=8) compared with those without all hemorrhages (75% versus 10%, P:<0.001), symptomatic ICH (38% versus 5%, P:<0.02), and ICH attributable to rTPA, occurring within 36 hours (38% versus 2.4%, P:<0.01), respectively. NINDS protocol violations are relatively common and are associated with symptomatic cerebral and systemic hemorrhages. When the NINDS protocol is strictly followed, hemorrhage rates in community-based rTPA use are similar to those in the NINDS trial.

The Canadian Activase for Stroke Effectiveness Study (CASES): Interim results

39 Background Therapy for acute stroke using rtPA was approved in Canada in February 1999. The Canadian Activase for Stroke Effectiveness Study Group was formed to study the use of rtPA in Canada in a 30-month post-marketing study. Purpose To both prospectively assess the safety of rtPA in the Canadian context and to examine whether the efficacy of rtPA for acute stroke, demonstrated in the NINDS trial, can be translated into effectiveness in routine clinical practice across Canada. Methods The CASES group is a collaboration among the Canadian Stroke Consortium (CSC), the Canadian Stroke Society, the Heart & Stroke Foundation of Canada, Hoffman-LaRoche Canada and physicians across the country. Centres across the country were registered and recruitment is ongoing. The study protocol has been approved by the research ethics board at each centre. Demographics, stroke risk factors, blood pressure, biochemistry, hematology, and CT scans are being collected. NIHSS and mRS scores are being collected prospectively. Outcomes will be monitored at discharge and at 3 months. Results In the first 20 months,72 centres are registered and 525 patients have been treated. The median NIHSS score is 14 (range 2–35). 30% of patients have minimal or no neurological deficit (NIHSS 0–1)and 47% are independent (mRS 0–2) at 90 days. The symptomatic hemorrhage rate is 4.0% (95%CI 2.5% to 6.0%). Multivariate analysis has failed to identify predictors of symptomatic ICH. The rate of protocol violations is 10%, the majority of which are time window violations. Based upon a phone survey of hospitals in Canada with CT scanners, the data set is 75% complete. Conclusions CASES is an ongoing prospective evaluation of the effectiveness of rtPA in acute stroke. The symptomatic hemorrhage rate is low (4.0%). Alteplase for ischemic stroke is safe and effective in Canada.

The Canadian Activase for Stroke Effectiveness Study (CASES): Interim Results

39 Background Therapy for acute stroke using rtPA was approved in Canada in February 1999. The Canadian Activase for Stroke Effectiveness Study Group was formed to study the use of rtPA in Canada in a 30-month post-marketing study. Purpose To both prospectively assess the safety of rtPA in the Canadian context and to examine whether the efficacy of rtPA for acute stroke, demonstrated in the NINDS trial, can be translated into effectiveness in routine clinical practice across Canada. Methods The CASES group is a collaboration among the Canadian Stroke Consortium (CSC), the Canadian Stroke Society, the Heart &amp; Stroke Foundation of Canada, Hoffman-LaRoche Canada and physicians across the country. Centres across the country were registered and recruitment is ongoing. The study protocol has been approved by the research ethics board at each centre. Demographics, stroke risk factors, blood pressure, biochemistry, hematology, and CT scans are being collected. NIHSS and mRS scores are being collected prospectively. Outcomes will be monitored at discharge and at 3 months. Results In the first 20 months,72 centres are registered and 525 patients have been treated. The median NIHSS score is 14 (range 2–35). 30% of patients have minimal or no neurological deficit (NIHSS 0–1)and 47% are independent (mRS 0–2) at 90 days. The symptomatic hemorrhage rate is 4.0% (95%CI 2.5% to 6.0%). Multivariate analysis has failed to identify predictors of symptomatic ICH. The rate of protocol violations is 10%, the majority of which are time window violations. Based upon a phone survey of hospitals in Canada with CT scanners, the data set is 75% complete. Conclusions CASES is an ongoing prospective evaluation of the effectiveness of rtPA in acute stroke. The symptomatic hemorrhage rate is low (4.0%). Alteplase for ischemic stroke is safe and effective in Canada.

Microvascular repair with 1-mm polytetrafluoroethylene (PTFE) grafts: effect of recombinant tissue-type plasminogen activator (rt-PA) on the patency rate and healing process.

The present study assesses the effect of recombinant tissue-type plasminogen activator (rt-PA) on the patency rate and healing process of microvascular polytetrafluoroethylene (PTFE) grafts. Wistar rats were used, divided into four groups of 25 animals each. After dissection of the carotid artery a segment of the vessel, 1 cm long, was resected and replaced by equal length graft. Two different type fibril length (30- or 60-microm) grafts of the same wall thickness (0.18 mm) were used. Normal saline or 3 mg/kg of body weight of rt-PA was applied locally in each group of different fibril length grafts. Patency tests were performed at 15 min and 4 weeks after blood flow was reestablished. All grafts were harvested and examined histologically. The results showed that local application of rt-PA improves patency statistically significantly in both types of fibril length grafts. Patency in 60-microm fibril length grafts was statistically significantly higher than that of 30-microm fibril length grafts, whether rt-PA was used or not. The use of rt-PA had no influence on the healing process of either type of graft.

The development of new drugs for acute stroke

Stroke represents the third common cause of death and hospitalization. However, there are yet no drugs that have reliable effects on acute stroke in Japan. Therefore, the development of new drugs that can support patients is required. There are various candidate drugs for acute stroke such as antithrombotic agents, anticoagulants, thrombolytic agents, neuroprotectants, and so on. Recently clinical trials suggest that aspirin may improve outcome, although these studies demonstrated a modest benefit of aspirin. Abciximab (ReoPro) is a human/mouse monoclonal antibody directed against the platelet receptor glycoprotein IIb/IIIa. It appears to be safe and might improve functional outcome. The large randomized trails were started to test the hypothesis that thrombolysis by an intravenous administration of a recombinant tissue type plasminogen activator (rtPA) could restore cerebral blood flow and improve patient outcome in acute ischemic stroke. These results can support the use of intravenous rtPA for stroke treatment within 3 h after onset, but not beyond 3 h. Development of an effective neuroprotective agent for the treatment of acute stroke remains problematic. Antioxidants, MCI-186 and ebselen, have finished phase III of clinical trials in Japan and were effective. We hope that efficacious drugs for acute stroke can be used for patients.

Reperfusion therapy for stroke.

Stroke is a heterogeneous disease, but about 85% of strokes are as a result of cerebral ischaemia due to arterial occlusion. It seems logical to assume that, as in myocardial infarction, treatment designed to dissolve clots should be helpful. We now have a substantial amount of data on the use of aspirin, heparin and thrombolytic drugs in the treatment of acute ischaemic stroke. Aspirin 300 mg daily has a modest effect in reducing mortality and handicap when used within 48 hours of stroke onset. The beneficial effects of low dose, medium dose subcutaneous unfractionated heparin, and various low molecular weight heparins in reducing early recurrent ischaemic stroke seem to be outweighed by haemorrhagic side effects. Streptokinase used within six hours of stroke onset results in excess mortality with some reduction in handicap in survivors, while in carefully selected patients recombinant tissue plasminogen activator (r-TPA) may be less hazardous. At the moment it is unclear which stroke patients will benefit from the use of r-TPA, and the use of criteria, as outlined by the NINDS group, means that only a very small proportion of stroke victims are suitable for thrombolytic therapy. Further research is necessary, while the concept of a 'Brain Attack' with appropriate urgency being used in the assessment of possible stroke needs development.

Antithrombotic Treatments in Acute Ischemic Stroke

A therapeutic role for antiplatelet agents and anticoagulants within 6 hours of the onset of ischemic stroke symptoms has not been tested. With one exception, their use in early stroke (< 48 hours) did not produce a favorable outcome. The use of rt-PA in appropriate patients presenting with ischemic stroke within 3 hours of symptom onset has been accompanied by significant benefit, which has exceeded the risk of intracerebral hemorrhage in one trial. The recent group of clinical studies has provided evidence for factors which may contribute to hemorrhagic transformation. These studies also demonstrate the following: i) recanalization of carotid and vertebrobasilar artery territory occlusions is technically feasible within 3 to 6 hours of symptom onset, ii) the frequency of hemorrhage is increased in ischemic stroke patients receiving PAs, iii) the interval from symptom onset to treatment to achieve clinical improvement varies individually and contributes to hemorrhagic risk, and iv) the optimal PAs, their dose-rate, and delivery systems have not yet been defined in either the carotid or vertebrobasilar territory. Taken together, the NINDS trial, ECASS, and ECASS II indicate the enormous importance of patient selection to reduce the hemorrhagic risk which accompanies the use of PAs in stroke. However, it is currently not possible to separate benefit from hemorrhagic risk in a given patient based upon simple clinical criteria, although contributors to this risk have been identified. Clearly, attempts to reduce the risk of hemorrhage should contribute to the overall benefit of selected ischemic stroke patients treated with rt-PA and with other PAs. This experience may also provide a clinical basis for the prospective study of antiplatelet agents and anticoagulants in acute ischemic stroke.

Alteplase (r‐TPA) vs streptokinase

The GUSTO trial and an Australian consensus meeting in 1993 led to the recommendation that recombinant tissue plasminogen activator (r-TPA) was the preferred thrombolytic in patients with acute myocardial infarction (AMI) and ST segment elevation under the age of 75, whose infarction was anterior, who could be treated within four hours of the onset of symptoms and who did not have a contraindication to thrombolysis. Available data suggest that streptokinase (SK) should not be administered in a patient who has received this drug three days or more previously. New data on the risks of stroke confirm that the use of r-TPA is associated with a higher risk of intracranial haemorrhage than SK, and those with a high risk profile for intracranial haemorrhage (hypertension and advanced age) should receive SK rather than r-TPA. It may be justified to give r-TPA to any patient with a large infarct regardless of location, within four hours of the onset of infarction in an attempt to achieve TIMI flow grade 3 (complete) reperfusion, reduce mortality and improve left ventricular function and clinical outcomes. The focus for the future will be on how to treat more patients earlier with thrombolytic agents, rather than the choice of agent.

Thrombolysis in acute ischemic stroke.

The administration of rt-PA to patients with acute ischemic stroke can result in improved functional outcomes. The safe and effective use of rt-PA in routine medical practice requires that patients seek help early, have a well-defined onset of their symptoms, be carefully examined for contraindications to rt-PA, receive a CT scan and interpretation to exclude hemorrhage, and receive the drug within a 3-hour period (Table 5). Intravenous rt-PA is given in a dosage of 0.9 mg/kg (up to a maximum of 90 mg) with 10 percent of the dose administered as a bolus followed by a 60-minute infusion within 3 hours of the onset of symptoms. If these conditions cannot be achieved, the drug should not be administered. Although most patients will not meet the criteria of the NINDS trial, rt-PA is an important advance in the treatment of acute ischemic stroke.

Fibrinólise no AVC agudo: estado actual.

The use of thrombolytic therapy in acute ischemic stroke is still today a somewhat controversial subject. We come across authors who defend its undisputed use in adequately selected cases, others who are more sceptical and habitually place a question mark on this subject and a third group in expectation. Intra-arterial thrombolysis has very precise indications, its use in vertebrobasilar ischemic stroke remains inconclusive, eventually with a wider window. Five important randomised studies have taken place in recent years with thrombolysis administered intravenously. All three studies with Estreptoquinase--MAST-E, MAST-I and ASK--ended prematurely due to the high rates of mortality and intracranial haemorrhage observed in the group of patients treated with this drug. From the two main studies with rt-PA-ECASS and NINDS, the American trial showed somewhat higher results. The Guidelines from the American Heart Association for the use of rt-PA in ischemic stroke are presented. Fibrinolysis, when successful, only permits the restoration of blood flow in the area of ischemic suffering. This implies that, simultaneously, other therapeutic measures will have to be implemented.

Asymmetric Angioneurotic Edema Associated With Thrombolysis for Acute Stroke

We present a case of acute asymmetric angioneurotic edema associated with the use of recombinant tissue plasminogen activator (rtPA) for acute ischemic stroke. rtPA was administered for an acute ischemic stroke in accordance with the recently reported National Institute of Neurological Disorders and Stroke protocol, after which marked asymmetric angioedema requiring upper-airway control developed. Although atypical and anaphylactoid reactions have been reported with the use of rtPA for acute myocardial infarction, to our knowledge this is the first case report of asymmetric angioedema associated with the use of rtPA for acute ischemic stroke. [Pancioli A, Brott T, Donaldson V, Miller R: Asymmetric angioneurotic edema associated with thrombolysis for acute stroke. Ann Emerg Med August 1997;30:227-229.]

Catheter-directed lysis of iliofemoral vein thrombosis with use of rt-PA.

The aim of our study was to evaluate the results of catheter-directed thrombolysis and complementary procedures to treat acute iliofemoral deep vein thrombosis (DVT). A total of 24 consecutive patients with acute iliofemoral DVT underwent intrathrombus drip infusion of alteplase (3 mg/h; mean dosage 86 mg, range 45-174 mg), while intravenous heparin (1000 U/h) was continued. Complementary procedures were hydrodynamic thrombectomy in 3 and primary insertion of a Wallstent in 9 patients. Patency of 19 thrombosed veins (79 %) was restored with prompt symptomatic relief. An underlying anatomical anomaly or lesion was present in 13 patients: iliac vein compression syndrome (n = 8), absent (n = 2) or obstructed (n = 1) vena cava or venous stenosis (n = 2). Ten of the abnormalities were unknown before lysis and eight were relieved by stent deployment. Puncture site bleeding was the only complication but led to transfusion in 6 patients (25 %). Symptomatic reocclusion occurred in 4 patients. Catheter thrombolysis of iliofemoral vein thrombosis revealed many anatomical abnormalities which may predispose to thrombosis and are often amenable to stenting.

Intravenous thrombolytic therapy in acute stroke.

The article reviews the experimental basis of thrombolytic therapy, and summarizes the results of the recent trials of thrombolysis. Five large clinical trails have evaluated intravenous thrombolytic therapy for the treatment of hyperacute (< 6 h) stroke. Three of these studies were negative, one was equivocal, and one was strongly positive. The failure of demonstrate efficacy definitively in four of these trials may be related to a number of methodological factors, including the type and dose of drug administered, the timing of drug administered, and the method of patient selection for treatment. The NINDS recombinant tissue plasminogen activator (rt-PA) study showed that thrombolytic therapy can be of substantial benefit when administered within 3 h of stroke onset using strict patient selection criteria and rt-PA is now FDA approved for treatment of acute stroke. However, the risk of clinically significant bleeding is elevated. To achieve the favorable risk/benefit ratio demonstrated in the NINDS trial, patients must be screened by experienced clinicians for contraindications to thrombolysis and the acute computerized tomography (CT) brain scan must be carefully evaluated for radiographic features that increase the risk of cerebral hemorrhage. Guidelines for the use of rt-PA are provided, as well as insights into future thrombolytic treatment strategies.

Intracoronary recombinant tissue-type plasminogen activator (rt-PA).

Intracoronary rt-PA has been used to treat patients with acute myocardial infarction primarily, after failure of intravenous thrombolytic therapy, and when angioplasty has not been technically possible. It has also been used to treat thrombotic closure complicating angioplasty, to treat nonocclusive thrombosis observed during angioplasty, and to pretreat patients with nonacute total occlusions before angioplasty. Intracoronary administration has the potential of providing high local concentrations for a given dose level and may allow lower total doses for the same degree of efficacy. More controlled data are needed on appropriate patient selection, angiographic and clinical endpoints, dose level and regimen, and comparable efficacy of rt-PA and other thrombolytic agents. However, the use of intracoronary rt-PA should be considered when intracoronary thrombus is evident and this route of administration is available.

Peripheral arterial occlusions: Local low-dose thrombolytic therapy with recombinant tissue-type plasminogen activator (rt-PA)

To study the efficacy and risks of local thrombolytic therapy of peripheral arterial occlusions using rt-PA. This open study was performed in one clinic in Munich, Germany. 288 patients suffering from occlusions of the lower limb arteries were subjected to 336 treatments performed with a permanently controlled technique. In a short pilot study 10mg rt-PA/h were administered for 5 h but in the majority of the cases only 2.5mg/h were administered for a maximum of 5 h. The average total dose of rt-PA was 2.97mg and the average time for lysis was 78 min. 43 (84.3%) out of 51 embolic occlusions and 168 (71.5%) out of 235 thrombotic occlusions were recanalised with a cumulative patency of 95% and 79.7% respectively after 2 years. One systemic bleeding occurred in the pilot study with 10mg rt-PA/h whereas with the 2.5mg/h dosage no systemic bleeding or embolism occurred in the 315 treatments. There were no deaths during hospitalisation. Six major and two forefoot amputations were necessary. Thirteen patients required a bypass operation and one an embolectomy. The advantages of our controlled technique are: short duration of treatment, small doses of activating agent, an accurately directed pathway with the possibility of dilating stenoses during the same session, no danger of systemic bleeding or embolism and, therefore, good prospects of success with minimal risk. The use of rt-PA for local lysis substitutes the inadequate tissue activator available for effective spontaneous lysis and is, therefore, almost physiological. The effect of a very low dose of rt-PA was as good as that of higher doses.

Pharmacokinetics of human recombinant tissue-type plasminogen activator, administered intra-abdominally, in a rat peritonitis model.

Human recombinant tissue-type plasminogen activator (rtPA), administered intraperitoneally, may promote intra-abdominal fibrinolysis in peritonitis, thereby preventing adhesion and abscess formation. The pharmacokinetics of a single intraperitoneal dose of 0.5 or 2.0 mg/ml human rtPA were assessed in rats with fecal peritonitis and related to their endogenous tPA and plasminogen activator inhibitor (PAI) activity. Endogenous PAI activity was strongly elevated both in peritoneal fluid and in plasma, whereas tPA activity was only slightly increased in the peritoneal fluid. Both doses of rtPA significantly enhanced fibrinolytic activity of the peritoneal fluid up to 24 h in a dose-dependent manner. However, tPA activity was lower than calculated from the tPA antigen levels and the specific activity of rtPA in the fluid of rats with peritonitis. Plasma tPA activity was low at both doses. A single dose of 0.5 or 2.0 mg/ml rtPA can raise fibrinolytic activity in the abdominal cavity up to 24 h. High endogenous peritoneal PAI levels may adversely effect intra-abdominal use of human rtPA in peritonitis.

Recombinant Tissue Plasminogen Activator for the Treatment of Lower Extremity Peripheral Vascular Occlusive Disease

Regional thrombolysis in the recanalization of peripheral vascular occlusive disease is an increasingly accepted therapeutic modality. Efficacy and complication rate are major issues in thrombolytic therapy. This prospective study was undertaken to determine if locally delivered recombinant tissue plasminogen activator (r-TPA) is safe and effective in clot lysis at non-weight-adjusted doses. Twenty patients (undergoing 21 infusions) from two centers underwent fibrinolytic therapy with use of r-TPA, at a dose rate of 2 mg/h. The mean duration of arterial occlusion was 27.2 days (range, 1-117 days). Concomitant intravenous heparin anticoagulation was administered to all patients. A coaxial infusion delivery system was employed. Hematologic parameters and angiographic follow-up were evaluated at 4-hour intervals during thrombolytic infusion. The chosen maximum r-TPA dose of 40 mg could be extended at investigator discretion. Complete clot lysis was achieved in 18 of 21 (85.7%) infusions at a mean total dose of 38.9 mg (range, 8-84 mg). The mean infusion duration was 19.7 hours. In 16 of 19 (84.2%) infusions, in which the nadir fibrinogen level was recorded, it remained greater than 65% of baseline. Three of 21 (14.3%) infusions resulted in three major bleeding complications, one of which resulted in death. In this two-center trial, catheter-directed r-TPA infusion at 2 mg/h is effective for clot lysis. When combined with concomitant heparin administration, this treatment may result in an unacceptably high frequency of bleeding complications.

Thrombolytic Therapy: Future Issues

A considerable amount of work has been devoted to thrombolytic therapy (about 3000 references from 1991 to 1995 in a Medline search). The most important and well established indication of thrombolytic treatment is acute myocardial infarction (MI). Megatrials have evidenced a significant 30 to 40% reduction in hospital mortality in the treated patients. However, lack of sufficient thrombolysis in approximately 25% of patients, reocclusion in 6 to 16% of patients and intracranial hemorrhage in about 0.5% of patients are the main concerns regarding thrombolysis. Three approaches should improve the results of thrombolytic therapy in acute MI: earlier medical treatment, use of more efficacious thrombolytic agents in combination with more active antithrombotic agents and reduction of severe bleeding with safer combination of drugs. An improved of laboratory monitoring may also reduce the incidence of severe hemorrhagic events. In acute pulmonary embolism (PE), a change of indication for treatment based on echocardiography and high probability ventilation-perfusion lung scan results (without requiring pulmonary angiography) could broaden the use of thrombolysis. However, thus far, there has not been a demonstration of a reduction in mortality in large controlled studies. Thrombolysis in acute ischemic stroke is an attractive treatment but thrombolytic treatment is still at an experimental stage. However, the successful use of rt-PA in acute MI has renewed the interest in thrombolysis for focal cerebro-vascular ischaemia. Large controlled studies with SK, rt-PA or UK locally or intravenously administered have been recently undertaken to evaluate the benefit/risk ratio of treatment which seems surprisingly variable in different subgroups of patients.(ABSTRACT TRUNCATED AT 250 WORDS)