Intravenous Streptokinase Research Articles

Reperfusion therapy in elderly patients with acute myocardial infarction: A randomized comparison of primary angioplasty and thrombolytic therapy

ObjectivesThis study sought to determine the short- and long-term outcome of primary coronary angioplasty and thrombolytic therapy for acute myocardial infarction (AMI) in patients older than 75 years of age. BackgroundThe benefit of reperfusion therapy in elderly patients with AMI is uncertain, although elderly people account for a large proportion of deaths. MethodsWe randomly assigned a total of 87 patients with an AMI who were older than 75 years to treatment with angioplasty or intravenous (IV) streptokinase. Clinical outcome was measured by taking the end points of death and the combination of death, reinfarction or stroke during follow-up. ResultsThe primary end point, a composite of death, reinfarction or stroke, at 30 days had occurred in 4 (9%) patients in the angioplasty group as compared with 12 (29%) in the thrombolysis group (p = 0.01, relative risk [RR]: 4.3, 95% confidence interval [CI]: 1.2 to 20.0). At one year the corresponding figures were 6 (13%) and 18 (44%), respectively (p = 0.001, RR: 5.2, 95% CI: 1.7 to 18.1). ConclusionsIn this series of patients with AMI who were older than 75 years, primary coronary angioplasty had a significant clinical benefit when compared with IV streptokinase therapy.

Thrombolyse par voie systémique d'une thrombose de la veine cave supérieure associée à un cathéter veineux central

We report the case of 47-year-old woman with a superior vena cava syndrome occuring one month and a half after she had been equipped with a central venous catheter. Her clinical symptoms were so severe that she was treated by intravenous streptokinase administered systemically during 24 hours. This treatment provided the resolution of symptoms without any further complication. The importance of a rapid diagnosis and early treatment are discussed.

Bedside markers of coronary artery patency and short-term prognosis of patients with acute myocardial infarction and thrombolysis

Background In this study we have evaluated the prognostic power of noninvasive markers of coronary artery reperfusion in patients with acute myocardial infarction who were treated with intravenous streptokinase. Methods In 967 consecutive patients with acute myocardial infarction who were treated within 6 hours of symptoms, we analyzed the prognostic power of resolution of chest pain and ST-segment elevation >50% at 90 minutes, abrupt creatine kinase rise before 12 hours, and T-wave inversion in infarct-related electrocardiographic leads within the first 24 hours after thrombolysis. Results Global in-hospital mortality rate was 12.0%. Each reperfusion marker was associated with improved outcome. Multivariate logistic regression analysis showed that 3 of the 4 markers of coronary artery reperfusion were significantly and independently associated to low in-hospital mortality rate. The presence of early T-wave inversion was associated with the lowest in-hospital mortality rate (odds ratio 0.25, confidence interval 0.10-0.56). When all markers of coronary artery reperfusion were included in the regression model, T-wave inversion (odds ratio 0.29, confidence interval 0.11-0.68) and abrupt creatine kinase rise (odds ratio 0.36, confidence interval 0.16-0.77) continued to be significantly associated with better outcome. Conclusion A systemic analysis of noninvasive markers of coronary artery reperfusion can provide the clinician with an excellent tool to predict clinical outcomes when treating myocardial infarction. (Am Heart J 1999;138:533-9.)

Influence of thrombolytic therapy on the incidence of left ventricular thrombi after acute anterior myocardial infarction: role of successful reperfusion.

Previous studies have reported controversial results regarding the effectiveness of systemic thrombolysis in preventing left ventricular (LV) thrombus after acute myocardial infarction (MI). This study was performed to evaluate the influences of thrombolysis, and particularly successful reperfusion, on the incidence of LV thrombus formation after acute anterior MI. In all, 191 patients suffering from a first attack of acute anterior MI were prospectively evaluated by two-dimensional echocardiography and coronary angiography, performed at the end of the first week and within the first two weeks of MI, respectively. Of these, 98 who presented within 12 h of onset of symptoms received intravenous streptokinase (1.5 million IU), while the remaining 93 patients who, either because of contraindications or late admission, did not receive thrombolytic treatment served as control group. All patients received aspirin and full-dose anticoagulation with intravenous heparin. Successful reperfusion in the streptokinase group was assessed by enzymatic and electrocardiographic evidence. The overall incidence of LV thrombi was 24.6% (47/191). When all patients were evaluated, no statistically significant difference was found between the frequency of LV thrombi in the patients who had thrombolysis (22.4%) and those who did not (26.8%), despite a trend toward the formation of fewer thrombi in the initial group (p > 0.05). However, the patients who had successful reperfusion with streptokinase (n = 64) had significantly reduced incidence of LV thrombi compared with those who did not receive thrombolytic therapy (20 vs. 26.8%, p < 0.05). Stepwise multivariate analysis suggested that LV abnormal wall motion score (p = 0.01) and presence of LV aneurysm were independent predictors of LV thrombus formation in patients with acute anterior MI. Not all patients who received streptokinase for acute anterior MI, but only those with successful reperfusion had reduced incidence of LV thrombi. The favorable effects of thrombolysis on LV thrombus formation are probably due to the preservation of global LV systolic function.

Survival 12 years after randomization to streptokinase: the influence of thrombolysis in myocardial infarction flow at three to four weeks

OBJECTIVESThe purpose of this study was to determine whether the mortality benefit of intravenous streptokinase administered within 4 h of the onset of acute myocardial infarction is maintained at 12 years, and whether Thrombolysis in Myocardial Infarction (TIMI) flow grades independently influence late survival.BACKGROUNDTreatment with reperfusion therapies and achievement of TIMI 3 flow are associated with increased short- and medium-term survival after infarction. Whether infarct artery flow independently influences survival more than five years after infarction is unknown.METHODSThe late survival of patients randomized to receive either streptokinase (1,500,000 IU over 30 to 60 min) or a matching placebo within 4 h of symptom onset in 1984–1986 was determined. Angiography was performed in surviving patients at three to four weeks, and TIMI flow grades were assessed blind to randomization and outcomes. The late vital status was determined in 99% of patients.RESULTSPatients randomized to receive streptokinase (n = 107) had improved survival compared with those randomized to placebo (n = 112) at five years (84% vs. 70%; p = 0.023) and 12 years (66% vs. 51%; p = 0.022). At five years 94% of patients with TIMI grade 3 flow, 81% of those with TIMI grade 2 flow and 72% of those with TIMI grade 0–1 flow survived (p = 0.005). At 12 years 72% of patients with TIMI 3, 67% of those with TIMI 2 and 54% of those with TIMI 0–1 flow survived (p = 0.023). Multivariate analysis identified the ejection fraction (p = 0.014), exercise duration (p = 0.013) and TIMI 3 flow (p = 0.04 compared with TIMI 0–2 flow) as important factors for five-year survival. At 12 years multivariate predictors of late survival were the ejection fraction (p = 0.006), exercise duration (p = 0.003) and myocardial score (p = 0.013). The end-systolic volume index was similar to the ejection fraction as a predictor of survival at five and 12 years.CONCLUSIONSThe survival benefits of streptokinase persist for 12 years after infarction. TIMI flow at three to four weeks is an independent predictor of five-year survival.

Acute coronary syndromes: Drug treatments

Acute coronary syndromes: Drug treatments

Critical importance of myocardial salvage: Relationship with the choice of reperfusion strategies

Clinical trials have left little doubt that in patients with symptoms of acute myocardial infarction, early reperfusion achieved with coronary thrombolytic therapy is beneficial in limiting infarct size [ 1 Koren G. Weiss A.T. Hasin Y. et al. Prevention of myocardial damage in acute myocardial ischemia by early treatment with intravenous streptokinase. N Eng J Med. 1985; 313: 1384-1389 Google Scholar , 2 Hasche E.T. Fernandes C. Freedman S.B. Jeremy R.W. Relation between ischemia time, infarct size and left ventricular function in humans. Circulation. 1995; 92: 710-719 Google Scholar , 3 Raitt M.H. Maynard C. Wagner G.S. Cerqueira M.D. Silvester R.H. Weaver W.D. Relation between symptom duration before thrombolytic therapy and final myocardial infarct size. Circulation. 1996; 93: 48-53 Google Scholar , 4 ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both or neither among 17 187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;2:349–360. Google Scholar ].

Early infarct artery collateral flow does not improve long-term survival following thrombolytic therapy for acute myocardial infarction

It is known that acutely developed collaterals can prevent the onset of acute myocardial infarction (AMI) in the presence of a total coronary occlusion. However, there still is controversy concerning long-term follow-up of coronary collateral circulation to the infarct-related artery. In this study we analyze the prognostic role of collateral flow (degrees 0 to 3) as well as anterograde flow (degrees 0 to 3) in patients with AMI treated with thrombolytic therapy. Four hundred twenty-two patients (median age 57 years, 355 men) with AMI were treated with intravenous streptokinase and followed prospectively for up to 8 years. At the end of the study period, patients with collateral coronary flow 3 (n = 30) and those with flow <3 (n = 392) at in-hospital coronary arteriography had survival rates of 66% and 85%, respectively (p <0.12). Meanwhile, patients with coronary anterograde flow 3 (n = 189) and those with flow <3 (n = 233) had survival rates of 89% and 80%, respectively (p <0.04). By censored regression analysis, a negative correlation was found between coronary collateral flow degree and survival (p = 0.0498) and, inversely, a positive correlation was found between coronary anterograde flow degree and survival (p = 0.0053). By Cox multivariate analysis, the following variables showed significant correlations with long-term survival: global left ventricular ejection fraction (p = 0.0003), anterograde flow degree (p = 0.0006), collateral flow degree (negative correlation, p = 0.0179), and medical treatment (negative correlation, p = 0.0464). Thus, patients treated with intravenous streptokinase during AMI and with adequate coronary collateral circulation had a worse prognosis than those who developed adequate anterograde flow, probably because of residual myocardial ischemia. Such patients may benefit from coronary revascularization (angioplasty or surgery) to restore anterograde blood flow and minimize myocardium at risk.

Coronary Thrombolysis

The clinical description of acute myocardial infarction (AMI) by Herrick 1 Herrick JB. Clinical features of sudden obstruction of the coronary arteries. JAMA. 1912; 59: 2015-2020 Crossref Google Scholar in 1912 embodied the concept that acute coronary thrombosis was responsible, and this view was widely adopted. The first trial of IV administration of thrombolytic therapy was published in 1959 2 Fletcher AP Sherry S Alkjaersig N et al. The maintenance of a sustained thrombolytic state in man: II. Clinical observations on patients with myocardial infarction and other thromboembolic disorders. J Clin Invest. 1959; 38: 11-19 Google Scholar and the first of intracoronary use was published in I960. 3 Boucek HJ Murphy WP. Segmental perfusion of the coronary arteries with fibrinolysin in man following a myocardial infarction. Am J Cardiol. 1960; 5: 525-533 Abstract Full Text PDF Google Scholar Over the next 25 years, 24 randomized studies of IV thrombolytic therapy were conducted, primarily in Europe, 4 Yusuf S Collins R Peto R et al. Intravenous and intracoronary fibrinolytic therapy in acute myocardial infarction: overview of results on mortality, reinfarction and side effects from 33 randomized controlled trials. Eur Heart J. 1985; 6: 556-585 PubMed Google Scholar the results varying from statistically significant benefit to no suggestion of benefit, and thrombolytic therapy was rarely used. In the late 1970s, there was a reawakening of interest in thrombolytic therapy for AMI, initially directed at intracoronary administration. 5 Chazov EL Mateeva LS Mazaer AV et al. Intracoronary administration of fibrinolysis in acute myocardial infarction. Ter Arkh. 1976; 48: 8-19 PubMed Google Scholar ,6 Rentrop KP Blanke H Karsch KR et al. Selective intracoronary thrombolysis in acute myocardial infarction and unstable angina pectoris. Circulation. 1981; 63: 307 Crossref PubMed Google Scholar The reality that most hospitals do not have cardiac catheterization laboratories and the recognition of the economic and logistic impediments to emergency cardiac catheterization, even in referral hospitals, stimulated a reevaluation of IV thrombolytic therapy. 7 Schroeder R Biamino G Leitner E-R et al. Intravenous short-term infusion of streptokinase in acute myocardial infarction. Circulation. 1983; 67: 536-548 Crossref PubMed Google Scholar ,8 Lo YSA. Intravenous versus intracoronary streptokinase in acute myocardial infarction. Clin Cardiol. 1985; 8: 609-619 Crossref PubMed Google Scholar

Early Noninvasive Identification of Failed Reperfusion After Intravenous Thrombolytic Therapy in Acute Myocardial Infarction

Objectives. This study sought to evaluate a biochemical approach to the early noninvasive assessment of reperfusion.Background. In patients with an acute myocardial infarction, a rapid noninvasive method of detecting failure of intravenous thrombolytic therapy to restore early Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow in the infarct-related artery (IRA) is needed.Methods. Serial blood samples were collected to assay creatine kinase-MB fraction (CKMB mass), cardiac troponin T and myoglobin concentrations in 105 patients with a myocardial infarction who underwent early angiography after intravenous streptokinase. The ratios of the 60- and 90-min concentrations to prethrombolytic values were used to determine an index that could identify failure to achieve TIMI grade 3 flow in the IRA at 90 min.Results. Significant increases in serum concentrations of markers at 60 min were more likely with TIMI grade 3 flow (59 patients) than with TIMI grade 0 to 2 flow (46 patients). Ratios ≤5 at 60 min after thrombolysis detected failure to achieve 90-min TIMI grade 3 flow with 92% to 97% sensitivity, 43% to 60% specificity and 63% to 76% positive and 86% to 94% negative predictive values. Ratios ≤10 at 90 min showed 88% to 95% sensitivity, 49% to 65% specificity and 61% to 69% positive and 86% to 94% negative predictive values for TIMI flow grade <3. The overall predictive values were thus similar for all three markers.Conclusions. In acute myocardial infarction treated with intravenous streptokinase, a simple measurement of increased serum concentrations of CKMB mass, cardiac troponin T or myoglobin at 60 and 90 min can accurately predict failure to achieve TIMI grade 3 flow in the IRA at 90 min.

ISIS-2: 10 year survival among patients with suspected acute myocardial infarction in randomised comparison of intravenous streptokinase, oral aspirin, both, or neither

Objective: To assess effects of intravenous streptokinase, one month of oral aspirin, or both, on long term survival after suspected acute myocardial infarction.Design: Randomised, “2×2 factorial,” placebo controlled trial.Setting: 417...

Efficacy of Streptokinase, but Not Tissue-Type Plasminogen Activator, in Achieving 90-Minute Patency After Thrombolysis for Acute Myocardial Infarction Decreases With Time to Treatment

Objectives. We sought to examine the relation between time to treatment and 90-min patency rates in patients receiving intravenous streptokinase (SK) or accelerated tissue-type plasminogen activator (t-PA).Background. Early patency of the infarct-related artery is a major determinant of survival after thrombolysis for acute myocardial infarction. Some data suggest that time to treatment may influence the efficacy of nonfibrin-specific thrombolytic agents in restoring early patency of the infarct-related vessel.Methods. We performed a retrospective analysis of a cohort of 481 patients receiving thrombolytic therapy for acute myocardial infarction <6 h after pain onset, all of whom underwent 90-min coronary angiography. Patency of the infarct-related artery was graded by two observers who had no knowledge of the treatment received or the time between pain and therapy.Results. There was no difference in baseline clinical or angiographic characteristics according to the timing or nature of treatment. Thrombolysis in Myocardial Infarction (TIMI) flow grade 2 or 3 patency rate after SK correlated negatively with the time between onset of pain and thrombolysis (r = 0.8, p = 0.05), whereas the 90-min patency rate after t-PA appeared stable as a function of time to treatment. When patients were categorized as having received treatment <3 or ≥3 h after pain onset, the patency rate was similar with t-PA, but significantly higher when SK was administered early rather than late, regardless of whether TIMI flow grades 2 and 3 were pooled (86.9% vs. 59.4%, p = 0.0001) or TIMI flow grade 3 alone was considered to indicate patency (81.7% vs. 53.6%, p = 0.0001). Multivariate logistic regression analysis showed a negative effect of time to treatment on the patency probability for SK (p = 0.0001) but not for t-PA.Conclusions. The efficacy of streptokinase but not t-PA in restoring early coronary patency after intravenous thrombolysis is markedly lower when patients are treated later after onset of pain.

Estimation of enzymatic infarct size: Direct comparison of the marker enzymes creatine kinase and α-hydroxybutyrate dehydrogenase

Background Estimation of infarct size with serum-time activity curves of creatine kinase (CK) (or CKMB) or α-hydroxy- butyrate dehydrogenase (HBDH) is widely used in clinical trials. However, an independent variable such as left ventricular function has not been directly compared with CK and HBDH infarct size measurements in the same group of patients. Methods and Results Infarct size was calculated by the CK area under the curve (AUC) and by the cumulative release of HBDH in 90 patients with acute myocardial infarction undergoing early thrombolysis. Infarct size estimates by CK AUC and HBDH release were closely correlated ( r = 0.88, p < 0.0001). HBDH release was significantly better ( p < 0.001) correlated to angiographically assessed ejection fraction 8 days after infarction ( r = 0.74) than to CK AUC ( r = 0.60), as was maximum HBDH ( r = 0.71) compared with CK maximum ( r = 0.59). In contrast to CK, maximum levels of HBDH only slightly overestimate myocardial damage in patients with early reperfusion. Data reanalyzed from the former placebo-controlled Intravenous Streptokinase in Acute Myocardial Infarction (ISAM) study revealed significant differences in favor of streptokinase for CK and CKMB AUC and for HBDH maximum, but no difference for CK and CKMB maximums. Conclusions For comparative clinical trials HBDH appears to be the preferable marker enzyme for estimates of infarct size and measure of reperfusion effectiveness. In clinical practice one routine measure of HBDH serum activity on the second day after infarction may be a useful approximate value of infarct size. (Am Heart J 1998;135:1-9.)

The role of antegrade and collateral flow in relation to left ventricular function post-thrombolysis

The aim of the study was to analyze the relationship between antegrade and collateral flow degree to the “culprit” coronary artery, and between both variables and left ventricular systolic function. We analyzed five hundred patients with acute myocardial infarction, treated prospectively and consecutively within 6 h of evolution with intravenous streptokinase. The degree of antegrade (0–3) and collateral blood flow (0–3) were correlated with 18 other variables. Results: (a) By simple regression analysis, antegrade flow degree correlated positively (p<0.0001), and collateral flow degree negatively (p=0.0073) with left ventricular ejection fraction; (b) By multiple regression analysis, antegrade flow degree (p=0.0032), but not collateral flow degree (p>0.1), correlated independently with left ventricular ejection fraction; (c) In the subgroup of patients with occluded “culprit” coronary artery, the mean ejection fraction was significantly higher for those with collateral flow 3 (60.2%±13.3) in relation to those with collateral flow <3 (53.9%±13.1, p=0.032, 95% CI 11.96 to 0.53%). In conclusion, antegrade coronary flow degree, but not collateral flow degree, correlated significantly and independently with left ventricular ejection fraction. However, in the subgroup of patients with occluded “culprit” coronary artery, collateral flow 3 led to better left ventricular systolic function, in relation to collateral flow <3.

Significance of initial ST segment changes for thrombolytic treatment in first inferior myocardial infarction.

OBJECTIVE: To evaluate the benefit to risk ratio of thrombolytic treatment in patients with small inferior acute myocardial infarction (AMI). Controlled studies relating the benefit from thrombolysis with initial electrocardiographic...

Platelet aggregation by IgG anti-streptokinase and anisoylated plasminogen-streptokinase activator complex: heterogenous responses in platelet-rich plasma but not in washed platelets

Platelet aggregation by IgG anti-streptokinase and anisoylated plasminogen-streptokinase activator complex: heterogenous responses in platelet-rich plasma but not in washed platelets

Is heparin of value in the management of acute myocardial infarction?

The role of heparin in conjunction with thrombolytic therapy for the management of patients with acute myocardial infarction continues to be controversial. Many issues, including the possible benefits and risks of this therapy, are unresolved. Administration of high-dose subcutaneous heparin in the presence of thrombolytic therapy results in a significant mortality reduction during the treatment period of 55 lives saved per 10,000 patients treated (p < 0.01). At 35 days mortality is not significantly decreased by 22 lives and 18 nonfatal infarctions, at a cost of 32 transfusions and 6 strokes (half of which result in full recovery) per 10,000 patients treated. There have been fewer than 1250 patients randomized in trials comparing intravenous heparin with no heparin in patients receiving thrombolytic therapy and aspirin. These trials are too small to draw reliable conclusions, although several trials have suggested that intravenous heparin is beneficial for maintaining patency after t-PA therapy. In the the Global Use of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) trial, patients receiving streptokinase were randomized to receive either delayed subcutaneous heparin or intravenous heparin. There were no differences in clinical endpoints. However, despite 36% crossover to intravenous heparin among patients randomized to receive subcutaneous heparin with streptokinase, patency of the infarct-related artery was 17% higher (84% vs. 72%, p < 0.05) at 5-7 days in patients randomized to receive intravenous heparin and streptokinase. This significant difference could potentially translate into an important effect on long-term prognosis. Therapy for acute myocardial infarction should include aspirin and a thrombolytic agent for patients without contraindications. Based on the current evidence, it is reasonable to also administer intravenous heparin with either streptokinase or TPA.

Thrombolysis after acute myocardial infarction.

Appropriate use of a thrombolytic agent may save 20 to 30 lives per 1000 treatments. Thrombolysis should be considered in all patients presenting with cardiac chest pain lasting more than...

Thrombolytic therapy in the treatment of stroke.

Approximately 80 to 90% of cerebral ischaemic events that occur within 24 hours of symptom onset are due to atherothrombotic or thromboembolic occlusions. This forms the rationale for the use of thrombolytic agents in patients with acute ischaemic stroke. Early studies determined that recanalisation occurred in approximately 21 to 72% of patients with occluded cerebral arteries after intra-arterial or intravenous administration of streptokinase, urokinase, alteplase (recombinant tissue-type plasminogen activator; rt-PA) or duteplase (a 2-chain rt-PA). Initial reports suggested that frequencies of haemorrhagic transformation and parenchymatous haematoma in the carotid territory were similar whether patients with middle cerebral artery stroke received thrombolysis via intra-arterial or intravenous administration. The Multicentre Acute Stroke Trial-Europe (MAST-E), the Australia Streptokinase (ASK), and the Multicentre Acute Stroke Trial-Italy (MAST-I) trials, which evaluated intravenous streptokinase 1.5 x 10(6) IU in patients with acute ischaemic stroke, were terminated prematurely because of excessive early mortality and symptomatic intracranial haemorrhage in streptokinase recipients compared with those treated with placebo. However, those studies had not been preceded by dose-ranging trials. Intravenous administration of alteplase 0.9 mg/kg within 3 hours [National Institute of Neurological Disorders and Stroke (NINDS) trial], or 1.1 mg/kg within 6 hours [European Cooperative Acute Stroke Study (ECASS)], of symptom onset in patients with acute ischaemic stroke resulted in an absolute 11 to 13% treatment-associated improvement in clinical measurement scales; such as the modified Rankin scale and Barthel index, compared with placebo recipients. In the ECASS trial, those results were limited to a 'target population' restricted to those who satisfied all entry criteria. In both trials, the frequency of symptomatic haemorrhage was greater in patients treated with alteplase than with placebo and reinforced the importance of careful patient selection. Strict patient selection remains central to the success of this approach.

Molecular Biology of Plasminogen Activators: What Are the Clinical Implications of Drug Design?

The initial work on thrombolytic therapy for acute myocardial infarction (AMI) focused on intracoronary administration of streptokinase. Continuing research has given rise to the development of both second- and third-generation agents and consequent refinements in thrombolytic regimens. Intravenous recombinant tissue plasminoger, activator (t-PA, or alteplase) proved superior to both intracoronary and intravenous streptokinase with regard to reperfusion efficacy and impact on survival. An accelerated dosage regimen was later devised to allow the administration of t-PA over a shorter period of time. Unfortunately, t-PA failed to lessen the risk of bleeding complications that had plagued the use of streptokinase. The wild-type t-PA molecule has since been modified in an attempt to achieve improved lytic characteristics with less bleeding risk. Among these third-generation agents is reteplase (r-PA); compared with alteplase, reteplase has a prolonged half-life and seems to offer more rapid thrombolysis. Promising results have been obtained in large, randomized trials of reteplase. Another new agent is the TNK mutant of t-PA, which also has a prolonged half-life and seems to produce more rapid and complete thrombolysis, as well as less risk of intracranial bleeding than with alteplase in animal models. Although large, randomized trials have not yet been conducted, encouraging results have emerged from preliminary dose-ranging trials with TNK. A third new agent, n-PA, has an even longer half-life and has shown improved lytic activity in animal models. A dose-ranging trial of n-PA is currently under way. Despite the fact that each of the third-generation drugs has shown considerable potential with regard to improving the efficacy of thrombolytic therapy, the risk of intracranial bleeding remains problematic and will need to be assessed in large, randomized trials. © 1996 by Excerpta Medica, Inc. Am J Cardiol 1996;78(suppl 12A):2–7