Effect Of Tissue Plasminogen Activator Research Articles

Risk adjustment effect on stroke clinical trials.

The ischemic stroke population is heterogeneous. Even in balanced randomized trials, patient heterogeneity biases estimates of the treatment effect toward no effect when dichotomous end points are used. Risk adjustment statistically addresses some of the heterogeneity and can reduce bias in the treatment effect estimate. The purpose of this study was to estimate the treatment effect of tissue plasminogen activator (tPA) in the National Institute of Neurological Disorders and Stroke (NINDS) tPA data set with and without adjustment for baseline differences. Using a prespecified predictive model, we calculated unadjusted and risk-adjusted odds ratios (ORs) for favorable outcome for the Barthel Index, National Institutes of Health Stroke Scale, and Glasgow Outcome Scale for the patients in the NINDS tPA stroke trial. To assess the importance of the difference, a new sample size was calculated through the use of the risk-adjusted analysis. We analyzed 615 subjects. The ORs for the Barthel Index were 1.76 (unadjusted) and 2.04 (adjusted). The National Institutes of Health Stroke Scale and Glasgow Outcome Scale analyses also demonstrated increased ORs after adjustment. The estimated sample size required for the adjusted comparison was 13% smaller than the unadjusted sample. Risk adjustment in this data set suggests that the true treatment effect was larger than estimated by the unadjusted analysis. Stroke clinical trials should include prospective risk adjustment methodologies.

Thrombolytic effects of 120-kHz and 1-MHz ultrasound and tissue plasminogen activator on porcine whole blood clots

Stroke is the third leading cause of death and the leading cause of disability in the United States. For patients with ischemic stroke, the thrombolytic drug tissue plasminogen activator (tPA) is the only FDA-approved treatment. To aid in the development of a stroke therapy, the synergistic thrombolytic effect of tissue plasminogen activator (t-PA) and ultrasound was assessed in vitro in a porcine clot model. Whole blood clots were prepared from fresh porcine blood by aliquoting 1.5 ml into 8-mm-i.d. glass tubes, immersing the tubes in a 37<th>°C water bath for 3 h and storing the clots at 5<th>°C for at least 3 days prior to use in comparative ultrasound and t-PA studies, which ensured complete clot retraction. The 120-kHz or 1-MHz ultrasound peak-to-peak pressure amplitude used for exposures was 0.35, 0.70, or 1.00 MPa. The range of duty cycles varied from 10% to 100% (continuous wave) and the pulse repetition frequency was 1.7 kHz. Clot mass loss was measured as a function of t-PA concentration (without ultrasound) from 0.25 to 8.5 times the human clinical dose. The mass loss increased monotonically as a function of [t-PA] and saturated at 4 times the clinical dose. The degree of the ultrasound enhancement of t-PA was also explored at 120 kHz and 1 MHz. With ultrasound exposure, clot mass loss increased by as much as 250% over sham (t-PA alone). A weak dependence of clot mass loss on duty cycle was noted. We conclude that 120-kHz and 1-MHz ultrasound enhances thrombolysis. [Work supported by Senmed Medical Ventures.]

Glycoprotein IIb/IIIa antagonist, murine 7E3 F(ab') 2, and tissue plasminogen activator in focal ischemia: evaluation of efficacy and risk of hemorrhage with combination therapy.

Tissue hypoperfusion during cerebral ischemia results from occlusion of large and small vessels. Combination treatment strategies using fibrinolytics to thrombolyse an embolic clot and antiplatelet agents to prevent reocclusion and the formation of new platelet thrombi in the microcirculation may offer advantages over single-agent therapy. The authors report on the effects of tissue plasminogen activator (rt-PA), a glycoprotein (GP) IIb/IIIa receptor antagonist, 7E3 F(ab') 2, or a combination of the two agents in a focal embolic model of cerebral ischemia in Wistar rats. Focal ischemia was produced by introducing an autologous thrombus into the right side middle cerebral artery. Forty-six male Wistar rats were randomly divided into 6 groups: control (n = 8), 7E3 F(ab') 2 (n = 9, 6 mg/kg), rt-PA (n = 9, 10 mg/kg), rt-PA (n = 6, 20 mg/kg), and 7E3 F(ab') 2 with either 10 mg/kg (n = 10) (low-dose combination) or 20 mg/kg (n = 6) (high-dose combination) rt-PA. Evaluation of neurobehavioral scores, cerebral angiography, bleeding time, and measurement of brain infarction volume were used to determine efficacy. All actively treated groups showed a significant reduction in the infarct volume. Animals treated with 7E3 F(ab') 2 showed reduced infarction volumes (24.0 +/- 5.1%) compared with controls (42.43 +/- 5.6%, P < 0.02). Treatment with rt-PA significantly reduced infarction volume (20.7 +/- 3.3, = 0.01) at 10 mg/kg and at 20 mg/kg (19.5 +/- 8.2%, P < 0.05). Compared with vehicle-treated animals, the low-dose combination (16.4 +/- 5.5, P < 0.003) and high-dose combination (23.7 +/- 6.2%, P < 0.05) showed significant reduction in infarction volume. Cerebral angiography revealed significantly better recanalization in the combination group (5/6 animals in the high dose and 4/6 in low dose) compared with animals treated with 7E3 F(ab') 2 (3/10) or rt-PA alone (2/6). Bleeding time significantly increased from 11.25 +/- 1.9 minutes in the control group to 17 +/- 3.1 minutes in the rt-PA group, 24.5 +/- 2.6 minutes in the 7E3 F(ab') 2 group, 25.7 +/- 3.1 minutes in the low-dose combination group, and 32.5 +/- 4.7 minutes in the high-dose combination group. The incidence of intercerebral hemorrhage was highest in the high-dose combination group (6 of 6 animals) and lowest in the single treatment with 7E3 F(ab') 2 alone (1 of 10 animals) ( P < 0.05). Our data show that murine 7E3 F(ab') 2 alone has therapeutic effects when used after cerebral ischemia. Although this study suggests that higher doses of thrombolytic combined with anti-GPIIb/IIIa therapy may increases the risk of intracranial hemorrhage, the data also support the notion that anti-GPIIb/IIIa agents can safely be combined with low doses of thrombolytic agent to produce significant attenuation of neuronal damage with no increase in the incidence of cerebral hemorrhage.

TPA via infusion catheters followed by continuous IV infusion for 3 days prevents intimal hyperplasia after balloon injury.

A rabbit model was used to examine the effects of tissue plasminogen activator (tPA) on development of intimal hyperplasia following balloon injury. Thirty-two hereditary hypercholesterolemic (KHC) rabbits underwent percutaneous transluminal coronary artery balloon catheterization and injury to the common iliac artery, after which they were divided into four groups: untreated (control); Dispatch catheterized-30 minutes local saline delivery [D(+)-tPA(-)]; D(+)-30 minutes local tPA delivery (0.6 mg/kg) [D(+)-tPA(30 min)]; and D(+)-30 minutes local tPA + 3 days intravenous infusion (0.6 mg/kg/24 h) [(D(+)-tPA(30 min + 3 d)]. Twenty-eight days later, the intimal cross-sectional areas of all three Dispatch catheterized groups were significantly smaller than those of control groups, as were the intimal/medial area ratios. Moreover, the intima/media ratios of the D(+)-tPA(30 min + 3 d) group were significantly smaller than those of the D(+)-tPA(-) group. Thus, local delivery of tPA via Dispatch catheters followed by continuous intravenous infusion of tPA for 3 days prevented intimal hyperplasia after angioplasty.

Comparison of impact of primary percutaneous transluminal coronary angioplasty and primary stenting on short-term mortality in patients with cardiogenic shock and evaluation of prognostic determinants

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Ultrasound assisted clot lysis for stroke therapy

Thrombolytics such as tissue plasminogen activator (tPA) have advanced the treatment of ischemic stroke. To aid in the development of a transcranial ultrasound thrombolysis system (TUTS), the synergistic thrombolytic effect of tissue plasminogen activator (tPA) and 1-MHz ultrasound was assessed in vitro in a porcine clot model. Thirty clots were made by incubating 2-ml aliquots of citrated whole pig blood with 2 μl of bovine thrombin (1 NIH Unit/μl) at 37 °C for 3 h, refrigerated overnight, blotted, and weighed. Clots were placed in an acoustically transparent latex sample holder filled with porcine fresh frozen plasma and tPA at a clinically relevant concentration of 0.0126 mg/ml. The clots were either sham exposed to ultrasound (0.0-atm amplitude) or exposed to 1-MHz pulsed ultrasound over a range of duty cycles (10%–100%) at two amplitudes (1.9 and 11.4 atm) for 30 min in a 37 °C water bath, and were weighed to determine the efficacy of thrombolysis. Clots that received continuous wave ultrasound treatment exhibited significantly more thrombolysis than those that were sham exposed (p=0.001, students t-test). The TUTS technology promises to improve the effectiveness of thrombolytic drugs so that ultimately lower concentrations of drugs can be used for faster recanalization of blocked arteries. [Work supported by The Neuroscience Institute, University of Cincinnati Medical Center.]

The Effect of Tissue Plasminogen Activator on Premacular Hemorrhage

Early vitrectomy is recommended for eyes with premacular hemorrhage, which causes fibrovascular proliferation and macular traction. The purpose of this study was to investigate the therapeutic effects of tissue plasminogen activator (tPA) on premacular hemorrhage, and the clearing of hemorrhage from the macula. The authors injected tPA (25-37.5 microg) into the vitreous cavity of 13 eyes with premacular hemorrhage. The causes of premacular hemorrhage were diabetic retinopathy in 11 eyes and traumatic injuries in 2 eyes. Prior to tPA injection, 4 eyes had complete posterior vitreous detachment (PVD) and 9 eyes had no PVD. After tPA injection, the hemorrhages in 10 eyes were completely absorbed. They were absorbed partially in 2 eyes and were not absorbed at all in 1 eye. Absorption of hemorrhage in the 4 eyes with complete PVD took an average of 5.5 days, and in the 6 eyes with no PVD, it took an average of 12.7 days (P=0.002). After tPA injection, visual acuity improved in 9 eyes, remained stable in 3 eyes, and worsened in 1 eye. In 5 eyes, pars plana vitrectomy (PPV) was required after tPA injection because of recurrent vitreous hemorrhage, macular traction or nonabsorbed premacular hemorrhage. TPA seems to be a good alternative method of treatment for premacular hemorrhage, especially in eyes with complete PVD. It appears to improve vision and defer the need for PPV.

Finding the most powerful measures of the effectiveness of tissue plasminogen activator in the NINDS tPA stroke trial.

We sought to identify the most powerful binary measures of the treatment effect of tissue plasminogen activator (tPA) in the National Institute of Neurological Disorders and Stroke (NINDS) rTPA Stroke Trial. Using the Classification and Regression Tree (CART) algorithm, we evaluated binary cut points and combination of binary cut points with the 4 clinical scales and head CT imaging measures in the NINDS tPA Stroke Trial at 4 times after treatment: 2 hours, 24 hours, 7 to 10 days, and 3 months. The first analysis focused on detecting evidence of "early activity" of tPA with the use of outcome measures derived from the 2-hour and 24-hour clinical and radiographic measures. The second analysis focused on longer-term outcome and "efficacy" and used outcome measures derived from 7- to 10-day and 3-month measures. After identifying the cut points with the ability to classify patients into the tPA and placebo groups using part I data from the trial, we then used data from part II of the trial to validate the results. Of the 5 most powerful outcome measures for early activity of tPA, 4 involved the National Institutes of Health Stroke Scale (NIHSS) score at 24 hours or changes in the NIHSS score from baseline to 24 hours. The best overall single outcome measure was an NIHSS score </=2 at 24 hours, which provided an odds ratio of 5.4 (95% CI, 2.4 to 12.1) and a projected sample size of 58 per treatment group assuming an alpha of 0.05 (2-sided test) and a power of 80% using part I data. The top 2 and 3 of the top 5 outcome measures for detecting the longer-term efficacy of tPA also involved the NIHSS score. A Rankin score of 0 or 1 at 3 months was the third most powerful outcome measure. Outcome measures identified by CART from part I data were not as sensitive in detecting the effectiveness of tPA when applied to part II data. Measures using the NIHSS and a Rankin score </=1 were the most sensitive discriminators of the effectiveness of tPA in the NINDS tPA Stroke Trial compared with the other clinical and radiological measures. The outcome measures identified in this exploratory analysis (eg, NIHSS score </=2 at 24 hours) would be best used as an outcome measure in future phase II trials of recanalization begun within the first 3 hours after stroke onset, with inclusion and exclusion criteria similar to those in the NINDS tPA Stroke Trial.

Effects of Tissue Plasminogen Activator and Urokinase on Human Platelet-dependent Thrombin Generation in vitro

Effects of Tissue Plasminogen Activator and Urokinase on Human Platelet-dependent Thrombin Generation in vitro

Efficacy of tissue plasminogen activator administration on patency of hemodialysis access catheters

Patients with end-stage renal disease use hemodialysis catheters for either temporary or permanent blood access. Recurrent thrombosis and fibrin sheath formation are common causes of poor or inadequate blood flow rates that require intervention. We studied the effect of tissue plasminogen activator (tPA) in reestablishing adequate blood flow rates through nonfunctional vascular catheters in 22 consecutive chronic hemodialysis patients. From January 1, 1999, to May 20, 1999, there were 56 instances in which tPA was used in an attempt to improve blood flow rates. In all instances, 2 mg of tPA was infused into each port of a dual-lumen internal jugular catheter. Dwell time ranged between 2 and 96 hours (median, 24 hours), and patient follow-up ranged between 47 and 140 days (median, 133.5 days). tPA was effective in establishing adequate blood flow rates (≥200 mL/min) during the next dialysis session in 49 of 56 cases (87.5%). Seven additional interventions were required because of early or late tPA failure (one fibrin sheath stripping, one catheter replacement for kinking, one catheter replacement for central venous stenosis, and four catheter replacements for persistently poor blood flow rates), and eight catheters were replaced for infection. Thus, further interventions to achieve adequate blood flow rates were required in 12.5% of the cases because of early or late tPA failure. tPA appears to be as effective as urokinase for reestablishing adequate blood flow rates through hemodialysis catheters that are thrombosed or have low blood flow rates.

Improving microcirculation of muscle flaps by tissue plasminogen activator in the rat cremaster muscle flap model

Currently, tissue-plasminogen activator (t-PA) is the most potent and nevertheless safe fibrinolytic in clinical use. Its indications are fibrinolysis in acute myocardial infarction, ischemic stroke, deep vein thrombosis, pulmonary thromboembolism, as well as different kinds of peripheral arterial embolism. However, controlled studies on the effect of t-PA in microsurgery and free tissue transplantation are lacking. This study was designed to evaluate the effect of tissue-plasminogen activator on skeletal muscle flap perfusion after a thrombogenic stimulus. 24 male Sprague-Dawley rats were divided into four experimental groups of six animals each. In group 1, the cremaster was isolated as an end organ flap, in group 2 after cremaster isolation a semicircular inverted suture as a thrombogenic insult was performed at the ipsilateral common iliac artery. In group 3, local t-PA infusion followed the inverted suture and in group 4, vehicle was infused. After 24 hours, we measured cremaster muscle flap hemodynamics using intravital microscopy. Capillary perfusion significantly decreased after the inverted suture from 6.23 (group 1) to 1.50 (group 2) functional capillaries per visual field (medians). t-PA significantly increased capillary perfusion after the thrombogenic insult from 1.50 (group 2) and 2.50 (group 4) to 6.00 (group 3) (medians). Restoring capillary perfusion after a thrombogenic insult t-PA may increase flap survival rates.

Postischemic attenuation of cerebral artery reactivity is increased in the presence of tissue plasminogen activator.

We investigated the combined effect of tissue plasminogen activator and ischemia on middle cerebral artery (MCA) reactivity to determine whether abnormal MCA function after 2 hours of ischemia was worse in arteries perfused with recombinant tissue plasminogen activator (rtPA). The intraluminal suture model of focal cerebral ischemia was used to induce 2 hours of ischemia in rats, after which occluded MCAs were removed and studied in vitro with an arteriograph system that allowed control of transmural pressure (TMP) and measurement of lumen diameter. Arteries were either nonischemic (control; n=8), nonischemic and perfused with 400 microg/mL rtPA (rtPA; n=5), ischemic (ISC; n=6), or ischemic and perfused with 400 microg/mL rtPA (ISC-rtPA; n=6). After a 1-hour equilibration at 75 mm Hg, TMP was increased to 125 mm Hg and lumen diameter was recorded at each pressure. Reactivity to acetylcholine (ACh, 0.1 to 10.0 micromol/L) and serotonin (0.01 to 10 micromol/L) was then determined. Control arteries responded myogenically to pressure and increased the amount of tone from 18.5+/-3.8% at 75 mm Hg to 24.8+/-3.0% at 125 mm Hg (P<0.05), which decreased diameter from 241+/-7 to 232+/-6 microm. In contrast, all other groups decreased tone at 125 mm Hg, which demonstrated a loss of myogenicity. The percent tone in each group at 75 versus 125 mm Hg was rtPA, 16.0+/-4.5% versus 11.8+/-3.8%; ISC, 23.5+/-4.5% versus 13. 5+/-3.1%; and ISC-rtPA, 23.5+/-4.2% versus 12.3+/-3.2% (P<0.05 for all). The percent increase in lumen diameter at each concentration of ACh was diminished in all groups compared with control; ISC-rtPA arteries responded the least, which suggests an additive effect of rtPA in ischemic arteries. The percent increase in lumen diameter at 10(-5)mol/L ACh was 23+/-4% for control versus 15+/-2% for rtPA; 17+/-3% for ISC arteries (P<0.05), and 8+/-2% for ISC-rtPA arteries (P<0.01). Sensitivity to serotonin was equally diminished in all groups compared with control: EC(50) (micromol/L) was 0.06+/-0.01 for control, 0.17+/-0.02 for rtPA, 0.22+/-0.07 for ISC, and 0.16+/-0. 04 for ISC-rtPA (P<0.05). These results demonstrate that both ischemia and rtPA perfusion diminish cerebral artery reactivity and that the combination may produce an additive effect. This impaired reactivity may contribute to reperfusion-induced injury during or after thrombolysis by altering upstream cerebrovascular resistance.

Tissue plasminogen activator improved function at 6 and 12 months after ischemic stroke

Source Citation Kwiatkowski TG, Libman RB, Frankel M, et al. Effects of tissue plasminogen activator for acute ischemic stroke at one year. National Institute of Neurological Disorders and Stroke R...

Effects of tissue plasminogen activator for acute ischemic stroke at one year

Effects of tissue plasminogen activator for acute ischemic stroke at one year

Inhibitory effect on the establishment of hepatic metastasis by transduction of the tissue plasminogen activator gene to murine colon cancer.

Hepatic metastasis is a major factor in limiting the prognosis of patients with colon carcinoma. Recent investigations indicate a correlation between plasminogen activator profiles and hepatic metastasis. We examined the effectiveness of tissue plasminogen activator (tPA) gene therapy using a hepatic metastasis model of murine colon carcinoma. Murine colon carcinoma Colon 26 cells transduced with an MFGtPA retroviral vector (Colon 26/tPA) or an MFGLacZ retroviral vector (Colon 26/LacZ) were injected into the liver via the superior mesenteric vein of BALB/c mice, whose survival rates were checked daily. The mean survival rate of mice with hepatic metastasis induced by Colon 26/LacZ was 23.1 days, whereas that of mice with Colon 26/tPA was >100 days. The in vitro proliferation of Colon 26/tPA was comparable with that of Colon 26/LacZ, and antitumor immunity to wild-type Colon 26 cells was not induced after an intrahepatic injection of Colon 26/tPA. We suggest that transduction of the tPA gene to murine colon cancer is useful against the establishment of hepatic metastasis.

The Role of Fibrinolytic System Proteins in Cholesterol Gallstone Formation

Accelerated nucleation, supersaturation of bile, and biliary stasis are known to be key factors in cholesterol gallstone formation. The mechanisms through which these factors interact to form stones are still incompletely understood. Among the proteins now known to be present in bile are several components of the fibrinolytic system: tissue plasminogen activator, urokinase-like plasminogen activator, and plasminogen activator inhibitors 1 and 2. The concentrations of plasminogen activator inhibitors 1 and 2 in gallbladder bile are increased in patients with gallstones. The aim of this study was to determine whether these fibrinolytic system proteins act as pro-nucleating agents for cholesterol gallstone formation. Nucleation assays were done on gallbladder bile from eight cholesterol stone patients and eight control patients. The effects of tissue plasminogen activator, urokinase-like plasminogen activator, and plasminogen activator inhibitors I and 2 on cholesterol crystal appearance time (CCAT) were tested, by direct observation using polarizing microscopy, after measurement of biliary lipids and calculation of cholesterol saturation indices. There was no significant difference in cholesterol saturation indices between bile that nucleated and bile that did not (mean, 2.0 +/- 1.5 versus 1.8 +/- 0.5). When all samples in which nucleation occurred were compared, tissue plasminogen activator significantly shortened CCAT median from 4.75 days (range, 2-21) to 3.5 days (2.5-18) (P < 0.05). This was similar to the effect of fibronectin (3.75 days; range, 2-20), a known pro-nucleator used as a nucleation accelerating control (P < 0.05). None of the other fibrinolytic system proteins significantly accelerated CCAT. The results of this study suggest that tissue plasminogen activator may act as a pro-nucleating agent for cholesterol gallstone formation in gallbladder bile.

Tissue Plasminogen Activator (tPA) Inhibits Interleukin-1 Induced Acute Lung Leak

Because plasminogen activators (PA) may participate in the inflammatory process associated with the acute respiratory distress syndrome (ARDS), we measured the effect of tissue plasminogen activator (tPA) on inflammation and acute lung leak caused by intratracheal instillation of IL-1α (50 ng) into male (300–400 g) Sprague–Dawley rats. Lung leak, lung myeloperoxidase (MPO) activity, and lung lavage neutrophil counts were increased in rats given IL-1 intratracheally compared to control rats that were given saline intratracheally. Giving tPA (12 mg/kg) intraperitoneally increased lung tPA concentration and reduced acute lung leak in rats given IL-1 intratracheally ( p < .01; lung leak index for sham-treated rats: 0.040 + 0.001, n = 6; IL-1: 0.10 + 0.01, n = 10; tPA + IL-1: 0.050 + 0.002, n = 6). In contrast, administering tPA did not change IL-1-induced increases in lung lavage neutrophils or lung MPO activity (sham: 0.003 × 106 + 0.001 × 10 6 cells; IL-1: 2.9 × 10 6 + 0.4 × 10 6 cells; tPA + IL-1: 2.7 × 10 6 + 0.4 × 10 6 cells; and sham: 0.6 + 0.2 U/g lung; IL-1: 11.2 + 2.9 U/g lung, tPA + IL-1: 11.1 + 1.6 U/g lung, respectively). Our results suggest that intraperitoneal tPA administration increases lung tissue tPA levels and decreases acute lung leak without reducing lung neutrophil infiltration in rats given IL-1α intratracheally. This work suggests that tPA may suppress neutrophil activation in vivo and accordingly have anti-inflammatory effects.

Recombinant tissue plasminogen activator in cases with fibrin formation after cataract surgery: a prospective randomised multicentre study

AIMSThis study investigated the effect of tissue plasminogen activator (tPA) in patients with severe intracameral fibrin after extracapsular cataract extraction or phacoemulsification with posterior chamber intraocular lens implantation.METHODSA randomised prospective...

Pathophysiological Insight Into the Possible Optimal Therapies for Acute Myocardial Infarction and Unstable Angina

The optimal treatment of unstable ischemic coronary syndromes has not been settled, and little in vivo pathological information in humans has been available to help guide the care of patients with these complicated problems. Dr Van Belle and colleagues1 have given us new insight into the underlying pathophysiological substrate in patients sustaining acute myocardial infarction who then underwent coronary angioscopy before coronary interventions up to 1 month after their index event. Of these patients, 98% were treated with aspirin, 66% had thrombolytic therapy, and 100% had been treated with heparin for at least 72 hours after admission. Despite this intense antithrombotic regimen, the residual lesions were angiographically severe in 76%, and complete occlusions were found in 14% of the patients. By angioscopy, the majority of the infarct-related lesions were yellow (79%), and many were ulcerated (36%) or had visible residual thrombus (77%). Eighteen percent of the patients had large clumps of platelets adherent to the plaque, even late in the course after infarction. The fact that these plaques remained “active” for up to 30 days is quite interesting and unsettling. There was an equal prevalence of yellow ulcerated …

Selection of thrombolytic therapy for individual patients: Development of a clinical model

We developed a logistic regression model with data from the GUSTO-I trial to predict mortality rate differences in individual patients who received accelerated tissue plasminogen activator (TPA) versus streptokinase treatment for acute myocardial infarction. A nomogram was developed from a reduced version of this model that approximated the underlying risk of patients treated with streptokinase, and thus the benefit of TPA. The 30-day mortality rate with accelerated TPA was 0.063 versus 0.073 with streptokinase and subcutaneously administered heparin and 0.074 with streptokinase and intravenously administered heparin. No baseline patient characteristics were significantly associated with a different relative effect of TPA. Older patients and those with anterior infarction, higher Killip classification (except Killip class IV), lower blood pressure, and increased heart rate had the greatest absolute benefit with accelerated TPA. Patients with acute myocardial infarction who had more high-risk characteristics derived a greater absolute benefit from treatment with accelerated TPA versus streptokinase. (Am Heart J 1997;133:630-9).