67. Sharma GVRK: Thrombolytic therapy of deep vein thrombosis, in Thrombolysis and Urokinase. New York, Academic Press; 1977: Notes : Lytic therapy can prevent these sequelae: impedence plethysmography shows normal flow patterns without deep venous reflux in 75 percent of patients after lytic therapy but in only 25 percent of patients treated with anticoagulation alone. 68. Bieger R, Boekhout-Mussert RJ, Hohmann F, Loeliger E: Is Streptokinase Useful in the Treaaatment of Deep Vein Thrombosis? Acta Med Scand 1976;199:81-88. Because of its fibrinolytic action, streptokinase is believe to reduce the severity if the postthrombotic syndrome in patients with deep vein thrombosis. A prospective and a retrospective study have been undertaken in an attempt to determine when this therapy is useful for patients with deep vein thrombosis. The prospective study included 15 patients with deep vein thrombosis: 5 were treated in the hospital with streptokinase and heparin and 5 only with heparin, 5 were treated at home with only phenprocoumon. All the patients received oral anticoagulant therapy for at least 6 months. Three to four months after the acute episode, phlebography and venous pressure measurements were carried out. Streptokinase appeared to give the best results but with more side-effects. In the retrospective study, 51 patients who had deep vein thrombosis in 1969 were reexamined 31-47 months later. It was found that more than 50% of the patients with a thrombosisin the femoral and/or iliac vein developed a severe posttrombotic syndrome, in contrast to only 9% of those with a thrombosis in the popliteal vein or lower. It is recommended. on the basis of both the prospective and retrospective study, that patients with a thrombosis in the femoral and/or iliac vein should be treated with either heparin or streptokinase during the early stage. It is probable that streptokinase will significantly decrease the frequency and severity of the postthrombotic syndrome in these patients in particular, although this has not yet been proven. 01-04-96. 69. Arneson H, Hoseth A: Streptokinase or heparin in the treatment of deep vein thrombosis, follow-up results of a prospective study. Acta Med Scand 1982;211:65 In a previous study on 42 patients with acute deep vein thrombosis, randomly allocated to treatment with streptokinase or heparin, we found that 71.4% of the streptokinase-treated patients achieved phlebographically significant thrombolysis as compared to 23.8% in the heparin group. These patients have been reevaluated after a mean observation period of 6.5 years. Seven patients had died and there were no other drop-outs. Thus, 35 patients were subjected to the follow-up study consisting of phlebography and clinical examination. The evaluation were performed without knowledge of the initial therapy. Seven patients had phlebographically normal veins, and all belonged to the streptokinase group. This difference between the treatment groups is statistically highly significant (p<0.01). At clinical examination, 13 of the 17 patients in the streptokinase group had normal legs and 4 exhibited moderate postthrombotic changes. In constrast, 3 of the heparin-treated patients showed serious postthrombotic changes with open leg ulcers, and only 6 of 18 patients in this group had normal legs. The present results strongly support the assumption that streptokinase therapy is the best treatment aat present in patients with acute deep vein thrombosis. This has been shown for the initial thrombolysis, and now also for the avoidance of late postthrombotic changes. 01-03-96. 70. Turpie AG, Levine MN, Hirsh J, et al: Tissue plasminogen activator (rt-PA) vs heparin in deep vein thrombosis. Results of a randomized trial. Chest 1990;97:172S-175S. AB-We performed a randomized trial comparing two dosing regimens of recombinant tissue plasminogen activator (rt-PA) plus heparin vs heparin alone in the treatment of acute proximal deep vein thrombosis in 83 patients. Of 12 patients who received 0.5 mg/kg rt-PA plus heparin over 4 h, seven (58 percent) had greater than 50 percent lysis of the thrombus, compared with none of 12 who received placebo plus heparin (p = 0.002). Of 28 patients who received 0.5 mg/kg rt-PA over 8 h, repeated in 24 h, six (21 percent) had greater than 50 percent lysis, compared with two (7 percent) of 30 patients who received placebo plus heparin (p = 0.11). The 4-h infusion of rt-PA produced a 40 percent reduction and the 8-h infusion an 11 percent reduction in plasma fibrinogen concentration. At long-term follow-up, three (25 percent) of 12 patients in whom greater than 50 percent lysis was achieved had symptoms of the postphlebitic syndrome, compared with 19 (56 percent) of 34 patients in whom lysis was less than 50 percent (p = 0.07). 71. Comerota AJ, Katz ML, Hashemi HA: Venous duplex imaging for the diagnosis of acute deep venous thrombosis. Haemostasis 1993;23 Suppl 1:61-71. Acute deep venous thrombosis (DVT) continues to be a common clinical problem requiring objective evaluation. Hemodynamic testing for acute DVT has been popular, but is inadequate for evaluating asymptomatic patients and symptomatic patients with isolated calf vein thrombi. Venous duplex imaging (VDI) has rapidly gained in popularity, and is generally accepted to be the noninvasive technique of choice for the evaluation of patients with acute DVT. Twenty-five reports evaluate gray-scale venous duplex imaging versus ascending phlebography in 2,781 symptomatic patients. The sensitivity for proximal DVT and calf DVT is 96 and 80%, respectively. Seven reports review the use of VDI for surveillance in 857 asymptomatic patients, with an overall sensitivity of 76% for proximal DVT and of 11% for isolated calf vein thrombosis. The results of color-flow duplex appear to be somewhat better; however, the numbers are considerably smaller. The results for identification of calf vein thrombosis in asymptomatic surveillance patients continue to be poor. VDI appears to be the best noninvasive diagnostic test for acute DVT, and may challenge ascending phlebography as the best diagnostic test for proximal DVT in symptomatic patients, although it will miss 20% of isolated calf DVT. VDI appears to be the best noninvasive screening technique for high-risk asymptomatic patients under surveillance; however, additional correlative studies with ascending phlebography are required. The addition of color Doppler images appears to have improved results, although these higher sensitivities may be the consequence of improved experience as much as the addition of color to the image. 72. Druy EM: Thrombolytic therapy in the treatment of axillary and subclavian vein thrombosis. J Vasc Surg 1985;2:821-827. If peripheral systemic lytic therapy is ineffective, direct infusion of lytic agents into the thrombus via catheter may be more effective for large deep vein thrombus in a low-flow area. 73. UPET: The Urokinase Pulmonary Embolism Trial: A national cooperative study. Circulation 1973;47 (Supp II):1-108. 74. USPET: Urokinase Streptokinase Pulmonary Embolism Trial: Phase II results. JAMA 1974;229:1606-1613. 75. Sasahara AA, Sharma GVRK: Does thrombolytic therapy alter the prognosis of pulmonary embolism? Haemostasis 1986;16:Suppl 3 76. Kessler CM, Druy E, Goldhaber SZ: Acute pulmonary embolism treated with thrombolytic agents: Current status of tPA and future implications for emergency medicine. Ann Emerg Med 1988;17:1216-1220. Pulmonary embolism is diagnosed 120,000 times yearly in the United States and contributes to 30,000 deaths. This probably represents an underestimate of incidence because massive acute pulmonary embolism may often result in rapid and therefore unexplained death in the absence of autopsy confirmation. The innovative and judicious use of thrombolytic agents by emergency department and paramedical ambulance personnel may lead to a decreased mortality for this disease. Clinical studies are necessary to determine if the cardiopulmonary compromise associated with massive pulmonary embolism can be rapidly reversed through thrombolysis and whether that reversal will lead to increased survival. The use of thrombolytic agents will gain favor only if their risk:benefit and cost:benefit ratios are acceptable. We discuss the results of using first- and second-generation thrombolytic agents in the treatment of pulmonary embolism and review the encouraging data that have emerged from our studies with recombinant tissue-type plasminogen activator (tPA). This agent has relative fibrin specificity and may provide therapeutic advantages over the conventional thrombolytic agents, urokinase and streptokinase, particularly when the latter are administered in the currently recommended dose schedules for treatment of pulmonary embolism Department of Medicine School of Medicine George Washington University Washington DC 20037. 77. Heit J: Thrombolytic agent dosage for pulmonary embolism: Current research and clinical experience, in Comerota AJ (ed): Latest concepts and management of acute venous thromboembolic disease. Coronado, Abbott Pharmaceuticals; 1992:24-33. 78. Sharma GVRK, Folland ED, McIntyre KM: Long-term hemodynamic benefit of thrombolytic therapy in pulmonary embolic disease. J Am Coll Cardiol 1990;15:65A 79. Sharma GVRK: Rationale for aggressive management of pulmonary embolism using thrombolytic agents, in Comerota AJ (ed): Latest concepts and management of acute venous thromboembolic disease. Coronado, Abbott Symposium; 1992:20-24. 80. Sharma GVRK, Burleson V, Sasahara AA: Effect of thrombolytic therapy on pulmonary capillary blood volume in patients with pulmonary embolism. New Engl J Med 1980;303:842 81. De Soyza NDB, Murphy ML, De Soyza ND: Persistent post-embolic pulmonary hypertension. Chest 1972;62 (6):665-668. Nine of thirteen patients with initial postembolic pulmonary hypertension still had persistent pulmonary hypertension an average of 49 months later. 82. Dalen JE, Dexter L: Pulmonary embolism. JAMA 1969;207:1505 83. Riedel M, Stanek V: Long term follow-up of patients with pulmonary thromboembolism. Chest 1982;81:151-158. 84. Goldhaber SZ, Haire WD, Feldstein ML, et al: Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion. Lancet 1993;341:507-511. Data from a non-randomised study have hinted that in patients with acute pulmonary embolism (PE), thrombolysis followed by heparin more rapidly reverses right-ventricular dysfunction and restores pulmonary tissue perfusion than does heparin alone. We have pursued this idea in a randomised protocol. 46 haemodynamically stable patients were randomised to recombinant tissue plasminogen activator (alteplase, rt- PA) 100 mg over 2 h followed by intravenous heparin and 55 to heparin alone. Right-ventricular wall motion was assessed qualitatively, and right-ventricular end diastolic area was estimated by planimetry from echocardiograms at baseline and at 3 and 24 hours. Pulmonary perfusion scans were obtained at baseline and 24 hours. In 39% of rt- PA patients but in only 17% of heparin alone patients right-ventricular wall motion at 24 hours had improved from baseline and in 2% and 17%, respectively, it worsened (p = 0.005). rt-PA patients also had a significant decrease in right-ventricular end-diastolic area during the 24 hours after randomisation and a significant absolute improvement in pulmonary perfusion (14.6% vs 1.5%). No clinical episodes of recurrent PE were noted among rt-PA patients, but there were 2 fatal and 3 non-fatal clinically suspected recurrent PEs within 14 days in patients randomised to heparin alone. rt-PA rapidly improves right-ventricular function and pulmonary perfusion among patients with PE and may lead to a lower rate of adverse clinical outcomes Department of Medicine Brigham and Women's Hospital Boston Massachusetts 02115. 85. Prewitt RM, Hoy C, Kong A, et al: Thrombolytic therapy in canine pulmonary embolism. Comparative effects of urokinase and recombinant tissue plasminogen activator. Am Rev Respir Dis 1990;141:290-295. CS- Department of Medicine, University of Manitoba, Winnipeg, Canada AB- We compared thrombolytic and pulmonary hemodynamic effects of recombinant tissue plasminogen activator (rtPA) and urokinase (UK) in canine micropulmonary thromboembolism. Dogs were embolized with radioactive autologous blood clot to increase mean pulmonary artery pressure (from 13 to 34 mm Hg, p less than 0.005) and decrease cardiac output (2.5 to 1.6 L min, p less than 0.005). Four groups of six dogs were treated. We employed two doses of UK, 30,000 U/kg (UK30) and 60,000 U/kg (UK60), and two doses of rtPA, 1 mg/kg (rtPA1) and 2 mg/kg (rtPA2). Drugs were infused over 15 min. Rate and extent of pulmonary thrombolysis were assessed by continuously counting over both lung fields with a gamma camera. Compared with treatment with UK, both rtPA regimes significantly increased thrombolysis. Mean total pulmonary thrombolysis was 14 and 23% with UK30 and UK60, respectively, and 35 and 43% with rtPA1 and rtPA2. Corresponding to the increased thrombolysis, pulmonary hemodynamics improved most with rtPA. From 90 min to 3 h, pulmonary artery pressure was significantly lower with both rtPA regimes than with either UK regime. These results indicate, at least in the model employed, that compared with treatment with UK, pulmonary thrombolysis and corresponding hemodynamic improvement are greatest with rtPA. 86. Come P, Kim D, Come PC, et al: Early reversal of right ventricular dysfunction in patients with acute pulmonary embolism after treatment with intravenous tissue plasminogen activator. J Am Coll Cardiol 1987;10:971-978. To assess abnormalities of right heart function and their reversal with thrombolysis in pulmonary embolism, serial imaging and Doppler echocardiographic studies were performed before and after a 6 hour intravenous infusion of 80 to 90 mg of recombinant tissue-type plasminogen activator (rt-PA) in seven patients with segmental or lobar acute pulmonary embolism. None of the five men and two women had known prior pulmonary hypertension. Substantial clot lysis and improvement in pulmonary blood flow, as determined by serial pulmonary angiography and perfusion lung scanning, were achieved in all. Coincident with clot lysis, pulmonary artery systolic pressure decreased (from 42 +/- 11 to 26 +/- 7 mm Hg, p less than 0.005), right ventricular diameter decreased (from 3.9 +/- 1.0 to 2.0 +/- 0.5 cm, p less than 0.005) and left ventricular diameter increased (from 3.7 +/- 0.9 to 4.4 +/- 0.6 cm, p less than 0.01). Right ventricular wall movement, initially mildly, moderately or severely hypokinetic in one, two and four patients, respectively, normalized in five and improved to mild hypokinesia in two. Tricuspid regurgitation was present before lytic therapy in six patients. In five, flow velocity in the tricuspid regurgitant jets indicated a peak systolic right ventricular minus right atrial pressure gradient of 25 to 52 mm Hg. Tricuspid regurgitation was detected early after lytic therapy in only two patients. Systolic septal flattening was noted before but not after lysis. These findings confirm that pulmonary emboli may result in appreciable right ventricular dysfunction and dilation, resultant tricuspid regurgitation, abnormal septal position and decreased left ventricular size.(ABSTRACT TRUNCATED AT 250 WORDS) Cardiology Division Beth Israel Hospital Boston Massachusetts 02215. 87. Goldhaber SZ: Tissue plasminogen activator in acute pulmonary embolism. Chest 1989;95:282S-289S. The use of thrombolytic therapy to treat AMI has reawakened interest in thrombolysis for acute pulmonary embolism (PE). We have investigated the use of recombinant human tissue-type plasminogen activator (rtPA) in patients with acute PE. In an open label study, rtPA achieved more than 90% efficacy and safety. In a trial comparing rtPA with an FDA-approved dose of urokinase (UK), rtPA appeared more rapid and safer. We are now conducting a comparative trial of rtPA with a novel dosing regimen of UK. In addition, a concurrent trial is comparing rtPA vs heparin for improvement in right ventricular function, assessed by echocardiography, among PE patients. However, the greatest challenge in PE research is to undertake a large-scale trial that compares thrombolysis and heparin for reduction of clinically relevant end points such as mortality and recurrent PE Cardiovascular Division Brigham and Women's Hospital Harvard Medical School Boston 12005. 88. Shiffman F, Ducas J, Hollett P, et al: Treatment of canine embolic pulmonary hypertension with recombinant tissue plasminogen activator. Efficacy of dosing regimes. Circulation 1988;78:214-220. CS- Department of Medicine, University of Manitoba Health Sciences Centre, Winnipeg, Canada AB- We investigated effects of two dosing regimes of recombinant tissue plasminogen activator (rt-PA) and sodium heparin on pulmonary thrombolysis in a canine model of pulmonary hypertension, induced by injection of radioactive blood clots. By continuously counting over both lung fields with a mobile gamma camera, we correlated rate and extent of pulmonary thrombolysis with corresponding pulmonary hemodynamics. Treatment with heparin, over a 3-hour interval, did not result in significant thrombolysis or in a decrease in mean pulmonary artery pressure (PAP). In contrast, rt-PA caused marked pulmonary thrombolysis. While total clot lysis was similar when 1 mg/kg rt-PA was infused over 15 (rt-PA15) or 90 (rt-PA90) minutes (47% and 42%, respectively), rate of lysis during infusion was markedly increased with rt-PA15 (56% vs. 27%/hr, p less than 0.001). Corresponding to the increased rate of thrombolysis with rt-PA15, relative PAP decrease was greater at 15 and 30 minutes. At 4 hours, PAP decreased most with rt-PA90. However, two of the six dogs given rt-PA15 had an increase in PAP and lung radioactivity 1 hour after rt-PA. This was associated with dislodgment of a previously trapped clot. These results suggest that rt-PA may be appropriate therapy for pulmonary embolism and support further studies designed to optimize dosing regimes. 89. Goldhaber SZ, Kessler CM, Heit J, et al: Randomized controlled trial of recombinant tissue plasminogen activator versus urokinase in the treatment of acute pulmonary embolism Randomised controlled trial of recombinant tissue plasminogen activator versus urokinase in the treatment of acute pulmonary embolism. Lancet 1988;2:293-298. The effect of intravenous recombinant human tissue-type plasminogen activator (rt-PA) was compared with that of urokinase in 45 patients with angiographically documented pulmonary embolism (PE) in a randomised controlled trial. The two principal end-points were clot lysis at 2 h, as assessed by angiography, and pulmonary reperfusion at 24 h, as assessed by perfusion lung scanning. All patients received the full dose of rt-PA but urokinase infusions were terminated prematurely (on average after 18 h) in 9 patients because of allergy in 1 and uncontrollable bleeding in 8. By 2 h, 82% of rt- PA-treated patients showed clot lysis, compared with 48% of urokinase- treated patients (p = 0.008; 95% CI for the difference = 10-58%). Improvement in lung scan reperfusion at 24 h was identical in the two treatment groups. The reduction in fibrinogen did not differ significantly between the rt-PA and urokinase groups (45% vs 39% at 2 h and 34% vs 40% at 24 h). The results indicate that in the dose regimens employed, rt-PA acts more rapidly and is safer than urokinase in the treatment of acute PE Brigham and Women's Hospital Boston Massachusetts. 90. Schwarz F: Sustained improvement of pulmonary hemodynamics in patients at rest and during exercise after thrombolytic treatment of massive pulmonary embolism. Circulation 1985;71:117 91. Kober G: Die Kleinkreislaufhamodynamik im akuten und chrinischen stadium nach schwerer lungenembolie. Herz Kreisl 1980;12:11 92. Bass H, Banas JJ, Dalen JE: Pulmonary function studies: Aids to diagnosis of pulmonary embolism. Arch Intern Med 1970;126:266 93. Stein PD, Hull RD, Raskob G: Risks for major bleeding from thrombolytic therapy in patients with acute pulmonary embolism. Consideration of noninvasive management. Ann Intern Med 1994;121:313-317. OBJECTIVE: To assess the relative risks for bleeding with thrombolytic therapy in patients who are managed using pulmonary angiograms compared with those managed using noninvasive tests, primarily the ventilation-perfusion lung scan. DESIGN: A decision analysis based on data from other studies. METHODS: The risk for major bleeding in patients with pulmonary embolism who receive thrombolytic therapy after a noninvasive diagnosis was assessed from complications of thrombolytic therapy in patients with myocardial infarction, assuming that the same risk ratio for major bleeding when comparing an invasive with a noninvasive approach applied to patients with pulmonary embolism. The risk ratio was 3.3 (95% CI, 1.5 to 9.8) for major bleeding in patients with myocardial infarction. One or more major complications of pulmonary angiography occurred in 1.3% of patients (CI, 0.6% to 1.9%). RESULTS: The average reported risk was 14% (18 of 129 patients) (CI, 7.9% to 20.1%) for major bleeding in patients who had pulmonary angiography before receiving tissue plasminogen activator (tPA). The estimated risk was 4.2% (estimated CI, 1.4% to 9.3%) for major bleeding with tPA after a noninvasive diagnosis of pulmonary embolism. Assuming a risk of 1.3% for major complications from pulmonary angiography, a risk for major hemorrhage of 14.0% for an invasive diagnosis, and a risk of 4.2% for a noninvasive diagnosis, fewer complications would occur with noninvasive management if the prevalence of pulmonary embolism exceeded 21%. CONCLUSION: Among patients with suspected pulmonary embolism who are candidates for thrombolytic therapy, it is safer to use noninvasive diagnostic tests in many patients. 94. Meyerovitz MF, Goldhaber SZ, Reagan K, et al: Recombinant tissue-type plasminogen activator versus urokinase in peripheral arterial and graft occlusions: a randomized trial [see comments]. Radiology 1990;175:75-78. A randomized prospective trial was undertaken to compare intraarterial administration of recombinant human tissue-type plasminogen activator (rt-PA) with urokinase (UK) in 32 patients with peripheral arterial or bypass graft occlusions. Sixteen patients were randomized to receive rt-PA and 16 to receive UK. The rt-PA dose was administered as a 10-mg bolus into the thrombus, followed by 5 mg/h for up to 24 hours. The UK dose was administered as a 60,000 IU bolus into the thrombus, followed by 240,000 IU/h for 2 hours, 120,000 IU/h for 2 hours, and 60,000 IU/h for up to 20 hours. Serial arteriograms were obtained at baseline and at 4, 8 or 16, and 24 hours. The endpoint was defined as 95% of greater clot lysis. The cumulative numbers of patients with successful thrombolysis (rt-PA vs UK) were four vs none at 4 hours, seven vs one at 8 hours, seven vs three at 16 hours, and eight vs six at 24 hours. Lysis occurred more rapidly in the rt-PA group (P = .04). Major bleeding complications occurred in five rt-PA patients and two UK patients (P = .39). At 24 hours, fibrinogen levels were significantly lower in the rt-PA group than in the UK group (P = .01). There was no apparent difference in 30-day clinical success Department of Radiology Brigham and Women's Hospital Harvard Medical School Boston MA 02115. 95. Goldhaber SZ: TPA versus urokinase in acute pulmonary embolism: results of a randomized controlled trial. Vasa Suppl 1989;27:292-4:292-294. [No Abstract Available]. 96. Agnelli G, Parise P: Bolus thrombolysis in venous thromboembolism. Chest 1992;101:172S-182S. AB-Thrombolytic therapy is rarely used in venous thromboembolism because of the fear of hemorrhagic complications. Preliminary clinical experiences with recombinant tissue-type plasminogen activator (rt-PA) in patients with deep vein thrombosis have shown that even this fibrin- specific plasminogen activator causes an unacceptable rate of hemorrhagic complications. Theoretical considerations and the available experimental and clinical data suggest that infusion of rt-PA over a short period of time would result in a more favorable risk-benefit ratio. Shortening the period of rt-PA infusion results in higher peak plasma levels, thus allowing a higher concentration of the plasminogen activator on the surface and inside the occluding thrombus. In addition, a bolus infusion can prevent or minimize the interaction between rt-PA and the hemostatic system, reducing the likelihood of a systemic lytic state, of a platelet function defect, and, possibly, of bleeding side effects. In venous thromboembolism animal models, the efficacy of bolus rt-PA can be further increased by the adjunctive administration of an effective antithrombotic treatment. This is because the accretion of new fibrin on the thrombi counteracts the lysis of preformed fibrin and influences negatively the final thrombus size. Effective adjunctive antithrombotic treatment includes either high doses of heparin, producing an unclottable activated partial thromboplastin time (aPTT), or doses of recombinant hirudin, doubling the aPTT. When used as an alternative to rt-PA, bolus doses of a hybrid plasminogen activator with prolonged half-life efficiently reduce thrombus size by lysing preformed and newly formed fibrin. Preliminary clinical experience in patients with pulmonary embolism seems to confirm that rt-PA infused as a bolus is at least as effective as, and probably more effective than, rt-PA infused over a longer period. 97. Hacke W, Kaste M, Fieschi C, et al: Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: The european cooperative acute stroke study (ECASS). JAMA 1995;274:1017-1025. Thrombolysis is effective in a subset of stroke patients, and can restore normal neurologic function to many patients who would otherwise have a permanent disability. Unfortunately, another subset of patients will have more and larger hemorrhagic intracranial events, with an increased hemorrhagic stroke death rate. Better enrollment criteria and better early discriminators for hemorrhagic risk are needed before routine intravenous thrombolysis can be recommended for patients with acute CVA. 98. Marler JR: Tissue Plasminogen Activator for Acute Ischemic Stroke. The New England Journal of Medicine 1995;333:1581-1587. Background. Thrombolytic therapy for acute ischemic stroke has been approached cautiously because there were high rates of intracerebral hemorrhage in early clinical trials. We performed a randomized, double-blind trial of intravenous recombinant tissue plasminogen activator(t-PA) for ischemic stroke after recent pilot studies suggested that t-PA was beneficial when treatment was begun within three hours of the onset of stroke. Method. The trial had two parts. Part 1 (in which 291 patients were enrolled) tested whether t-PA had clinical activity, as indicated by an improvement of 4 points over base-line values in the score of the National Institutes of Health stroke scale (NIHSS) or the resolution of the neurologic deficit within 24 hours of the onset of stroke. Part 2 (in which 333 patients were enrolled) used a global test statistic to assess clinical outcome at three months, according to scores on the Barthel index, modified Rankin scale, Glasgow outcome scale, and NIHSS. Results. In part 1, there was no significant difference between the group given t-PA and that given placebo in the percentages of patients with neurologic improvement at 24 hours, although a benefit was observed for the t-PA group at three months for all four outcome measures. In part 2, the long-term clinical benefit of t-PA predicted by the results of part 1 was comfirmed (global odd ratio for a favorable outcome, 1.7; 95 percent confidence interval, 1.2 to 2.6). As compared with patients given placebo, patients treated with t-PA were at least 30 percent more likely to have minimal or no disability at three months on the assessment scales. Symptomatic intracerebral hemorrhage within 36 hours after the onset of stroke occurred in 6.4 percent of patients given t- PA but only 0.6 percent of patients given placebo (P<0.001). Mortality at three months was 17 percent in the t-PA group and 21 percent in the placebo group (P=0.30). Conclusions. Despite an increased incidence of symptomatic intracerebral hemorrhage, treatment with intravenous t-PA within three hours of the onset of ischemic stroke improved clinical outcome at three months. 01-04-96. 99. Goldhaber SZ, Feldstein ML, Sors H: Two trials of reduced bolus alteplase in the treatment of pulmonary embolism. An overview [comment]. Chest 1994;106:725-726. The Bolus Alteplase Pulmonary Embolism (BAPE) Group and a consortium of French investigators utilized essentially the same investigational protocol to test reduced dose bolus alteplase vs full dose 100 mg/2 h alteplase in the treatment of pulmonary embolism (PE). The principal hypothesis was that reduced dose bolus alteplase (n = 96) would result in fewer bleeding complications than full dose 100 mg of 2 h alteplase (n = 44) administered as a continuous infusion to hemodynamically stable patients with PE. To provide data on bolus alteplase's safety profile in a larger sample size than would have been feasible in either trial alone, we present an overview of the BAPE and French trials. There were no differences between the reduced dose bolus and full dose 2 h rt-PA groups with respect to bleeding complications. Therefore, the principal hypothesis of these two randomized controlled trials could not be confirmed. Efficacy was similar in the two treatment groups. Interpretation of the results will vary because the increased convenience and cost savings from using a reduced dose of bolus alteplase may be offset by a higher mortality rate. However, a trial that compared the mortality rates of the two treatment regimens would have required more than 800 patients Department of Medicine Brigham and Women's Hospital Harvard Medical School Boston 02115. 100. Levine M, Hirsh J, Weitz J, et al: A randomized trial of a single bolus dosage regimen of recombinant tissue plasminogen activator in patients with acute pulmonary embolism. Chest 1990;98:1473-1479. Experiments in animals have demonstrated that recombinant tissue plasminogen activator (rt-PA) produces continuing thrombolysis after it is cleared from the circulation and that thrombolysis is both increased and accelerated, and bleeding is reduced when rt-PA is administered over a short period. In previous studies in patients with thrombotic disease, rt-PA has been shown to be an effective thrombolytic agent when administered by continuous infusion over a period between 90 minutes and 8 hours. To determine whether a short course regimen of rt-PA can achieve thrombolysis, a double-blind randomized trial has been conducted in which patients with objectively established acute symptomatic pulmonary embolism who were receiving heparin were allocated to either a 2-minute infusion of rt-PA at a dose of 0.6 mg/kg (33 patients) or saline placebo (25 patients). Perfusion lung scanning was used to assess the change in pulmonary perfusion at 24 hours and seven days post-study drug administration. Thirty-four percent of the rt-PA patients had a greater than 50 percent resolution in the perfusion defect at 24 hours compared to 12 percent of placebo patients (p = 0.026). At 24 hours, the mean relative improvement in the perfusion defect was 37.0 percent in rt-PA treated patients compared to 18.8 percent in the placebo group (p = 0.017). By day 7, no difference in lung scan resolution was detected between the groups. There were no major bleeds in either group nor were there any differences in transfusion requirements between groups. Minor bleeding occurred in 15 of the rt-PA patients mainly at angiogram-catheter insertion and venipuncture sites. These results suggest that a bolus regimen of rt-PA produces accelerated thrombolysis and provides an alternative and convenient approach to thrombolytic therapy in patients with pulmonary embolism.