David C. Stump

Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction : results of the thrombolysis in myocardial infarction -TIMI), phase II trial

OBJECTIVES To assess the effects of invasive procedures, hemostatic and clinical variables, the timing of beta-blocker therapy, and the doses of recombinant plasminogen activator (rt-PA) on hemorrhagic events. DESIGN A multicenter, randomized, controlled trial. SETTING Hospitals participating in the Thrombolysis in Myocardial Infarction, Phase II trial (TIMI II). INTERVENTIONS Patients received rt-PA, heparin, and aspirin. The total dose of rt-PA was 150 mg for the first 520 patients and 100 mg for the remaining 2819 patients. Patients were randomly assigned to an invasive strategy (coronary arteriography with percutaneous angioplasty [if feasible] done routinely 18 to 48 hours after the start of thrombolytic therapy) or to a conservative strategy (coronary arteriography done for recurrent spontaneous or exercise-induced ischemia). Eligible patients were also randomly assigned to either immediate intravenous or deferred beta-blocker therapy. MEASUREMENTS Patients were monitored for hemorrhagic events during hospitalization. MAIN RESULTS In patients on the 100-mg rt-PA regimen, major and minor hemorrhagic events were more common among those assigned to the invasive than among those assigned to the conservative strategy (18.5% versus 12.8%, P less than 0.001). Major or minor hemorrhagic events were associated with the extent of fibrinogen breakdown, peak rt-PA levels, thrombocytopenia, prolongation of the activated partial thromboplastin time (APTT) to more than 90 seconds, weight of 70 kg or less, female gender, and physical signs of cardiac decompensation. Immediate intravenous beta-blocker therapy had no important effect on hemorrhagic events when compared with delayed beta-blocker therapy. Intracranial hemorrhages were more frequent among patients treated with the 150-mg rt-PA dose than with the 100-mg rt-PA dose (2.1% versus 0.5%, P less than 0.001). The extent of the plasmin-mediated hemostatic defect was also greater in patients receiving the 150-mg dose. CONCLUSIONS Increased morbidity due to hemorrhagic complications is associated with an invasive management strategy in patients with acute myocardial infarction. Our findings show the complex interaction of several factors in the occurrence of hemorrhagic events during thrombolytic therapy.

A randomized controlled trial of intravenous tissue plasminogen activator and early intravenous heparin in acute myocardial infarction.

To evaluate the coronary thrombolytic efficacy of tissue plasminogen activator (t-PA) and early intravenous heparin, 134 patients with acute myocardial infarction were randomly assigned to combination therapy or t-PA only. At a median of 2.78 hours from symptom onset, 64 patients received both t-PA (1.5 mg/kg/4 hr) and a bolus of 10,000 units heparin, whereas 70 patients received t-PA alone at the same dose. All patients underwent coronary angiography 90 minutes after initiation of therapy to determine infarct vessel patency status, after which time the control group patients were eligible to receive heparin. Baseline demographic and angiographic characteristics were similar for the groups. Infarct vessel patency was 50 of 63 (79%) for combination t-PA and heparin and 54 of 68 (79%) for t-PA alone. Bleeding complications, as reflected by need for transfusion, were similar in the two groups: 13% in the patients treated with t-PA and heparin compared with 18% in patients treated with t-PA only (p = 0.53). The only intracranial hemorrhage in the trial occurred in a patient initially treated without heparin. Fibrinogen at 50 minutes after therapy was 32% decreased from baseline for the t-PA and heparin-treated patients compared with a 39% decrease in the control group. Predischarge left ventricular ejection fraction was similar for the two groups: 49.0 +/- 10.1% versus 50.2 +/- 11.9% for combined versus t-PA only therapy, respectively. We conclude that early intravenous heparin does not facilitate the fibrinolytic effect of t-PA at the doses tested.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary arterial thrombolysis with combined infusion of recombinant tissue-type plasminogen activator and urokinase in patients with acute myocardial infarction.

To determine whether tissue-type plasminogen activator (t-PA) and urokinase (UK) act synergistically to achieve coronary thrombolysis, incremental doses of both drugs were infused intravenously over 60 min. In 146 consecutive patients treated 3.0 +/- 1.0 hr from symptom onset, coronary angiography was performed 90 min after the start of the infusion and at 7 days. The groups of patients treated by different dose regimen were as follows: group I, 14 patients treated with t-PA 25 mg and UK 0.5 million U; group II, 20 patients given t-PA 25 mg and UK 1.0 million U; group III, 24 patients given t-PA 1.0 mg/kg and UK 0.5 million U; group IV, 33 patients treated with t-PA 1.0 mg/kg and UK 1.0 million U; and group V, 55 patients given t-PA 1.0 mg/kg and UK 2.0 million U. In groups I and II, patency of the infarct-related vessel at 90 min was only 36% and 42%, respectively. With 1 mg/kg t-PA and increasing doses of UK (groups III to V), patency ranged from 72% to 75% (overall 73%). Repeat catheterization at 7 days demonstrated reocclusion in groups III to V in 10 of 110 (9%). The patency and reocclusion rates in groups III to V were not significantly different from those in our previous study of 386 patients treated with t-PA alone (150 mg over 6 to 8 hr). In that study the patency rate of the infarct-related vessel at 90 min was 75% (p = .66) and reocclusion occurred in 15% (p = .11).(ABSTRACT TRUNCATED AT 250 WORDS)

Randomized controlled trial of tissue plasminogen activator in proximal deep venous thrombosis

PURPOSE To compare the efficacy and safety of recombinant human tissue-type plasminogen activator (rt-PA, supplied as Activase) with heparin alone or rt-PA plus heparin in the treatment of venographically documented proximal deep venous thrombosis (DVT) of the leg. PATIENTS AND METHODS Sixty-four patients underwent 65 randomizations to rt-PA alone (n = 36), rt-PA plus heparin (n = 17), or heparin alone (n = 12) in a prospective, multicenter, randomized, open-label trial, with efficacy assessed by a radiology panel unaware of treatment assignment. Patients randomly assigned to rt-PA received 0.05 mg/kg/hour for 24 hours via a peripheral vein, with a maximum dose of 150 mg. All patients then received heparin and warfarin for the remainder of the hospitalization. Follow-up venography was performed 24 to 36 hours after initiation of therapy. RESULTS Complete or more than 50% lysis occurred in 10 (28%) patients treated with rt-PA, five (29%) patients with rt-PA plus heparin, and no patient treated with heparin. No lysis occurred in 16 (44%) patients treated with rt-PA plus heparin, and 10 (83%) patients who received heparin alone (p = 0.04). There was one major complication, a nonfatal intracranial hemorrhage in a patient who received rt-PA alone. At 7 to 10 days after initiation of treatment, the level of serum glutamic oxaloacetic transaminase nearly doubled among all patients, including those assigned to receive heparin alone. CONCLUSION (1) rt-PA and rt-PA plus heparin cause more clot lysis than heparin alone; (2) the addition of heparin to rt-PA does not improve the lysis rate; (3) DVT treated with heparin is commonly associated with a rise in the transaminase level; (4) heparin does not increase the risk of bleeding from rt-PA therapy; and (5) alternative dosing regimens and modes of administration of rt-PA should be investigated to improve further its efficacy and safety in the treatment of acute DVT.

Pharmacodynamics of thrombolysis with recombinant tissue-type plasminogen activator. Correlation with characteristics of and clinical outcomes in patients with acute myocardial infarction. The TAMI Study Group.

Coagulation analysis was performed on blood samples from 386 patients with acute myocardial infarction drawn before, during, and after a continuous intravenous infusion of 150 mg recombinant tissue-type plasminogen activator (rt-PA) (Activase). Plasma rt-PA rose to peak levels of 2.1 +/- 3.1 micrograms/ml (mean +/- SD). Fibrinogen levels measured by coagulation rate and by sulfite precipitation decreased from baseline levels of 3.0 +/- 0.9 and 3.2 +/- 1.0 g/l, respectively, to nadir levels of 1.4 +/- 0.75 and 1.8 +/- 0.92 g/l, respectively, and were associated with peak levels in serum of fibrinogen-degradation products (FDP) of 230 +/- 470 micrograms/ml. Forty percent of patients experienced a nadir functional-fibrinogen level of less than 1.0 g/l, whereas 20% fell below 0.5 g/l. Nadir fibrinogen levels did not correlate with patency of the infarct-related coronary artery at 90 minutes or with risk of coronary vessel reocclusion within 7-10 days. However, the risk of coronary artery reocclusion was inversely related to the baseline functional fibrinogen level (p = 0.0008), with the magnitude of its drop to nadir level (p = 0.0003) as well as to peak levels of FDP (p = 0.038). Quantitative blood loss correlated with all markers for systemic fibrinogenolysis including nadir fibrinogen level (r = -0.20, p = 0.0011), percent decrease of fibrinogen (r = 0.22, p = 0.001), and peak FDP levels (r = 0.14, p = 0.020). Both patients who experienced intracranial hemorrhage presented with high baseline fibrinogen levels and experienced extensive degradation of coagulable fibrinogen. Overall, patients at greatest risk of systemic fibrinogenolysis tended to be relatively older women with lower body weight.(ABSTRACT TRUNCATED AT 250 WORDS)

A controlled trial of prophylactic granulocyte transfusions during initial induction chemotherapy for acute myelogenous leukemia.

To evaluate the role of prophylactic granulocyte transfusions during remission-induction chemotherapy for acute myelogenous leukemia (AML) we randomized 102 infected patients either to receive daily granulocyte transfusions when blood granulocytes fell below 0.5 x 10(9) per liter (54 patients) or not to receive them (48). Although the percentage of patients acquiring any infection was similar in the transfusion and control groups (46 and 42 per cent, respectively), granulocyte transfusions decreased the proportion of patients with bacterial septicemia (9 per cent of those with transfusions vs. 27 per cent of the controls; P = 0.01). Granulocyte transfusions did not reduce the incidence of other infections or improve bone-marrow recovery, remission rate and duration, or survival. Seventy-two per cent of the patients given transfusions had transfusion reactions. Pulmonary infiltrates were more common in the transfusion group than in the control group (57 per cent vs. 27 per cent; P = 0.002). Thirty-five per cent of the patients with pulmonary filtrates died, as compared with 5 per cent of those without filtrates. We conclude that prophylactic granulocyte transfusions should not be used during remission-induction chemotherapy in AML because the risks outweigh the benefits.

Bleeding during Thrombolytic Therapy for Acute Myocardial Infarction: Mechanisms and Management

Hemorrhage is the major adverse effect of thrombolytic therapy, but its incidence can be reduced by careful selection of patients and avoidance of unnecessary invasive procedures. More than 70% of bleeding episodes occur at vascular puncture sites. Hypofibrinogenemia and elevation of fibrinogen degradation products have been weakly correlated with the risk of hemorrhage. Although depletion of factors V and VIII may occur, the role of such depletion in bleeding is unknown. Several in-vitro studies have shown plasmin-induced platelet dysfunction, but clinical data are limited. Nevertheless, the role of platelet inhibition should be considered because many patients are treated with antiplatelet agents. Most patients who have bleeding can be managed by interruption of thrombolytic and anticoagulant therapy, volume replacement, and manual pressure applied to an incompetent vessel. Protamine should be considered if heparin has been administered within 4 hours of the onset of bleeding. In the few patients who fail to respond to these conservative measures, judicious use of transfusion products may be indicated. Transfusion of cryoprecipitate, fresh frozen plasma, and platelets should be considered with clinical and laboratory reassessment after each administration. A target fibrinogen level of 1 g/L is desirable with cryoprecipitate infusion. Antifibrinolytic agents are available as a last alternative. We have developed an algorithm for using these products.

A randomized, blinded trial comparing the hemostatic effects of pentastarch versus hetastarch

BACKGROUND: HES solutions provide a sterile, alternative colloidal fluid to albumin solutions and/or plasma in the management of patients who need plasma volume expansion. Solutions of HES are widely accepted internationally but are used only modestly in the United States, largely because of concerns over hemostasis.

Combined tissue-type plasminogen activator and prostacyclin therapy for acute myocardial infarction

Current limitations of recombinant tissue-type plasminogen activator (rt-PA) therapy for acute myocardial infarction include failure to achieve recanalization in 25% of patients, reocclusion and reperfusion injury. Iloprost, a stable analogue of prostacyclin (PGI2), has been demonstrated to facilitate thrombolysis and reduce myocardial stunning in experimental models. To evaluate combined therapy, rt-PA (100 mg 3 h) and Iloprost (2 ng/kg per min for 48 h) were administered to 25 patients and then rt-PA alone (same dose) was given to an additional 25 patients with evolving myocardial infarction. At 90 min after drug administration, infarct-related vessel patency was observed in 11 (44%) of 25 who received rt-PA plus Iloprost compared with 15 (60%) of 25 who received rt-PA alone (p = 0.26). At 1 week, reocclusion had occurred in 3 (14%) of 21 patients who received combined therapy compared with 6 (26%) of 23 patients treated with rt-PA alone (p = 0.46). Ejection fraction increased significantly from baseline to 7 days for rt-PA alone whereas it decreased with combined therapy (rt-PA alone whereas it decreased with combined therapy (rt-PA alone: 47.3 +/- 11.5% at baseline to 50.4 +/- 9.8% at 7 days; rt-PA plus Iloprost: 51.3 +/- 10.1% at baseline to 49.0 +/- 9.4% at 7 days; difference between groups p = 0.05). At 4 h after therapy, fibrinogen decreased 33% for rt-PA plus Iloprost compared with a 52% for rt-PA alone (p = 0.001). Fibrinogen degradation products increased 60% more for rt-PA alone than for rt-PA plus Ilprost. Thus, the combination of rt-PA plus Iloprost at the doses employed did not improve immediate or follow-up coronary artery patency or left ventricular functional recovery compared with that achieved with rt-PA alone.

Alteplase as an Alternative to Urokinase

Abbreviations: DVT deep vein thrombosis, PAOD peripheral arterial occlusive disease, rt-PA recombinant tissue plasminogen activator, UK urokinase For the past 20 years, urokinase (UK) has been the primary agent used in the United States for catheter-directed thrombolytic therapy of acute limb ischemia and deep vein thrombosis (DVT), and for restoration of patency in hemodialysis access and clotted intravenous access devices (1–4). However, in 1999, the Food and Drug Administration suspended the sales and distribution of UK (Abbokinase; Abbott Laboratories, Abbott Park, IL) in the United States (5). Unfortunately, few American interventionalists had previous experience in the use of alternative agents to UK. To address this urgent clinical crisis, a multidisciplinary Advisory Panel on Catheter-Directed Thrombolytic Therapy consisting of vascular specialists was organized by the Society of Cardiovascular and Interventional Radiology (SCVIR) and convened in New York, NY, on August 9, 1999, to develop preliminary recommendations for the benefit of SCVIR members. The goal of the advisory panel was to: (i) identify alternative plasminogen activators; (ii) review the published literature on alternative plasminogen activators; (iii) review the multidisciplinary advisory panel experience with the use of alternative agents; and (iv) develop preliminary clinical guidelines for managing acute limb ischemia, DVT, thrombosed dialysis grafts, and clotted intravascular catheters and ports. This document is a summary of the Advisory Panel meeting and is intended for the establishment of guidelines in the use of alternative agents to UK in clinical practice. The meeting was supported by an unrestricted educational grant from Genentech, Inc. (South San Francisco, CA) and sponsored by the SCVIR.