Thrombolytic Regimens Research Articles

Effects of thrombolytic regimen, early catheterization, and predischarge angiographic variables on six-week left ventricular function

The Thrombolysis and Angioplasty in Acute Myocardial Infarction phase 5 (TAMI-5) trial randomized patients to 1 of 3 thrombolytic regimens (alteplase, urokinase, or both), then further randomized them to acute or deferred catheterization. The group of patients randomized to acute catheterization had improved infarct zone but not global left ventricular function on predischarge left ventriculography. To better explore the late effects of these strategies on global and regional left ventricular function, a subset of patients (n = 296) were prospectively evaluated at 6 weeks by multiple uptake gated acquisition (MUGA) radionuclide ventriculography scan. Of these patients, 219 had interpretable studies with paired predischarge and late left ventriculographic data for comparison. At 6 weeks, choice of thrombolytic regimen had no impact on either global or infarct-zone left ventricular function. Further, catheterization strategy (acute vs deferred) did not influence global or infarct-zone function at 6 weeks. In patients randomized to acute catheterization, those undergoing rescue angioplasty had worse infarct-zone wall motion at 6 weeks than patients with a patent infarct vessel not requiring rescue angioplasty (p = 0.002). The early benefit on regional left ventricular function of triage to acute catheterization after thrombolysis for acute myocardial infarction did not persist at 6 weeks, which is most likely attributable to a high incidence of reocclusion. The worse infarctzone regional wall motion in patients undergoing rescue angioplasty in the acute-catheterization group likely reflects failed reperfusion and illustrates the difficulty in identifying and consequences of early thrombolytic failures.

TIMI grade 3 flow and reocclusion after intravenous thrombolytic therapy: A pooled analysis

Early and sustained flow of grade 3 according to Thrombolysis in Myocardial Infarction (TIMI) criteria and reocclusion rates are the key measures that define the physiologic efficacy of thrombolytic agents in the treatment of acute myocardial infarction. We performed a systematic overview of angiographic studies after intravenous thrombolysis with accelerated and standard-dose tissue-plasminogen activator (TPA), anisoylated plasminogen streptokinase activator complex (APSAC), and streptokinase. There were 5475 angiographic observations from 15 studies for TIMI flow analysis and 3147 angiographic observations from 27 studies for reocclusion. At 60 and 90 minutes, the rates of TIMI grade 3 flow were 57.1% and 63.2%, respectively, with accelerated TPA, 39.5% and 50.2% with standard-dose TPA, 40.2% and 50.1% with APSAC, and 31.5% at 90 minutes with streptokinase. Overall reocclusion with standard-dose TPA was 11.8% versus 6.0% for accelerated TPA, 4.2% for streptokinase, and 3.0% for APSAC. Although the incidence of TIMI grade 3 flow increased over time with all thrombolytic regimens, decreased patency was observed at 180 minutes with accelerated TPA. Still, accelerated TPA is the most effective agent to establish early (90-minute) TIMI grade 3 flow. (Am Heart J 1997;133:273-82.)

The importance of antibody specificity in measuring cross-linked fibrin degradation products by ELISA.

We and others have previously shown that plasma concentrations of XL-FDPs are accurately characterized with an enzyme-linked immunosorbent assay (ELISA) based on the monoclonal antibody DD-3B6/22, which is specific for D-dimer, and a pan-specific tag antibody (DD-4D2/182) in patients with thrombotic disorders. However, in patients treated with fibrinolytic agents, increases in non-cross-linked fibrin(ogen) degradation products are detected by the pan-specific tag antibody due to formation of complexes between non-cross-linked derivatives and XL-FDPs. Assays based on the use of fibrin degradation product-specific tag antibodies appear to be more specific, but whether they would be clinically more informative is unclear. Accordingly, in the current study we measured concentrations of XL-FDPs with two ELISAs; one based on the pan-specific tag antibody (DD-4D2/182) and another based on a fibrin degradation product-specific tag antibody (DD-1D2/48) in patients treated with three well-characterized thrombolytic regimens: one associated with minimal fibrinogenolysis (100 mg tissue-type plasminogen activator [t-PA]) over 3 h), moderate fibrinogenolysis (100 mg t-PA over 90 min), and one with marked fibrinogenolysis (1.5 MU streptokinase [SK]). In patients treated with t-PA, increases in XL-FDPs were closely correlated with fibrinogenolysis, as characterized by increases in the concentration of the Bbeta1-42 peptide, when measured with the pan-specific tag ELISA (r = 0.7), but not when measured with the fibrin degradation product-specific tag assay (r = 0.2). In patients treated with SK, concentrations of XL-FDPs were significantly higher (> 2000 ng/ml) with the pan-specific tag ELISA compared with the fibrin degradation product-specific tag ELISA (< 1000 ng/ml) 1, 2 and 8 h after start of the infusion (P < 0.01). Concentrations of XL-FDPs were also higher in patients treated with SK compared with t-PA when measured with the pan-specific tag ELISA, but lower with SK with the fibrin-specific ELISA (P < 0.01). The value of measurement of XL-FDPs in patients treated with fibrinolytic agents will need to be reappraised with the use of fibrin degradation product-specific assays, which appear to provide more accurate information on the kinetics of cross-linked fibrin lysis in patients treated with t-PA or SK.

Coronary Revascularization Surgery After Myocardial Infarction: Impact of Bypass Surgery on Survival After Thrombolysis

Objectives. This study sought to investigate the impact of surgical revascularization on outcome after myocardial infarction.Background. Small variations in rates of coronary artery bypass graft surgery (CABG) were noted among thrombolytic regimens in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial, prompting the question of whether survival differences were partly related to differences in CABG rates.Methods. Patients in the GUSTO trial were randomized to one of four thrombolytic strategies. Of 40,861 patients with complete data, 3,526 underwent surgical revascularization during their initial hospital admission. Thirty-day and 1-year mortality rates were estimated using Kaplan-Meier techniques, and the impact of CABG as a time-dependent covariate on death was evaluated using a Cox survival model, adjusting for baseline prognostic factors.Results. The median time from study enrollment to CABG was 7 days across treatment groups. A 15% reduction in mortality for the tissue-type plasminogen activator (t-PA)–treated group was evident by the seventh day. Bypass surgery was a significant independent predictor of 30-day mortality (risk ratio 1.87) and a weaker predictor of 1-year mortality (risk ratio 1.21). Operative mortality was highest in patients with acute mitral regurgitation, ventricular septal defect or poor left ventricular function and in those undergoing CABG within the first 4 days of randomization.Conclusions. The survival benefit of accelerated t-PA was not related to surgical revascularization. Bypass surgery was associated with excess mortality in the first year, but the added short-term mortality associated with CABG may be balanced by anticipated long-term benefit in specific groups of patients.(J Am Coll Cardiol 1997;29:240–9)

Incidence and predictors of bleeding after contemporary thrombolytic therapy for myocardial infarction. The Global Utilization of Streptokinase and Tissue Plasminogen activator for Occluded coronary arteries (GUSTO) I Investigators.

Although the benefit of thrombolytic therapy in reducing mortality in acute myocardial infarction is well established, the types of bleeding and risk factors for bleeding are less well described in large trials. We analyzed the baseline characteristics, outcomes, and incidence of bleeding by location, severity, and treatment assignment among 41,021 patients in the GUSTO-I trial of thrombolysis for acute myocardial infarction. Of the 40,903 patients for whom there were complete data, 1.2% suffered severe bleeding and 11.4% experienced moderate hemorrhage at a variety of sites. The most common sources of bleeding were procedure related. The thrombolytic regimen was strongly related to the incidence of bleeding; comparatively more bleeding was seen with the therapies of streptokinase plus intravenous heparin and the streptokinase and tissue plasminogen activator plus intravenous heparin combination. In multivariate analysis, the four most powerful independent predictors of hemorrhage were older age, lighter body weight, female sex, and African ancestry; they remained the most important predictors of bleeding when multivariate analysis was performed on patients who did not undergo invasive procedures. The presence of serious hemorrhage was associated with other undesirable outcomes (recurrent events, left ventricular dysfunction, arrhythmia, or stroke). Important predictors of bleeding in this population are increased age, lighter weight, female sex, African ancestry, and experiencing invasive procedures. Other nonhemorrhagic adverse clinical outcomes were associated with moderate and severe bleeding, which was in turn associated with increased length of hospital stay and mortality at 30 days.

Adjunctive Antiplatelet Therapy in Acute Myocardial Infarction: The Road to Improved Infarct-Related Artery Patency.

A direct relationship exists between infarct artery patency and survival in patients with acute myocardial infarction. Currently available thrombolytic regimens produce 90 minute patency rates on the order of 80%. Preliminary trials suggest that adjunctive anti-platelet therapy with glycoprotein IIb/IIIa inhibitors, in conjunction with thrombolytic therapy, may significantly improve 90 minute infarct related artery patency and thereby survival, in patients with acute myocardial infarction.

When is thrombolysis justified in patients with acute ischemic stroke? A bioethical perspective.

Thrombolytic therapy for acute ischemic stroke raises several unsettled bioethical issues related to risk versus benefit. Excluding the National Institutes of Neurological Disorders and Stroke (NINDS) rt-PA trial, the risk of intracerebral hemorrhage averages 10.3%, and there is a 44% increase in the odds of death among fibrinolysis-treated patients. Some investigators have suggested that as yet unidentified subgroups may benefit despite an increased early risk of hemorrhage and death, while others have warned that the widespread use of thrombolysis cannot currently be recommended despite recent Food and Drug Administration approval. The NINDS rt-PA trial showed a net benefit, but the relative risk to benefit ratio in individual patients is uncertain because of incomplete subgroup analysis. We explore these and related issues by applying the bioethical principle of justification to the selection of stroke patients for thrombolysis. Justification of a therapy rests on the criteria of safety, efficacy (net benefit under ideal conditions), effectiveness (net benefit under routine conditions), efficiency (cost-effectiveness or cost benefit), and outcome (proportionality and informed consent). The ethical principal of proportionality states that positive outcomes must be proportional to negative outcomes; only the NINDS trial sets equipoise between risk and benefit. The relative risk to benefit ratio and cost-effectiveness of thrombolysis will likely vary among treating physicians and patient subgroups. Although some potential selection factors such as early CT changes, National Institutes of Health Stroke Scale score > 22, and age > 77 years have been identified, it is not yet possible to predict response to treatment in individual patients. The effectiveness of thrombolysis outside of a clinical trial has not yet been demonstrated, and it is not clear that thrombolysis is cost-effective for all potential patient subgroups. No stroke thrombolysis regimen has met all five justification criteria. Proportional outcome standards that take into account patient preferences must be established. The risk to benefit ratio of thrombolysis in patient subgroups requires clarification and should incorporate cost-efficiency analyses. These issues should be kept in mind when considering thrombolysis therapy in patients with acute ischemic stroke and when designing clinical trials.

Clinical Trials in Thrombolytic Therapy: What Do They Tell Us? INJECT 6-Month Outcomes Data

Numerous controlled clinical trials have documented the efficacy of thrombolytic agents in reducing the risk of mortality after myocardial infarction (MI). As a result, it is no longer ethical to test a new thrombolytic regimen against placebo. Rather, promising new therapies must be compared with proven treatments. This has been the direction taken in trials of reteplase, a new recombinant plasminogen activator. Initial studies of double-bolus reteplase demonstrated its superior ability to produce TIMI grade 2 or 3 flow at 90 minutes when compared with accelerated alteplase. A subsequent randomized, double-blind, 9-country study, the International Joint Efficacy Comparison of Thrombolytics (INJECT) trial was designed to determine whether the efficacy of reteplase is at least equivalent to that of streptokinase. The 2 treatments were associated with similar frequencies of in-hospital cardiac events, bleeding, and strokes. Likewise, no significant difference was apparent between the reteplase and streptokinase groups with regard to 35-day mortality (the primary endpoint), the combined endpoint of 35-day mortality plus continuing disability from in-hospital stroke, or 6-month mortality. Unadjusted data from the 3 countries that contributed the majority of patients seemed to indicate a survival benefit, irrespective of treatment allocation, among patients who underwent interventional procedures. However, no such benefit was apparent when the data were adjusted for differences in the baseline characteristics of the patients enrolled in the different countries. Rather, intervention within the first 3 days post-MI was found to place patients at a substantially higher risk of 35-day mortality. Further insights into the relative efficacy of reteplase should emerge from the ongoing third Global Utilization of Strategies to Open Occluded Coronary Arteries (GUSTO-III) trial. © 1996 by Excerpta Medica, Inc. Am J Cardiol 1996;78(suppl 12A):20–23

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

Acute coronary syndromes: Virchow's triad revisited

In 1996, the over-a-century-old hypothesis presented by Rudolf Virchow that vascular thrombosis is caused by vessel-wall injury, alterations in blood flow, and abnormal blood coagulability, continued to spawn research. In atherosclerosis research, the role of statins was further emphasised in the CARE trial, which showed a significant reduction in death from coronary causes and stroke in patients with myocardial infarction and an average cholesterol (<6.2mmol/L [<240mg/dL]). Benefit was also found with antioxidant vitamin E in patients with established ischaemic heart disease, consistent with the lipidoxidation theory of coronary artery disease. Improved thrombolytic and anti thrombotic regimens, and technological advances in invasive cardiology, substantially increased survival among patients admitted with acute coronary syndromes. New plasminogen activators with reduced clearance and more pronounced fibrin specificity, including recombinant staphylokinase and T N K tissue plasminogen activator compared favourably with standard accelerated aheplase in achieving early recanalisation. The G U S T O IIb angiographic substudy found a moderate but significant benefit for immediate percutaneous coronary angioplasty (PTCA) over thrombolytic therapy in patients with acute myocardial infarction, but cost will be an obstacle to widespread use of PTCA. A provocative study (N Engl J Med 1996; 334: 7) that reported better reperfusion (86% TIMI III flow at 90 min) and smaller infarcts after thrombolysis in patients with preceding unstable angina may help to individualise treatment for patients. Recognition of the role of thrombin and platelets has spurred the use of hirudin as a direct antithrombin agent and the introduction of more potent platelet inhibitors, such as glycoprotein IIb/IIIa-receptor blockers and ticlopidine. Ticlopidine virtually eliminated immediate stent thrombosis and the serious bleeding complications often observed with the combination of aspirin and anticoagulants. An early risk reduction of non-fatal (re)infarction with recombinant hirudin in GUSTO IIb was not sustained over time, probably because of continuing or rebound thrombin generation (N Engl J Med 1996; 334: 775). Glycoprotein IIb/IIIa-receptor blockers (c7E3), in contrast, improved early vessel patency after PTCA and had prolonged clinical benefit, suggests an effect beyond reduction of platelet

La Diffe´rence

Recanalization of coronary arteries, induced by either thrombolytic therapy or angioplasty, has revolutionized the management of acute myocardial infarction. The mean in-hospital death rate for patients who reach the hospital in time and receive thrombolytic therapy is ≈6% to 7%.1 This is a dramatic reduction compared with the death rate in the 1960s of 30% to 35%. Thrombolytic therapy is easy to administer and is carried out routinely in community hospitals throughout North America and many other parts of the world. In addition to the reduced death rate, there is likely to be a reduced morbidity; however, this is more difficult to prove. Clinical trials to date on thrombolytics have concentrated on mortality, in part because this is the major, if not the sole, end point required by the Food and Drug Administration to approve a new drug. In the original Global Utilization of t-PA and Streptokinase for Occluded Coronary Arteries (GUSTO-I) trial,1 the 41 021 patients who were enrolled received one of four thrombolytic agents. Patients who had ST-segment elevation and presented within 6 hours of onset were enrolled unless there was a contraindication. Enrollment had no age limit and included patients in cardiogenic shock and those with previous bypass surgery; thus, this population was highly representative of the patient population at large presenting with acute myocardial infarction. The overall objective of GUSTO-I was to compare four thrombolytic regimens: streptokinase followed by subcutaneous heparin, streptokinase followed by intravenous heparin, tissue plasminogen activator (TPA*) ≤100 mg given over 60 minutes followed by intravenous heparin, and a combination of intravenous TPA and streptokinase followed by intravenous heparin. All patients received aspirin and atenolol if there were no contraindications. The 30-day mortality rate in that trial was 6.3% for patients who received accelerated TPA, 7.2% for those receiving streptokinase and subcutaneous …

The rationale for thrombolytic therapy.

Substantial progress has been made toward understanding the pathophysiological processes that lead to acute myocardial infarction. Research has shown that the mechanism of infarction is the rupture of an atherosclerotic plaque with a subsequent thrombogenic response from exposed subendothelial tissue, leading to additional or complete obstruction of the vessel. Myocardial cell death then proceeds in a wavefront fashion from the subendocardium to the epicardium. Time to myocardial reperfusion and the extent of collateral flow are the primary determinants of final infarct area. This knowledge led to the development of therapeutic strategies to achieve early and sustained reperfusion of the infarct-related vessel, the presumption being that this would result in increased myocardial salvage and better residual left ventricular function in addition to reductions in infarct expansion and electrical instability. The results of several large thrombolytic trials have supported this model, showing that patients who receive thrombolytic therapy derive a constant relative survival benefit when compared with control patients. The largest comparative thrombolytic trial to date has shown that therapies that result in early, more complete reperfusion are indeed associated with lower mortality; however, these therapies may be associated with higher rate of complications such as intracranial haemorrhage and reocclusion. Future evaluations must include assessment of the benefits relative to the risks of newer, more potent thrombolytic regimens.

The future of thrombolysis in the treatment of acute myocardial infarction.

The ability of thrombolytic therapy to lower mortality in patients with acute myocardial infarction was first demonstrated in 1986 by the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico. In the ensuing 10 years, large efforts have been undertaken to develop more effective and safer thrombolytic agents. In addition, the value of adjunctive agents influencing thrombotic and thrombolytic processes was demonstrated, and newer agents are under active investigation. This review focuses on theoretical and practical aspects of optimizing thrombolytic therapy and on genetically engineered third generation plasminogen activators. Optimized thrombolytic therapy may make this form of therapy available to patients who are currently considered ineligible, and it will lead to earlier, more complete reperfusion of infarct-related coronary arteries. The benefits and risks of optimized thrombolytic regimens relative to those of mechanical reperfusion strategies will require constant reassessment while both forms of treatment develop.

Implications of the GUSTO trial for thrombolytic therapy.

This article discusses the impact of previous clinical observations on the development of the GUSTO-I protocol, particularly the absence of a survival benefit of alteplase (rt-PA) over streptokinase in the GISSI-2/International Study Group and ISIS-3 trials in spite of a higher efficacy for clot lysis. The demonstrated superiority of front-loaded alteplase in this large trial is translated into useful guidelines for the practising clinician. Risk-benefit analysis indicates that, in general, this thrombolytic regimen is most indicated in patients presenting with large amounts of jeopardized ischaemic myocardium in the absence of a particularly increased risk of haemorrhagic stroke. Finally, the impact of this study for future development in the field of acute coronary syndromes is evaluated, more specifically for the design of new trials with new fibrinolytic and antithrombotic agents. These include mutants of alteplase, staphylokinase, direct antithrombins and inhibitors of the glycoprotein IIb/IIIa platelet receptor.

Computer simulation of systemic circulation and clot lysis dynamics during thrombolytic therapy that accounts for inner clot transport and reaction.

We developed a computer model to predict lysis rates of thrombi for intravenous thrombolytic regimens based on the convective/diffusive penetration of reacting and adsorbing fibrinolytic species from the circulation into the proximal face of a dissolving clot. Solution of a one-compartment plasma model provided the dynamic concentrations of fibrinolytic species that served as inlet conditions for stimulation of the one-dimensional spatiodynamics within a dissolving fibrin clot of defined composition. The model predicted the circulating levels of tissue plasminogen activator (TPA) and plasminogen levels found in clinical trials for various intravenous therapies. To test the model predictions under in vitro conditions, plasma clots were perfused with TPA (0.1 mumol/L) and plasminogen (1.0 mumol/L) delivered at constant permeation velocity of 0.1 or 0.2 mm/min. The model provided an accurate prediction of the measured lysis front movement. For TPA administration regimens used clinically, simulations predicted clot dissolution rates that were consistent with observed reperfusion times. For unidirectional permeation, the continual accumulation of adsorbing species at the moving lysis front due to prior rounds of solubilization and rebinding was predicted to provide for a marked concentration of TPA and plasmin and the eventual depletion of antiplasmin and macroglobulin in an advancing (approximately 0.25 mm thick) lysis zone. Pressure-driven permeation greatly enhances and is a primary determinant of the overall rate of clot lysis and creates a complex local reaction environment at the plasma/clot interface. With simulation of reaction and transport, it becomes possible to quantitatively link the administration regimen, plasminogena activator properties, and thrombolytic outcome.

Safer thrombolytic regimens needed

Safer thrombolytic regimens needed

Safer thrombolytic regimens needed

Safer thrombolytic regimens needed

Prognostic significance of the admission electrocardiogram in acute myocardial infarction

We sought to access the ST segment and the terminal portion of the QRS complex in the initial electrocardiogram (ECG) as tools to predict outcome in patients with acute myocardial infarction given thrombolytic therapy. Previous studies assessing early risk stratification of patients with acute myocardial infarction by ECG criteria have focused on the number of leads with ST segment elevation or the absolute magnitude of ST deviation. A new classification independent of the absolute values of ST deviation was pursued. Patients with ST elevation and positive T waves in at least two adjacent leads who received thrombolytic therapy were classified into two groups based on the absence (1,232 patients) or presence (1,371 patients) of distortion of the terminal portion of the QRS complex on the admission ECG. There were no differences between groups in the prevalence of previous angina, hypertension, current smoking, anterior infarction, time from onset of symptoms to therapy of type of thrombolytic regimen. Patients with QRS distortion were less likely to have had a previous infarction (12.0% vs. 18.4%, p = 0.02) or diabetes mellitus (16.9% vs. 21.4%, p = 0.003). They had higher peak creatine kinase levels (1,617 +/- 1,670 vs. 1,080 +/- 1,343 IU, p = 0.00001). Hospital mortality for those with and without QRS distortion was 6.8% and 3.8%, respectively (p = 0.0008). Multivariable logistic regression analysis confirmed that hospital mortality was independently associated with distortion of terminal portion of the QRS complex (odds ratio 1.78, 95% confidence interval 1.19 to 2.68, p = 0.004). Distortion of the terminal portion of the QRS complex on the admission ECG is independently associated with a higher hospital mortality rate in patients with acute myocardial infarction given thrombolytic therapy.

Comparisons of characteristics and outcomes among women and men with acute myocardial infarction treated with thrombolytic therapy. GUSTO-I investigators

To compare baseline characteristics, complications, and treatment-specific outcomes of women and men with acute myocardial infarction treated with thrombolytic therapy. Randomized controlled trial. A total of 10315 women and 30706 men with acute myocardial infarction treated in 1081 hospitals in 15 countries as part of the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I). One of four thrombolytic regimens: (1) streptokinase with subcutaneous heparin; (2) streptokinase with intravenous heparin; (3) streptokinase plus alteplase (tissue-type plasminogen activator) with intravenous heparin; or (4) accelerated alteplase with intravenous heparin. Mortality, stroke, and nonfatal complications during 30-day follow-up. Women were on average 7 years older than men and delayed 18 minutes (median) longer after symptom onset before presenting to the hospital. After adjustment for age, women more often had a history of diabetes, hypertension, and smoking than men. Time to treatment was significantly longer in women (1.2 vs 1.0 hours; P<.001). Women had more nonfatal complications after treatment, including shock (9% vs 5%; P<.001), congestive heart failure (22% vs 14%; P<.001), serious bleeding (15% vs 7%; P<.001), and reinfarction (5.1% vs 3.6%; P<.001). Women had twice as many total strokes as men (2.1% vs 1.2%; P<.001), secondary to their older age at presentation. The unadjusted mortality rate was twice as high in women as men (11.3% vs 5.5%; P<.001); the relative risk (RR) of death was greater among women than men after adjustment for differences in baseline characteristics (RR=1.15; 95% confidence interval, 1.0 to 1.31). Although women and men underwent angiography at similar rates, there were small but significant differences in their rates of revascularization procedures (angioplasty: 35% of women and 32% of men; bypass surgery: 7% of women and 9% of men; P<.001 for both). The higher rate of stroke in women after treatment with alteplase (2.0% vs 1.9% with streptokinase and intravenous heparin) was offset by a greater relative reduction in mortality (10.3% vs 11.1%). Women who received thrombolytic therapy for treatment of acute myocardial infarction were at greater risk for both fatal and nonfatal complications than men.

Comparisons of Characteristics and Outcomes Among Women and Men With Acute Myocardial Infarction Treated With Thrombolytic Therapy

Objective. —To compare baseline characteristics, complications, and treatment-specific outcomes of women and men with acute myocardial infarction treated with thrombolytic therapy. Design. —Randomized controlled trial. Patients and Setting. —A total of 10315 women and 30706 men with acute myocardial infarction treated in 1081 hospitals in 15 countries as part of the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I). Intervention. —One of four thrombolytic regimens: (1) streptokinase with subcutaneous heparin; (2) streptokinase with intravenous heparin; (3) streptokinase plus alteplase (tissue-type plasminogen activator) with intravenous heparin; or (4) accelerated alteplase with intravenous heparin. Main Outcome Measures. —Mortality, stroke, and nonfatal complications during 30-day follow-up. Results. —Women were on average 7 years older than men and delayed 18 minutes (median) longer after symptom onset before presenting to the hospital. After adjustment for age, women more often had a history of diabetes, hypertension, and smoking than men. Time to treatment was significantly longer in women (1.2 vs 1.0 hours; P P P P P P P P Conclusion. —Women who received thrombolytic therapy for treatment of acute myocardial infarction were at greater risk for both fatal and nonfatal complications than men. ( JAMA . 1996;275:777-782)