Temporal trends in the treatment of over 1.5 million patients with myocardial infarction in the US from 1990 through 1999: the National Registry of Myocardial Infarction 1, 2 and 3.

OBJECTIVES: We sought to determine trends in the treatment of myocardial infarction from 1990 through 1999 in the U.S. and to relate these trends to current guidelines. BACKGROUND: Limited data are available to show how recent clinical trials and clinical guidelines have impacted treatment of myocardial infarction. METHODS: Temporal trends in myocardial infarction treatment and outcome were assessed by using data from 1,514,292 patients in the National Registry of Myocardial Infarction (NRMI) 1, 2 and 3 from 1990 through 1999. RESULTS: During this interval, the use of intravenous thrombolytic therapy declined from 34.3% to 20.8%, but the use of primary angioplasty increased from 2.4% to 7.3% (both p = 0.0001). The median "door-to-drug" time among thrombolytic therapy recipients fell from 61.8 to 37.8 min (p = 0.0001), primarily owing to shorter "door-to-data" and "data-to-decision" times. The prevalence of non-Q wave infarctions increased from 45% in 1994 to 63% in 1999 (p = 0.0001). From 1994 through 1999, there was increased usage of beta-blockers, aspirin and angiotensin-converting inhibitors, both during the first 24 h after admission and on hospital discharge (all p = 0.0001). Between 1990 and 1999, the median duration of hospital stay fell from 8.3 to 4.3 days, and hospital mortality declined from 11.2% to 9.4% (both p = 0.0001). CONCLUSIONS: The NRMI data from 1990 through 1999 demonstrate that the recommendations of recent clinical trials and published guidelines are being implemented, resulting in more rapid administration of intravenous thrombolytic therapy, increasing use of primary angioplasty and more frequent use of adjunctive therapies known to reduce mortality, and may be contributing to the higher prevalence of non-Q wave infarctions, shorter hospital stays and lower hospital mortality.

Relationship of symptom-onset-to-balloon time and door-to-balloon time with mortality in patients undergoing angioplasty for acute myocardial infarction.

CONTEXT: Rapid time to treatment with thrombolytic therapy is associated with lower mortality in patients with acute myocardial infarction (MI). However, data on time to primary angioplasty and its relationship to mortality are inconclusive. OBJECTIVE: To test the hypothesis that more rapid time to reperfusion results in lower mortality in the strategy of primary angioplasty. DESIGN: Prospective observational study of data collected from the Second National Registry of Myocardial Infarction between June 1994 and March 1998. SETTING: A total of 661 community and tertiary care hospitals in the United States. SUBJECTS: A cohort of 27,080 consecutive patients with acute MI associated with ST-segment elevation or left bundle-branch block who were treated with primary angioplasty. MAIN OUTCOME MEASURE: In-hospital mortality, compared by time from acute MI symptom onset to first balloon inflation and by time from hospital arrival to first balloon inflation (door-to-balloon time). RESULTS: Using a multivariate logistic regression model, the adjusted odds of in-hospital mortality did not increase significantly with increasing delay from MI symptom onset to first balloon inflation. However, for door-to-balloon time (median time 1 hour 56 minutes), the adjusted odds of mortality were significantly increased by 41% to 62% for patients with door-to-balloon times longer than 2 hours (for 121-150 minutes: odds ratio [OR], 1.41; 95% confidence interval [CI], 1.08-1.84; P=.01; for 151-180 minutes: OR, 1.62; 95% CI, 1.23-2.14; P<.001; and for >180 minutes: OR, 1.61; 95% CI, 1.25-2.08; P<.001). CONCLUSIONS: The relationship in our study between increased mortality and delay in door-to-balloon time longer than 2 hours (present in nearly 50% of this cohort) suggests that physicians and health care systems should work to minimize door-to-balloon times and that door-to-balloon time should be considered when choosing a reperfusion strategy. Door-to-balloon time also appears to be a valid quality-of-care indicator. JAMA. 2000.

The volume of primary angioplasty procedures and survival after acute myocardial infarction. National Registry of Myocardial Infarction 2 Investigators.

BACKGROUND: There is an inverse relation between mortality from cardiovascular causes and the number of elective cardiac procedures (coronary angioplasty, stenting, or coronary bypass surgery) performed by individual practitioners or hospitals. However, it is not known whether patients with acute myocardial infarction fare better at centers where more patients undergo primary angioplasty or thrombolytic therapy than at centers with lower volumes. METHODS: We analyzed data from the National Registry of Myocardial Infarction to determine the relation between the number of patients receiving reperfusion therapy (primary angioplasty or thrombolytic therapy) and subsequent in-hospital mortality. A total of 450 hospitals were divided into quartiles according to the volume of primary angioplasty. Multiple logistic-regression models were used to determine whether the volume of primary angioplasty procedures was an independent predictor of in-hospital mortality among patients undergoing this procedure. Similar analyses were performed for patients receiving thrombolytic therapy at 516 hospitals. RESULTS: In-hospital mortality was 28 percent lower among patients who underwent primary angioplasty at hospitals with the highest volume than among those who underwent angioplasty at hospitals with the lowest volume (adjusted relative risk, 0.72; 95 percent confidence interval, 0.60 to 0.87; P<0.001). This lower rate, which represented 2.0 fewer deaths per 100 patients treated, was independent of the total volume of patients with myocardial infarction at each hospital, year of admission, and use or nonuse of adjunctive pharmacologic therapies. There was no significant relation between the volume of thrombolytic interventions and in-hospital mortality among patients who received thrombolytic therapy (7.0 percent for patients in the highest-volume hospitals vs. 6.9 percent for those in the lowest-volume hospitals, P=0.36). CONCLUSIONS: Among hospitals in the United States that have full interventional capabilities, a higher volume of angioplasty procedures is associated with a lower mortality rate among patients undergoing primary angioplasty, but there is no association between volume and mortality for thrombolytic therapy.

Reperfusion therapy in patients with acute myocardial infarction and prior coronary artery bypass graft surgery (National Registry of Myocardial Infarction-2).

We reviewed data from the National Registry of Myocardial Infarction-2 to determine the differences in characteristics and outcomes in patients with acute myocardial infarction (AMI) who have undergone previous coronary artery bypass grafting (CABG), and those who have not, and between post-CABG patients who were treated with alteplase (recombinant tissue-type plasminogen activator [rt-PA]) and those who were treated with primary percutaneous transluminal coronary angioplasty (PTCA). Demographic, therapeutic, and outcome data from patients with AMI were collected at > 1,000 hospitals in the United States in collaboration with National Registry of Myocardial Infarction-2. Of the 45,925 patients receiving reperfusion therapy, 2,544 of the 39,574 treated with rt-PA (6.4%) had a history of CABG, and 375 of the 6,351 treated with primary PTCA (5.9%) had a history of CABG. Patients with a history of CABG were older, more likely to be men, and had more comorbidities, but prior CABG was still an independent predictor of mortality after multivariate regression analysis (odds ratio 1.23; 95% confidence interval 1.05 to 1.44). Among the post-CABG patients who received rT-PA or underwent PTCA, there was no significant difference in in-hospital mortality rate or the combined end point of death and nonfatal stroke. Thus, (1) prior CABG is an independent predictor of mortality, and (2) for post-CABG patients with AMI who are not in shock and who are lytic-eligible, reperfusion therapy with rt-PA and PTCA result in similar outcomes with regard to in-hospital mortality and the combined end point of death and nonfatal stroke.

Value of saphenous vein graft markers during subsequent diagnostic cardiac catheterization.

BACKGROUND: Although saphenous vein graft (SVG) markers have been available for many years, they have not been widely used in coronary artery bypass graft (CABG) surgery. This is likely due to the paucity of data regarding the utility of these markers in postsurgery cardiac catheterization. METHODS: We performed a prospective study of all post-CABG patients undergoing cardiac catheterization at Barnes-Jewish Hospital over a 6-month period to test our hypothesis that SVG markers would have a beneficial effect on these procedures. Differences in total procedure (arterial) time, time to image only the SVGs, fluoroscopy time, amount of contrast used, number of aortotomies, and number of views required were compared in patients with and without markers. RESULTS: Post-CABG patients undergoing catheterization who had markers (n = 76) required significantly less total procedure time (p = 0.007), fluoroscopy time (p = 0.02), and contrast use (p = 0.008). Even after adjusting for the numbers of SVG ostia and numbers of cine views, patients with markers still required less catheterization and fluoroscopy time (p < 0.01, p < 0.02) and time to image only the SVGs (p < 0.05) than those without markers (n = 106). CONCLUSIONS: SVG markers improve the efficiency of post-CABG catheterizations; they decrease the exposure of patients and cardiologists to ionizing radiation, and they decrease the exposure of patients to potentially toxic contrast agents. SVG markers are beneficial to the vast majority of post-CABG patients.

Clinical experience with primary percutaneous transluminal coronary angioplasty compared with alteplase (recombinant tissue-type plasminogen activator) in patients with acute myocardial infarction: a report from the Second National Registry of Myocardial Infarction (NRMI-2).

OBJECTIVES: We sought to compare outcomes after primary percutaneous transluminal coronary angioplasty (PTCA) or thrombolytic therapy for acute myocardial infarction (MI). BACKGROUND: Primary PTCA and thrombolytic therapy are alternative means of achieving reperfusion in patients with acute MI. The Second National Registry of Myocardial Infarction (NRMI-2) offers an opportunity to study the clinical experience with these modalities in a large patient group. METHODS: Data from NRMI-2 were reviewed. RESULTS: From June 1, 1994 through October 31, 1995, 4,939 nontransfer patients underwent primary PTCA within 12 h of symptom onset, and 24,705 patients received alteplase (recombinant tissue-type plasminogen activator [rt-PA]). When lytic-ineligible patients and patients presenting in cardiogenic shock were excluded, baseline characteristics were similar. The median time from presentation to initiation of rt-PA in the thrombolytic group was 42 min; the median time to first balloon inflation in the primary PTCA group was 111 min (p < 0.0001). In-hospital mortality was higher in patients in shock after rt-PA than after PTCA (52% vs. 32%, p < 0.0001). In-hospital mortality was the same in lytic-eligible patients not in shock: 5.4% after rt-PA and 5.2% after PTCA. The stroke rate was higher after lytic therapy (1.6% vs. 0.7% after PTCA, p < 0.0001), but the combined end point of death and nonfatal stroke was not significantly different between the two groups (6.2% after rt-PA and 5.6% after PTCA). There was no difference in the rate of reinfarction (2.9% after rt-PA and 2.5% after PTCA). CONCLUSIONS: These findings suggest that in lytic-eligible patients not in shock, PTCA and rt-PA are comparable alternative methods of reperfusion when analyzed in terms of in-hospital mortality, mortality plus nonfatal stroke and reinfarction.

Observations of the treatment of women in the United States with myocardial infarction: a report from the National Registry of Myocardial Infarction-I.

BACKGROUND: To determine whether there are sex differences in the demographics, treatment, and outcome of patients with acute myocardial infarction in the United States, data from the National Registry of Myocardial Infarction-I from September 1990 to September 1994 were examined. METHODS: The National Registry of Myocardial Infarction-I is a national observational database consisting of 1234 US hospitals in which each hospital submits data from each patient with acute myocardial infarction to a central data collection center. For these analyses, the following variables were examined in 354 435 patients with acute myocardial infarction: demographics; use of medical therapy including thrombolytic agents; use of procedures including cardiac catheterization, percutaneous transluminal coronary angioplasty, and coronary artery bypass surgery; length of hospital stay; adverse events (stroke, major bleeding, or recurrent myocardial infarction); and causes of death. RESULTS: In comparison with men, women experiencing acute myocardial infarction in the United States are older, with 55.7% older than 70 years. Women have a higher mortality rate than men even when controlled for age and die less often from arrhythmia but more often from cardiac rupture whether or not thrombolytic therapy is used. Treatment with aspirin, heparin, or beta-blockers is less frequent in women. When thrombolytic therapy is used, women are treated an average of almost 14 minutes later than men and experience a greater incidence of major bleeding. Cardiac catheterization, percutaneous transluminal coronary angioplasty, and coronary artery bypass surgery are used less often in women. CONCLUSIONS: Observations from the National Registry of Myocardial Infarction-I document important sex differences in demographics, treatment, and outcome of patients with acute myocardial infarction in the United States.

Use of reperfusion therapy for acute myocardial infarction in the United States: data from the National Registry of Myocardial Infarction 2.

BACKGROUND: There is clear evidence that reperfusion therapy improves survival in selected patients with an acute myocardial infarction. However, several studies have suggested that many patients with an acute myocardial infarction do not receive this therapy. Whether this underutilization occurs in patients appropriate for such therapy remains unclear. METHODS AND RESULTS: We examined the use of reperfusion therapy in patients with an acute myocardial infarction hospitalized at 1470 hospitals participating in the National Registry of Myocardial Infarction 2. We identified 84 663 patients who were eligible for reperfusion therapy as defined by diagnostic changes on the initial 12-lead ECG, presentation to the hospital within 6 hours from symptom onset, and no contraindications to thrombolytic therapy. Twenty-four percent of these eligible patients did not receive any form of reperfusion therapy (7.5% of all patients). When multivariate analyses were used, left bundle-branch block (odds ratio [OR]=0.22; 95% CI=0.20 to 0.24), lack of chest pain at presentation (OR=0.22; 95% CI=0.21 to 0.24), age >75 years (OR=0.40, 95% CI=0.36 to 0.43), female sex (OR=0.88, 95% CI=0.83 to 0.92), and various preexisting cardiovascular conditions were independent predictors that the patient would not receive reperfusion therapy. CONCLUSIONS: Reperfusion therapy may be underutilized in the United States. Increased use of reperfusion therapy could potentially reduce the unnecessarily high mortality rates observed in women, the elderly, and other patient groups with the highest risk of death from an acute myocardial infarction.

Intracoronary recombinant tissue-type plasminogen activator (rt-PA).

Intracoronary rt-PA has been used to treat patients with acute myocardial infarction primarily, after failure of intravenous thrombolytic therapy, and when angioplasty has not been technically possible. It has also been used to treat thrombotic closure complicating angioplasty, to treat nonocclusive thrombosis observed during angioplasty, and to pretreat patients with nonacute total occlusions before angioplasty. Intracoronary administration has the potential of providing high local concentrations for a given dose level and may allow lower total doses for the same degree of efficacy. More controlled data are needed on appropriate patient selection, angiographic and clinical endpoints, dose level and regimen, and comparable efficacy of rt-PA and other thrombolytic agents. However, the use of intracoronary rt-PA should be considered when intracoronary thrombus is evident and this route of administration is available.

A composite view of cardiac rupture in the United States National Registry of Myocardial Infarction.

OBJECTIVES: This study was done to determine the incidence, timing and prevalence as a cause of death from cardiac rupture in patients with acute myocardial infarction. BACKGROUND: Several clinical trials and overview analyses have suggested that the survival benefit conferred by thrombolytic therapy may be offset by a paradoxic increase in early deaths from cardiac rupture. METHODS: Demographic, procedural and outcome data from patients with acute myocardial infarction were collected at 1,073 United States hospitals collaborating in the United States National Registry of Myocardial Infarction. RESULTS: Among the 350,755 patients enrolled, 122,243 received thrombolytic therapy. In-hospital mortality for the overall patient population, those not treated with thrombolytics (n = 228,512) and those given thrombolytics were 10.4%, 12.9% and 5.9%, respectively (p<0.001). Cardiogenic shock was the most common cause of death in each patient group. Although the incidence of cardiac rupture was low (<1.0%), it was responsible for 7.3%, 6.1% and 12.1%, respectively, of in-hospital deaths (p<0.001). Death from rupture occurred earlier in patients given thrombolytic therapy, with a clustering of events within 24 h of drug administration. Despite the early risk, death rates were comparatively low in thrombolytic-treated patients on each of the first 30 days. By multivariable analysis, thrombolytics, prior myocardial infarction, advancing age, female gender and intravenous beta-blocker use were independently associated with cardiac rupture. CONCLUSIONS: This large registry experience, including over 350,000 patients with myocardial infarction, suggests that thrombolytic therapy accelerates cardiac rupture, typically to within 24 to 48 h of treatment. The possibility that rupture represents an early hemorrhagic complication of thrombolytic therapy should be investigated.

Anatomically and physiologically based reference level for measurement of intracardiac pressures.

BACKGROUND: Many reference levels have been proposed for the measurement of intracardiac pressures, but none have met with universal acceptance. In the first part of our study, we evaluated 10 cardiologists' understanding of how hydrostatic pressure influences intracardiac pressures as measured with fluid-filled catheters. In the second part, we proposed and validated a new zero level (H): the uppermost blood level in the left ventricular (LV) chamber relative to the anterior chest wall for a patient in the supine position. A comparison was made of LV minimum diastolic pressure measured by reference to H versus measurements made with the zero level at midchest. METHODS AND RESULTS: Using two-dimensional echocardiography, we determined H in the LVs of seven normal patients (five male, two female; age, 49 +/- 9 years) undergoing routine cardiac catheterization. H was determined from a left parasternal short-axis view and calculated as the average distance between end diastole and end systole of the endocardium of the uppermost segment of the LV anterior wall below the fourth or fifth intercostal space of the left sternal border on the anterior surface of the chest wall, with the patient in the supine position. A micromanometer/fluid-filled lumen catheter was then positioned in the LV, and we compared the micromanometer LV minimum pressure (LVPmin) obtained when the reference fluid-filled transducer was aligned at midchest with the LVPmin obtained when the reference fluid-filled transducer was aligned at H. LVPmin referenced to a midchest fluid-filled external transducer was measured as 5.1 +/- 1.6 mm Hg (range, 2.4 to 7.2 mm Hg) versus -0.6 +/- 0.6 mm Hg (range, -1.6 to 0.4 mm Hg) when referenced to H (P < .001). A significant linear relation was found to exist between patient anterior-posterior chest diameter and the magnitude of hydrostatic pressure influences related to pressure referenced at midchest (r = .88; P < .01). CONCLUSIONS: External fluid-filled transducers should be used with the goal of removing hydrostatic pressure and other influences so that the presence of subatmospheric pressure during diastole in any of the cardiac chambers is accurately measured. To achieve this goal, intracardiac pressure should be referenced to an external fluid-filled transducer aligned with the uppermost blood level in the chamber in which pressure is to be measured. The current practice of referencing the zero level of LV diastolic pressure to an external fluid-filled transducer positioned at the midchest level results in systematic overestimation due to hydrostatic effects and produces physiologically significant error in the measurement of diastolic intracardiac pressure.

Treatment of myocardial infarction in the United States (1990 to 1993). Observations from the National Registry of Myocardial Infarction.

BACKGROUND: Multiple clinical trials have provided guidelines for the treatment of myocardial infarction, but there is little documentation as to how consistently their recommendations are being implemented in clinical practice. METHODS AND RESULTS: Demographic, procedural, and outcome data from patients with acute myocardial infarction were collected at 1073 US hospitals collaborating in the National Registry of Myocardial Infarction during 1990 through 1993. Registry hospitals composed 14.4% of all US hospitals and were more likely to have a coronary care unit and invasive cardiac facilities than nonregistry US hospitals. Among 240,989 patients with myocardial infarction enrolled, 84,477 (35.1%) received thrombolytic therapy. Thrombolytic recipients were younger, more likely to be male, presented sooner after onset of symptoms, and were more likely to have localizing ECG changes. Among the 60,430 patients treated with recombinant tissue-type plasminogen activator (rTPA), 23.2% received it in the coronary care unit rather than in the emergency department. Elapsed time from hospital presentation to starting rTPA averaged 99 minutes (median, 57 minutes). Among patients receiving thrombolytic therapy, concomitant pharmacotherapy included intravenous heparin (96.9%), aspirin (84.0%), intravenous nitroglycerin (76.0%), oral beta-blockers (36.3%), calcium channel blockers (29.5%), and intravenous beta-blockers (17.4%). Invasive procedures in thrombolytic recipients included coronary arteriography (70.7%), angioplasty (30.3%), and bypass surgery (13.3%). Trend analyses from 1990 to 1993 suggest that the time from hospital evaluation to initiating thrombolytic therapy is shortening, usage of aspirin and beta-blockers is increasing, and usage of calcium channel blockers is decreasing. CONCLUSIONS: This large registry experience suggests that management of myocardial infarction in the United States does not yet conform to many of the recent clinical trial recommendations. Thrombolytic therapy is underused, particularly in the elderly and late presenters. Although emerging trends toward more appropriate treatment are evident, hospital delay time in initiating thrombolytic therapy remains long, aspirin and beta-blockers appear to be underused, and calcium channel blockers and invasive procedures appear to be overused.

Clinical benefits of thrombolytic therapy in acute myocardial infarction.

The value of coronary artery reperfusion resulting from pharmacologically induced fibrinolysis in patients with evolving myocardial infarction has been rigorously evaluated. Improved left ventricular function and even more impressive improvements in survival rates have been demonstrated consistently in controlled studies. Benefit is related to the restoration of myocardial blood flow. Maximal benefit is achieved with early and sustained restoration of coronary artery patency. Benefits observed during initial hospitalization are sustained for at least 1 year in the majority of patients, even without subsequent mechanical revascularization. To date, analysis of subgroups has not identified a population of patients with evolving infarction that should routinely be excluded from consideration for thrombolysis. As with many potent pharmacologic agents, activators of the fibrinolytic system are associated with a degree of risk whenever they are administered to a patient. Therefore, patients must be assessed carefully prior to initiating treatment, especially for potential bleeding hazards, and appropriate follow-up evaluation and concomitant therapy needs to be planned. However, given the overwhelming body of data now available regarding its benefits and relative safety, thrombolysis should be considered as conventional therapy for patients with acute evolving myocardial infarction (AMI).

Tissue-type plasminogen activator: intracoronary applications.

Intracoronary tissue-type plasminogen activator (t-PA) was employed successfully before, after, or in place of coronary artery angioplasty in four patients referred for emergency cardiac catheterization during evolving myocardial infarction. The potential roles of intracoronary thrombolysis, dose considerations for intracoronary t-PA, factors influencing the choice of plasminogen activator, and safety issues are discussed.

Factors contributing to the emergence of coronary thrombolysis.

Coronary thrombosis is now recognized as the most common proximate cause of acute myocardial infarction, and thrombolysis is evolving as an accepted therapeutic approach to patients presenting in the early stages of myocardial infarction. The ascent of thrombolysis in treatment hierarchies reflects multiple factors, including improved understanding of the pathophysiology of myocardial infarction, advances in the characterization of thrombosis and thrombolysis, the availability of clot-selective thrombolytic agents, the widespread availability of safe arteriographic procedures, and the contemporaneous development of effective percutaneous balloon angioplasty. Selection of patients most likely to benefit from thrombolysis with the lowest risk for complications remains difficult. Undoubtedly, some patients will benefit greatly from an aggressive approach to evolving myocardial infarction.

Sustained fibrinolysis after administration of t-PA despite its short half-life in the circulation.

To characterize the duration of the fibrinolytic response to tissue-type plasminogen activator (t-PA) and streptokinase (SK) in patients with acute myocardial infarction we serially assayed crosslinked fibrin degradation products (XL-FDP) and B beta 15-42 fibrinopeptide. Use of specific monoclonal antibodies permitted quantification and differentiation of fibrin from fibrinogen degradation products. Marked elevations of XL-FDP occurred within 1 hour after administration of t-PA (n = 13) or SK (n = 35) to greater than 1000 ng/ml in 79% of the patients. All patients given t-PA exhibited elevations of XL-FDP greater than 1000 ng/ml, most exhibited values greater than 5000 ng/ml (79% of patients). In contrast 6 of the patients given SK failed to exhibit XL-FDP greater than 1000 ng/ml. XL-FDP greater than 5000 ng/ml occurred in only 14%. The difference in the response to t-PA compared to SK was particularly striking 7 hours or more after administration of activator at which time XL-FDP were markedly elevated in patients given t-PA (5821 +/- 1683 ng/ml) compared with decreasing values in patients given SK (2924 +/- 1186 ng/ml) (p less than 0.01). Levels of B beta 15-42 were significantly higher after t-PA compared with SK beginning 3 hours after treatment, consistent with a greater intensity of fibrinolytic response to t-PA. Marked elevations of this short lived degradation product of fibrin (t 1/2 = 10-20 minutes) in the samples drawn late after administration of t-PA (44.3 +/- 12.8 nM) but not after SK (11.7 +/- 4.5 nM) confirmed prolonged fibrinolytic activity of plasmin after t-PA.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacodynamics of tissue-type plasminogen activator characterized by computer-assisted simulation.

Prospective characterization of pharmacodynamics of tissue-type plasminogen activator (t-PA) is needed for diverse clinical applications. Accordingly, we used physiologically based, computer simulation of participating biochemical reactions in response to concentrations of circulating t-PA seen with infusions of 1 to 7 hr duration in 45 patients. Predicted values were compared with those from a "training set" obtained in six patients given t-PA for coronary thrombosis and six receiving therapy for peripheral arterial occlusion. Subsequently, results of simulation were compared prospectively with observations from a "test set" of 33 consecutive patients given low doses of t-PA for as long as 7 hr or higher doses for 1 to 2 hr and with data from 101 patients given t-PA in the European Cooperative Trial. Fits between observed and predicted values were close. Based on observations in the training set, the alpha 2-macroglobulin reaction with circulating plasmin and ongoing synthesis of plasminogen were incorporated in the simulations. Fibrinogenolysis in vitro was documented despite supplementation of samples with aprotinin, particularly when concentrations of t-PA were high. This phenomenon can lead to overestimation of fibrinogen depletion and was found to be obviated by the use of PPACK, a novel serine protease inhibitor. Results indicate that the simulation approach developed permits economic, prospective evaluation of regimens of t-PA suitable for diverse conditions and delineation of the impact of individual constituents and reactions on pharmacodynamics of t-PA and on the risk of induction of a systemic lytic state.