Patricia G. Fitzpatrick

Multicenter reperfusion trial of intravenous anisoylated plasminogen streptokinase activator complex (APSAC) in acute myocardial infarction: Controlled comparison with intracoronary streptokinase

The recent establishment of a firm therapeutic role for reperfusion in acute myocardial infarction has stimulated interest in the development of more ideal thrombolytic agents. Anisoylated plasminogen streptokinase activator complex (APSAC) is a new plasminogen activator possessing properties that are promising for intravenous thrombolytic application in acute myocardial infarction. To assess the reperfusion potential of intravenous APSAC, a multi-center, angiographically controlled reperfusion trial was performed. An approved thrombolytic regimen of intracoronary streptokinase served as a control. Consenting patients with clinical and electrocardiographic signs of acute myocardial infarction were studied angiographically and 240 qualifying patients with documented coronary occlusion (flow grade 0 or 1) were randomized to treatment in less than 6 h of symptom onset (mean 3.4 h, range 0.4 to 6.0) with either intravenous APSAC (30 U in 2 to 4 min) or intracoronary streptokinase (160,000 U over 60 min). Both groups also received heparin for greater than or equal to 24 h. Reperfusion was evaluated angiographically over 90 min and success was defined as advancement of grade 0 or 1 to grade 2 or 3 flow. Rates of reperfusion for the two treatment regimens were 51% (59 of 115) at 90 min after intravenous APSAC and 60% (67 of 111) after 60 min of intracoronary streptokinase (p less than or equal to 0.18). Reperfusion at any time within the 90 min was observed in 55 and 64%, respectively (p less than or equal to 0.16). Time to reperfusion occurred at 43 +/- 23 min after intravenous and 31 +/- 17 min after intracoronary therapy. The success of intravenous therapy was dependent on the time to treatment: 60% of APSAC patients treated within 4 h exhibited reperfusion compared with 33% of those treated after 4 h (p less than or equal to 0.01). Reperfusion rates were also dependent on initial flow grade (p less than or equal to 0.0001): 48% (81 of 168) for grade 0 (APSAC = 43%, streptokinase = 54%), but 78% for grade 1 (APSAC = 78%, streptokinase = 77%). APSAC given as a rapid injection was generally well tolerated, although the median change in blood pressure at 2 to 4 min was greater after APSAC than after streptokinase (-10 versus -5 mm Hg). Mean plasma fibrogen levels fell more at 90 min after the sixfold higher dose of APSAC than after streptokinase (to 32 versus 64% of control). Reported bleeding events were more frequent after APSAC but occurred primarily at the site of catheter insertion and no event was intracranial.(ABSTRACT TRUNCATED AT 400 WORDS)

Normal d-dimer levels in emergency department patients suspected of acute pulmonary embolism

OBJECTIVES We sought to determine:1) whether normal D-dimer enzyme-linked immunosorbent assay (ELISA) assays predicted the absence of pulmonary embolism (PE) in the high-volume emergency department (ED) of the Brigham and Womens Hospital, and 2) whether ED physicians accepted normal D-dimer levels as confirmation of no PE without further diagnostic testing such as lung scanning, chest computed tomography (CT) scanning, or pulmonary angiography. BACKGROUND Although the plasma D-dimer ELISA is a sensitive screening test for excluding acute PE, this laboratory marker has not been widely integrated into clinical algorithms such as creatine kinase-MB fraction or troponin testing for acute myocardial infarction. METHODS We mandated that ED physicians order D-dimer ELISA tests on all patients suspected of acute PE. We reviewed the clinical record of each ED patient initially evaluated for suspected PE during the year 2000. We determined whether additional imaging tests for PE were obtained and whether the final diagnosis was PE. RESULTS Of 1,106 D-dimer assays, 559 were elevated and 547 were normal. Only 2 of 547 had PE despite a normal D-dimer. The sensitivity of the D-dimer ELISA for acute PE was 96.4% (95% confidence interval [CI]: 87.5% to 99.6%), and the negative predictive value was 99.6% (95% CI: 98.7% to >99.9%). Nevertheless, 24% of patients with normal D-dimers had additional imaging tests for PE. CONCLUSIONS The D-dimer ELISA has a high negative predictive value for excluding PE. By paying more attention to normal D-dimer results, fewer chest CT scans and lung scans will be required, and improvements may be realized in diagnostic efficiency and cost reduction.

Comparison of intravenous milrinone and dobutamine for congestive heart failure secondary to either ischemic or dilated cardiomyopathy

Milrinone and dobutamine are positive inotropic agents with beneficial hemodynamic effects in patients with congestive heart failure. This study was undertaken to compare the effects of intravenous milrinone and dobutamine in patients with stable New York Heart Association class III or IV congestive heart failure and to test the hypothesis that intravenous milrinone is at least as beneficial as dobutamine in this setting. Seventy-nine patients were randomized to either dobutamine therapy at incremental doses of 2.5, 5, 7.5, 10, 12.5 and 15 micrograms/kg/min, or milrinone as a bolus of 50 or 75 micrograms/kg followed by an infusion of 0.5 to 1.0 micrograms/kg/min. Both agents significantly increased heart rate, cardiac index and stroke volume index and decreased pulmonary artery wedge pressure and systemic vascular resistance compared with baseline levels (p less than 0.01). During sustained infusion for 48 hours, no difference in hemodynamic effects was observed between the 2 drugs. Ventricular tachycardia occurred in 5 patients (3 taking milrinone, 2 taking dobutamine); 1 patient taking milrinone had ventricular fibrillation. Milrinone and dobutamine elicited similar beneficial hemodynamic results with relatively few adverse effects.

Rapid Lysis of Coronary Artery Thrombi with Anisoylated Plasminogen: Streptokinase Activator Complex: Treatment by Bolus Intravenous Injection

The ability of anisoylated plasminogen: streptokinase activator complex (APSAC) to induce coronary artery reperfusion after bolus intravenous injection (2 to 4 minutes) was assessed in 29 patients with acute transmural myocardial infarction and complete coronary artery occlusion. A 5-mg dose resulted in reperfusion in 3 of 14 patients (21%); a 5-mg plus 10-mg regimen was successful in 3 of 7 (43%); and a 30-mg dose induced reperfusion in 9 of 15 (60%). Rethrombosis occurred in only 1 of 15 patients (7%) who received 30 mg, as determined by repeat angiography at 24 hours. The mean interval after injection until reperfusion was 35 minutes with the 30-mg dose, and bleeding occurred at the femoral artery catheterization site in only 3 of 15 patients (20%). Intracoronary streptokinase therapy achieved reperfusion in only 2 of the 6 patients in whom the 30-mg dose failed, indicating that this dose of APSAC was sufficient by itself in 9 of 11 (83%) successfully treated patients. Because therapy can be completed within 2 to 4 minutes, APSAC appears to be a most suitable fibrinolytic agent for early treatment of the coronary artery thrombosis associated with acute transmural myocardial infarction.

Relationship of the lytic state to successful reperfusion with standard- and low-dose intracoronary streptokinase.

The influence of a systemic lytic state on reperfusion obtained after intracoronary streptokinase (SK) therapy has been evaluated in 15 patients with acute myocardial infarction and complete coronary occlusion. Coronary angiographic studies and measurements of blood fibrinolytic parameters were repeated at 15 min intervals during the infusion of a standard dose of SK and were compared with the results with approximately one-tenth the standard dose. Successful reperfusion was obtained in only 20% (2/10) of patients receiving the low dose, compared with a 75% to 80% success rate in patients receiving the standard dose as initial treatment (4/5) or as follow-up treatment of patients in whom low-dose therapy failed (6/8). There was a striking association between reperfusion and development of the lytic state in that all 12 treatments resulting in reperfusion also caused a lytic state and all seven treatments that failed to produce a lytic state also failed to induce reperfusion (p less than .001). Among the successfully treated patients, the dose of SK that induced a lytic state was relatively constant. However, coronary arterial thrombi differed in susceptibility to treatment. Sensitive thrombi (5/12) dissolved before the lytic state occurred and at a lower SK dose than that needed to cause a lytic state; more resistant thrombi (7/12) required a longer time and a significantly larger SK dose to dissolve. These results indicate that intrinsic properties of the thrombus influence the rate and outcome of treatment and that a minimal dose of SK (about 200,000 U) is required to ensure lasting reperfusion in susceptible patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of reperfusion on electrocardiographic and enzymatic infarct size: results of a randomized multicenter study of intravenous anisoylated plasminogen streptokinase activator complex (APSAC) versus intracoronary streptokinase in acute myocardial infarction

The effect of early coronary artery reperfusion on ECG and enzymatic parameters was examined in 240 patients with acute myocardial infarction. These patients had participated in a randomized trial comparing intravenous anisoylated plasminogen streptokinase activator complex (APSAC) (n = 123) and intracoronary streptokinase (n = 117) therapy. Reperfusion occurred in 59 of 115 (51%) patients receiving APSAC and 67 of 111 (60%) patients receiving streptokinase (p = NS). There was greater early resolution of ST segment elevation in the reperfused than in the nonreperfused patients (p less than or equal to 0.003) and more rapid Q wave evolution (p less than or equal to 0.03). Sigma Q was lower in reperfused than in nonreperfused patients at 8 hours (1.41 +/- 1.18 versus 2.11 +/- 2.10 mV; p less than or equal to 0.05) and at 24 hours (1.43 +/- 1.25 mV versus 2.08 +/- 1.88 mV; p less than or equal to 0.02). Time to peak level was shorter in the reperfused patients for creatine kinase (CK) (10.7 +/- 5.5 hours versus 14.9 +/- 5.9 hours; p less than 0.0001) and lactic acid dehydrogenase (LDH) (29.6 +/- 13.6 hours versus 34.4 +/- 10.5 hours; less than or equal to 0.03) enzymes. Peak LDH-1 was lower in the reperfused group (274 +/- 149 U/L versus 341 +/- 173 U/L; p less than or equal to 0.04). Reperfusion at a mean of 3.9 hours after the onset of infarction was associated with more rapid resolution of ST segment elevation, faster Q wave evolution, smaller ECG infarct size, earlier cardiac enzyme release, and smaller enzymatic infarct size than later or no reperfusion.

Dependence of assessment of coronary artery reperfusion during acute myocardial infarction on angiographic criteria and interobserver variability

The angiographic films of 240 patients with acute myocardial infarction were studied in a randomized trial of intravenous anisoylated plasminogen streptokinase activator complex (APSAC) versus intracoronary streptokinase therapies. The interobserver variability of grading coronary artery perfusion by the Thrombolysis in Myocardial Infarction Study Group (TIMI) criteria was measured as well as the effect of different definitions of reperfusion on the determination of reperfusion rate. There was good agreement in the reading of infarct artery flow grades between 2 blinded observers for each grade considered separately (k = 0.726 +/- 0.014) and for grades 0 or 1 (no perfusion) versus grades 2 or 3 (perfusion) (k = 0.905 +/- 0.011). Discordance between grades 0 or 1 versus 2 or 3 occurred in 74 (5%) of the 1,615 angiographic readings. Discrepancies of clinical significance which affected qualification for study entry, reperfusion or reocclusion status occurred in only 15 patients (6%). Grade 1 flow was found to have the most variable interpretation. Reperfusion rates for APSAC and streptokinase differed significantly when reperfusion was defined by 3 different criteria. The reperfusion rate ranged from 51 to 72% for APSAC and from 60 to 75% for streptokinase depending upon criteria selected. For comparison of the results of different thrombolytic studies, a standard semiquantitative system for grading infarct artery perfusion should be used, readings should be blinded and the criteria used for the definition of reperfusion should be clearly specified.

Use of thrombolytic therapy for acute myocardial infarction: effects of gender and age on treatment rates.

AbstractBackground: Although there have been efforts to increase the utilization of thrombolytic therapy, there are still many patients who might benefit from this treatment who do not receive it. Women and the elderly have been particularly undertreated, despite evidence that their survival can be improved with thrombolysis. This study was undertaken to determine the relative rates of treatment of women vs. men and the elderly vs. younger subjects and to examine factors that might explain differences in treatment frequency. Methods and Results: This is a retrospective study of patients who presented to the Emergency Departments of four local hospitals in 1993 and 1994 with evidence for acute ST-elevation myocardial infarction. Demographic data, past medical history, information on co-morbid illnesses, and times to hospital arrival, first electrocardiogram, physician notification, and thrombolytic therapy were recorded as was survival to hospital discharge. Data for patients who did or did not receive thrombolytic therapy were compared. Men were treated more frequently in both tertiary and community hospitals. Women were older, but within each age bracket, men were treated more often. The time of arrival was similar for men and women, but men who arrived within 6 hours or 6–12 hours after pain onset were treated at a higher rate than women. For patients without contraindications, treatment was not affected by gender or age. However, treatment rates decreased with increased prevalence of exclusionary factors, and since both women and the elderly tended to have more such factors, elderly women were treated at a markedly lower rate. The single clinical factor that increased thrombolytic usage in women compared to men was a history of prior myocardial infarction. Conclusion: Despite convincing evidence that thrombolytic therapy is beneficial in women and the elderly, these groups have been relatively neglected unless attention is called to clinical risk, for example, by history of prior myocardial infarction.

Hemodynamic and regional blood flow response to milrinone in patients with severe congestive heart failure: A dose-ranging study

This study was undertaken to assess the hemodynamic efficacy, changes in regional blood flow, and safety of milrinone over a range of intravenous bolus injections (12.5 to 125 micrograms/kg), a continuous 18-hour infusion (0.2 to 0.7 microgram/kg/min), and following oral administration. All eighteen patients with New York Heart Association class III or IV congestive heart failure demonstrated hemodynamic improvement following intravenous bolus therapy. Dose-related increases in cardiac index occurred, ranging from a 12 +/- 6% increase following a 12.5 micrograms/kg bolus to a 37 +/- 10% increase after 75 micrograms/kg. Pulmonary wedge pressure fell 17 +/- 5% following 12.5 micrograms/kg and 28 +/- 9% following 75 micrograms/kg. Little change was apparent during the continuous infusion except for a late increase in cardiac index, but similar changes occurred in response to a single oral dose. Forearm blood flow increased significantly after 3 hours in the two higher infusion groups, but there was no consistent change in hepatic blood flow. We conclude that hemodynamic parameters and forearm blood flow are improved in patients with severe congestive heart failure following intravenous and short-term oral milrinone therapy.

Relation of plasma D-dimer concentrations to coronary artery reperfusion before and after thrombolytic treatment in patients with acute myocardial infarction☆

This study was designed to investigate the possible role of pre- and posttreatment plasma D-dimer concentration as a reflection of coronary artery thrombolysis. Blood was collected from 206 patients with angiographically documented acute coronary occlusion presenting within 6 hours of symptom onset who were enrolled in a prospective study comparing intravenous APSAC (30 U) (IV-APSAC) with intracoronary streptokinase (160,000 U) (IC-SK). D-dimer concentrations in 104 patients after IV-APSAC therapy were higher than in 90 patients after IC-SK (mean +/- standard error, 1,009 +/- 60 vs 603 +/- 45, p less than 0.001), but there was no difference in patients with and without reperfusion (1,096 +/- 88 vs 875 +/- 67, p = 0.1 for IV-APSAC, and 587 +/- 48 vs 634 +/- 95, p = 0.6 for IC-SK). The median concentrations before treatment were similar in the IV-APSAC and IC-SK groups (93 and 90 ng/ml, respectively). These were higher than the value in 25 ambulatory control subjects (72 ng/ml) but lower than in 29 post-AMI (6 to 30 hours) patients and in preoperative orthopedic patients (140 ng/ml each). There was no difference in D-dimer concentrations in patients with grade 0 or grade 1 coronary artery occlusion (median 85 vs 90 ng/ml) or in patients with or without ultimate successful reperfusion (median 85 vs 93 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)