Tolerance and complications in a multicenter trial of intravenous APSAC and intracoronary streptokinase in acute myocardial infarction.

Adverse events data of a randomized, multicenter, angiographically controlled trial of intracoronary streptokinase and intravenous anistreplase, or anisoylated plasminogen streptokinase activator complex (APSAC) are presented. The frequency of severe adverse events is similar for streptokinase and anistreplase; no unexpected adverse experiences were reported with either drug. The most frequently encountered side effect was bleeding, overwhelmingly from the groin puncture site from angiography.

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)

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.

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)

Cardiac output by rebreathing in patients with cardiopulmonary diseases.

Noninvasive estimates of cardiac output by rebreathing soluble gases (Qc) can be unreliable in patients with cardiopulmonary diseases because of uneven distribution of ventilation to lung gas volume and pulmonary blood flow. To evaluate this source of error, we compared rebreathing Qc with invasive measurements of cardiac output performed by indicator-dilution methods (COID) in 39 patients with cardiac or pulmonary diseases. In 16 patients with normal lung volumes and 1-s forced expiratory volumes (FEV1), Qc measured with acetylene [Qc(C2H2)] overestimated COID insignificantly by 2 +/- 9% (SD). In subjects with mild to moderate obstructive lung disease, Qc(C2H2) slightly overestimated COID by 6 +/- 15% (P = 0.11). In patients with restrictive disease or combined obstructive and restrictive disease, Qc(C2H2) underestimated COID significantly by 9 +/- 14% (P less than 0.04). The magnitude of the discrepancy between Qc and COID correlated with size of the volume rebreathed and an index of uneven ventilation calculated from helium mixing during rebreathing that determined a dead space to inspired volume ratio (VRD/VI). Rebreathing volumes less than 40% of the predicted FEV or VRD/VI of 0.4 or greater identified all subjects with a discrepancy between Qc(C2H2) and COID of 20% or greater.

Dose-ranging studies of anisoylated plasminogen streptokinase activator complex. Studies in healthy volunteers and in patients with acute myocardial infarction.

Anisoylated plasminogen streptokinase activator complex (APSAC) is well tolerated when given as an intravenous bolus dose over 2 to 4 minutes. The intravenous administration of 30U was rapidly effective in patients with coronary artery occlusion, with 82% of successfully treated patients responding to the initial APSAC dose after a mean time of about 30 minutes. The plasma fibrinogen and plasminogen concentrations decreased in all patients receiving APSAC 30U, which indicates that APSAC at this dose is not sufficiently fibrin-specific to dissolve thrombi without producing a lytic state. Side effects, complications and mortality were as expected for thrombolytic agents, with only 1 bleeding episode other than at the catheterisation site. Thus, APSAC offers unique advantages of rapid and simple bolus intravenous administration, with reperfusion rates achieved that are similar to those expected for intracoronary streptokinase and for intravenous tissue plasminogen activator.

Comparative tolerance and complications in a multicentre trial of intracoronary streptokinase and intravenous anisoylated plasminogen streptokinase activator complex in acute myocardial infarction.

The safety and tolerance data of the preliminary results of a randomised, parallel group, multicentre trial of intracoronary streptokinase and intravenous anisoylated plasminogen streptokinase activator complex (APSAC) in patients with myocardial infarction are presented. The frequency of side effects was similar in the 2 groups. The most frequently encountered side effect was bleeding, overwhelmingly from the groin puncture site from angiography. There was no significant difference between amount or incidence of bleeding complications between the two groups, as measured by number of bleeding episodes, transfusion requirements, or mean drop in haematocrit or haemoglobin.

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.

Hemodynamic and respiratory effects of dezocine, ciramadol, and morphine.

The hemodynamic and respiratory effects of dezocine and ciramadol, two agonist-antagonist analgesics, were compared with those of morphine in 30 patients undergoing diagnostic cardiac catheterization. Each subject received a single intravenous dose of dezocine (0.125 mg/kg), ciramadol (0.6 mg/kg), or morphine (0.125 mg/kg) in a double-blind fashion. Hemodynamic and respiratory parameters were measured at baseline and 5, 10, and 20 minutes after dosing. Dezocine increased the cardiac index (CI; 2.67 to 2.92 L/min/m2), stroke volume index (SVI; 43.6 to 47.6 ml/beat/m2), left ventricular stroke work index (LVSWI; 57.4 to 64.7 gm-m/m2), and pulmonary vascular resistance (PVR; 105.6 to 154.0 dynes X sec/cm5). Ciramadol increased the CI (2.78 to 3.22 L/min/m2), SVI (40.9 to 48.2 ml/beat/m2), LVSWI (51.1 to 57.9 gm-m/m2), and mean pulmonary arterial pressure (PA; 14.7 to 18.9 mm Hg). Morphine had no effect on CI, SVI, LVSWI, PA, or PVR, but it significantly lowered systolic and diastolic blood pressures. There were no appreciable changes in heart rate, left ventricular end-diastolic pressure, mean arterial pressure, or mean pulmonary capillary wedge pressure after any of the drugs. All three drugs significantly decreased systemic vascular resistance. There were no clinically significant changes in respiratory parameters. We conclude that dezocine, ciramadol, and morphine have no clinically important adverse effects on cardiac performance.

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)

Activities of some enzymes in serum after therapy with intracoronary streptokinase in acute myocardial infarction.

Enzyme kinetics for creatine kinase (CK), CK-MB, aspartate aminotransferase (AST), and lactate dehydrogenase (LD) in serum were followed in 14 patients who had suffered acute myocardial infarction and who were given intracoronary streptokinase shortly (mean 4.9 h, SD 2.6 h) after onset of symptoms. In the 10 patients for whom thrombolysis was successful, CK activity peaked earlier (12.8 vs 21.6 h) and at higher values (3548 vs 2436 U/L) than in the four patients for whom the treatment was unsuccessful. The mean maximum rate of increase in CK was threefold greater in the former group (574 vs 169 U/L per hour), but the total amount of CK released into the circulation and the fractional disappearance rates were similar for both groups. The profiles for AST and CK-MB for successfully treated patients closely resembled those for CK. LD, however, peaked significantly later than CK (25.7 vs 12.8 h). Early peaking of CK or CK-MB after nonsurgical reperfusion can be potentially useful as a noninvasive in vitro index to the success of therapy of myocardial infarction with thrombolytic agents.

Clinical evaluation of a radiometric assay specific for creatine kinase isoenzyme MB.

A new radiometric assay specific for creatine kinase isoenzyme MB was evaluated with respect to its precision and agreement with a conventional electrophoretic CK-MB assay for the diagnosis of myocardial infarction. The reference interval we find for serum CK-MB in healthy subjects is 0--30 micrograms/L. The coefficients of variation at 197 and 40 micrograms of CK-MB per liter, were 5.2 and 11.5%, respectively. In a clinical study of 52 consecutive patients admitted into a Coronary Care Unit with a diagnosis of suspected myocardial infarction, there was overall agreement in CK-MB results by the two assays for 51 of 52 patients. A more sensitive and quantitative assay that is specific for CK-MB can be helpful in cases where diagnosis of myocardial infarction is equivocal.