Toxicology studies with recombinant staphylokinase and with SY 161-P5, a polyethylene glycol-derivatized cysteine-substitution mutant.

SY 161-P5, a polyethylene glycol derivatized (PEGylated) mutant of the recombinant Staphylokinase (rSak) variant SakSTAR, exhibiting reduced antigenicity is in clinical development for treatment of acute myocardial infarction as a single bolus injection. A series of safety studies were performed in vivo as a routine toxicology program with SY 161-P5 (PEG-rSakSTAR) and with the recombinant Staphylokinase variant Sak42D (rSak42D). For both compounds, intravenous single bolus injections of up to 100-fold therapeutic equivalent, as well as repeated injections during 7 to 28 days revealed no significant pathological findings in mice, rats or hamsters. However, New Zealand white rabbits developed clinically silent, multifocal myocarditis following single or repeat doses of SY 161-P5 or of Sak42D. These findings were dose-independent and reversible. A similar species-specific cardiotoxic effect has previously been described for other proteolytic proteins, including the approved drugs Streptokinase and Acetylated Plasminogen Streptokinase Complex (APSAC). The large experience with these drugs, as well as the clinical data accumulated both with PEGylated and non-PEGylated rSak variants to date, do not indicate cardiotoxic hazards associated with the use of these drugs in humans.

Differential inhibition of thrombin activity and thrombin generation by a synthetic direct thrombin inhibitor (napsagatran, Ro 46-6240) and unfractionated heparin in patients with deep vein thrombosis. ADVENT Investigators.

BACKGROUND: Direct thrombin inhibitors belong to a new class of antithrombotic drugs whose effects on blood coagulation in vivo in patients suffering from acute thrombotic conditions have not yet been fully explored. METHODS AND RESULTS: One hundred and five patients with acute proximal deep-vein thrombosis were randomized to receive a continuous intravenous infusion of napsagatran, a novel synthetic thrombin inhibitor, at a fixed dose of 5 mg/h (n = 36) or 9 mg/h (n = 25) for five days, or APTT-adjusted unfractionated heparin (UFH, n = 44) for the same time. In these patients, thrombin activity and thrombin generation could be assessed by measuring thrombin-antithrombin III complexes (TAT) and prothrombin fragment 1+2 (F1+2), respectively, on three occasions. At baseline, TAT and F1+2 did not differ among the three groups. On Day 2 (steady state), TAT significantly decreased in all groups, and the decrease was significantly more pronounced in the patients given higher-dose napsagatran. F1+2 decreased significantly only in UFH-treated patients. Two hours after cessation of the infusion, the TAT levels increased in the two napsagatran groups but not in the UFH group, whilst F1+2 went back to the baseline levels in the napsagatran-treated patients but remained low in the UFH-treated patients. There was no rebound effect. CONCLUSIONS: The data presented suggest that direct thrombin inhibition with napsagatran at 9 mg/h is more potent than UFH in attenuating thrombin activity, but is less potent than UFH in inhibiting thrombin generation. The real significance of these findings will have to be substantiated in further trials with clinically relevant endpoints.

An exploratory trial of two dosages of a novel synthetic thrombin inhibitor (napsagatran, Ro 46-6240) compared with unfractionated heparin for treatment of proximal deep-vein thrombosis -- results of the European multicenter ADVENT trial.

One hundred and ten patients with acute proximal deep-vein thrombosis were randomized in a sequential dose-finding design, to receive continuous intravenous infusion of napsagatran, a novel synthetic thrombin-inhibitor, at a fixed dose of 5 mg/h (n = 37) or 9 mg/h (n = 26), or APTT-adjusted unfractionated heparin (n = 47). Oral anticoagulants were started on the 2nd day and the study drug was discontinued from the 5th treatment day, as soon as the International Normalized Ratio was above 2. Control venogram (97 venogram pairs evaluable) after 5-8 days of treatment showed improvement in 3 napsagatran-treated patients (versus none in heparin-treated patients) and worsening in 4 napsagatran-treated patients (versus 2 in heparin-treated patients). The venographic Marder's score did not change among the treatment groups. New lung scan perfusion defects (99 scintigram pairs evaluable) occurred in 4 (11%), 4 (21%), and 4 (10%) patients in the napsagatran (5 mg/h) group, in the napsagatran (9 mg/h) group, and in the heparin control group, respectively. There was no statistically significant difference in any of these endpoints between the 3 groups. No major bleeding was observed and the rare minor bleedings occurred at a similar rate in the three treatment groups. In conclusion, the ADVENT trial has shown data that suggest comparable efficacy and safety of a synthetic, direct thrombin inhibitor (napsagatran) and conventional heparin therapy for treatment of proximal DVT. These results suggest that synthetic direct thrombin inhibitors are a promising class of antithrombotic agents which deserves further development in this field.

Platelet membrane receptor glycoprotein IIb/IIIa antagonism in unstable angina. The Canadian Lamifiban Study.

BACKGROUND: Ligand binding to the platelet membrane receptor glycoprotein (GP) IIb/IIIa, the final and obligatory step to platelet aggregation, can now be inhibited by pharmacological agents. This study was designed to evaluate the potential of lamifiban, a novel nonpeptide antagonist of GP IIb/IIIa, for the management of unstable angina. METHODS AND RESULTS: In a prospective, dose-ranging, double-blind study, 365 patients with unstable angina were randomized to an infusion of 1, 2, 4, or 5 micrograms/min of lamifiban or of placebo. Treatment was administered for 72 to 120 hours. Outcome events were measured during the infusion period and after 1 month. Concomitant aspirin was administered to all patients and heparin to 28% of patients. Lamifiban, all doses combined, reduced the risk of death, nonfatal myocardial infarction, or the need for an urgent revascularization during the infusion period from 8.1% to 3.3% (P = .04). The rates were 2.5%, 4.9%, 3.3%, and 2.4% with increasing doses. At 1 month, death or nonfatal infarction occurred in 8.1% of patients with placebo and in 2.5% of patients with the two high doses (P = .03). The highest dose of lamifiban additionally prevented the need for an urgent intervention. Lamifiban dose-dependently inhibited platelet aggregation. Bleeding times were significantly prolonged with platelet inhibition of > 80%. Major (but neither life-threatening nor intracranial) bleedings occurred in 0.8% of patients with placebo and 2.9% with lamifiban. CONCLUSIONS: The nonpeptide GP IIb/IIIa antagonist lamifiban protected patients with unstable angina from severe ischemic events during a 3- to 5-day infusion and reduced the incidence of death and infarction at 1 month, suggesting considerable promise for this new therapeutic approach.

Comparative effects of enoxaparin and heparin on arterial and venous clot lysis with alteplase in dogs.

The effects of Enoxaparin with a specific anti-thrombin (anti-IIa) activity of 32 U/mg and a specific anti-factor-XA (anti-Xa) activity of 96 U/mg, and of heparin with a specific anti-IIa and anti-Xa activity of 192 U/mg, on thrombolysis with alteplase (Actilyse) were compared in a randomized blinded study using a combined arterial and venous thrombosis model in the dog. All dogs received an intravenous bolus of 5 mg/kg lysine-acetyl salicylate and 0.5 mg/kg alteplase over 60 min. Twenty-eight dogs were randomly assigned to seven treatment groups: placebo, Enoxaparin 1.5, 3 or 6 mg/kg, or heparin 0.5, 1 or 2 mg/kg, given as a 50% intravenous bolus and a 50% infusion over 2 h. Steady-state plasma levels ranged from 0.37 to 1.0 anti-IIa U/ml and 0.9 to 3.1 anti-Xa U/ml for Enoxaparin and from 0.4 to 2.3 anti-IIa U/ml and 0.42 to 3.2 anti-Xa U/ml for heparin. The activated thromboplastin time with 6 mg/kg Enoxaparin prolonged to 94 +/- 19 s and with 2 mg/kg heparin to > 150 s. The time to reflow was 120 +/- 36 min with placebo, 19 +/- 5 min with 6 mg/kg Enoxaparin (p = 0.03 vs control), and 22 +/- 5 min with 2 mg/kg of heparin (p = 0.03 vs control). Arterial patency, expressed in min reflow during the 180 min observation period correlated significantly with the dose of anticoagulant given (r = 0.73, p = 0.003 for Enoxaparin and r = 0.61, p = 0.012 for heparin).(ABSTRACT TRUNCATED AT 250 WORDS)

Correlation between level of heparinization and patency of the infarct-related coronary artery after treatment of acute myocardial infarction with alteplase (rt-PA).

BACKGROUND AND OBJECTIVES: The conjunctive use of intravenous heparin may influence the efficacy of alteplase for coronary thrombolysis in patients with acute myocardial infarction. In this study we examined the relation between the level of intravenous anticoagulation with heparin and sustained coronary artery patency in a subgroup of patients of the European Cooperative Study Group (ECSG) trial. METHODS: In the ECSG trial, patients treated with alteplase and aspirin were randomized to concomitant fixed doses of intravenous heparin (a bolus dose of 5,000 U followed by a continuous infusion of 1,000 U/h or placebo). The current study group comprised 149 of 324 ECSG patients allocated to heparin therapy and 132 of 320 ECSG patients allocated to placebo administration who had both an interpretable coronary angiogram obtained within 6 days of treatment and sufficient plasma samples to assess the level of anticoagulation. Activated partial thromboplastin times, fibrinogen and D-dimer levels were determined on plasma samples at baseline and at 45 min and 3, 12, 24 and 36 h after the start of alteplase administration. RESULTS: The coronary artery patency rate was higher in patients allocated to heparin therapy than in those allocated to placebo (80% and 71%, respectively, p = 0.05). Patients allocated to heparin were classified into three subgroups: 48 patients (32%) with all activated partial thromboplastin times at least twice their own baseline value (optimal anticoagulation), 40 patients (27%) with the lowest activated partial thromboplastin time at 3, 12, 24 or 36 h between 130% and 200% of the baseline value (suboptimal anticoagulation) and 61 patients with at least one activated partial thromboplastin time less than 130% of baseline (inadequate anticoagulation). In the heparin group, coronary artery patency correlated with the level of anticoagulation: 90%, 80% and 72%, respectively, in patients with optimal, suboptimal and inadequate anticoagulation (p = 0.02, optimal vs. inadequate anticoagulation). Heparin administration was associated with a smaller reduction in fibrinogen and a smaller increase in D-dimer level during and after alteplase administration. No correlation was found between fibrinogen or D-dimer levels and coronary artery patency. No intracerebral hemorrhage occurred in these patients; however, bleeding was more frequent in the subgroup with optimal anticoagulation (p = 0.05). CONCLUSIONS: Intense anticoagulation with intravenous heparin enhances coronary artery patency after alteplase treatment of acute myocardial infarction.

G4120, an Arg-Gly-Asp containing pentapeptide, enhances arterial eversion graft recanalization with recombinant tissue-type plasminogen activator in dogs.

The effects of G4120, a cyclic Arg-Gly-Asp (RGD) containing peptide which inhibits fibrinogen binding to the platelet receptor GPIIb/IIIa, on thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) were investigated in a combined arterial and venous thrombosis model in heparinized dogs. The arterial thrombus model consisted of a 3 cm everted (inside-out) carotid arterial segment inserted into a transsected femoral artery which occludes within 30 min with platelet-rich material and which is resistant to recanalization with 0.5 mg/kg rt-PA. The venous thrombus was a 125I-fibrin labeled whole blood clot produced in the contralateral femoral vein. In 5 dogs given an intravenous bolus of 0.05 mg/kg G4120 followed by a continuous infusion of 0.05 mg/kg per hour for 3 h (group I), arterial occlusion persisted throughout a 4 h observation period and was still present at 24 h in all dogs; the extent of venous clot lysis after 120 min was 27 +/- 7%. In 5 dogs given the same infusion of G4120 in combination with 0.5 mg/kg rt-PA over 60 min, recanalization of the arterial graft occurred in all dogs, within 13 +/- 2 min and persisted throughout the observation period of 4 h (p = 0.01 versus G4120 or rt-PA alone); at 24 h, however, all grafts were occluded. Venous clot lysis in this group was 75 +/- 8% (p = 0.002 versus G4120 alone and p = NS versus rt-PA alone). Pathologic analysis revealed platelet-rich or mixed thrombus with platelet-rich and erythrocyte-rich zones.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative copper coil-induced thrombogenicity of the internal mammary, left anterior descending coronary, and popliteal arteries in dogs.

The internal mammary artery (IMA) is the graft of choice for coronary artery bypass surgery because of its resistance to atherosclerosis. Studies to elucidate the mechanism of this phenomenon have focused on vasoactive properties of the vessel wall; however, low thrombogenicity might also contribute to the protection of the IMA against atherosclerosis. To test this hypothesis, copper coils 3 mm long were introduced in 14 heparinized dogs into both the IMA and the left anterior descending coronary artery (LAD) (n = 7) or into both the IMA and the popliteal artery (POP) (n = 7). Arterial patency was monitored angiographically at 15-minute intervals for 4 hours. Occlusion occurred in all LADs and POPs and in 10 of the 14 IMAs. Spontaneous reflow after occlusion occurred in all IMAs and was followed by cyclic reocclusion and reflow in two animals. Short periods of reflow followed by reocclusion occurred in two of the seven LADs and three of the seven POPs. The patency status, categorized as persistent occlusion, reflow followed by reocclusion, reflow without reocclusion, or persistent patency, was significantly different between IMA and LAD (p less than 0.02) and between IMA and POP (p less than 0.04) but not between LAD and POP. Patent arteries at the end of the 4-hour period were observed in all of the 14 IMAs versus none of the seven LADs and two of the seven POPs (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma fibrinopeptide A levels in patients with acute myocardial infarction treated with alteplase. Correlation with concomitant heparin, coronary artery patency, and recurrent ischemia. The European Cooperative Study Group.

BACKGROUND: Fibrin generation during and after therapy with alteplase may depend on the level of concomitant anticoagulation. The hypothesis that fibrinopeptide A (FPA) levels, as markers of ongoing in vivo fibrin formation, correlate with the angiographic and clinical outcome of thrombolysis is tested. METHODS AND RESULTS: Serial plasma FPA levels were determined in 334 patients of the randomized European Cooperative Study Group trial comparing heparin versus placebo plus alteplase and aspirin in patients with acute myocardial infarction. Median FPA levels (with the 10th to 90th percentiles) were 21 ng/ml (2-390 ng/ml) before treatment in placebo-allocated patients (n = 166) and increased to 49 (15-580), 34 (4-320), 27 (2-240), 29 (2-430), and 30 (3-390) ng/ml after 0.75, 3, 12, 24, and 36 hours, respectively. In heparin-allocated patients (n = 168), median baseline FPA values were 18 ng/ml (2-210 ng/ml) and decreased to 6 (1-110), 5 (1-75), 5 (1-60), 7 (1-100), and 10 (1-170) ng/ml at corresponding time points (p less than 0.0001 for the difference at each time point). Adequate anticoagulation, defined as no activated partial thromboplastin time value below twice the pretreatment value at 3, 12, 24, and 36 hours after initiation of treatment, was obtained in 48 patients assigned to heparin. It was associated with normal median FPA levels (less than or equal to 4 ng/ml) at all time points compared with 12 (2-80), 16 (2-240), and 15 (2-240) ng/ml at 12, 24, and 36 hours, respectively, in heparin-assigned but inadequately anticoagulated patients (n = 102, p less than 0.001 for each time point). In the heparin-treated group, median FPA values tended to be lower at all time points in patients with patent vessels than in patients with occluded arteries, but the difference was significant only at 24 hours (p = 0.04). FPA levels did not correlate with clinically apparent recurrent ischemia or with left ventricular thrombosis on two-dimensional echocardiography. CONCLUSIONS: During and after thrombolytic therapy with alteplase, the enhanced fibrin generation is suppressed by sustained concomitant anticoagulation with intravenous heparin. Adequate anticoagulation warrants individual titration of the heparin dose. High plasma FPA levels 24 hours after alteplase therapy are specific but insensitive markers of vessel occlusion in anticoagulated patients. They do not correlate with clinical outcome.

Plasma levels of plasminogen activator inhibitor type 1, beta-thromboglobulin, and fibrinopeptide A before, during, and after treatment of acute myocardial infarction with alteplase.

Plasma levels of plasminogen activator inhibitor type-1 (PAI-1), beta-thromboglobulin (beta TG), and fibrinopeptide A (FPA) were followed over 24 hours in 30 patients treated with alteplase for acute myocardial infarction. Samples were taken at baseline (T Oh), after 90 minutes (under alteplase, no heparin, T 1.5h), after 120 minutes (under alteplase and heparin, T 2h), 30 minutes after thrombolytic therapy (T 3.5h), as well as 12 hours (T 12h) and 24 hours (T 24h) after baseline. PAI-1 antigen levels (55 +/- 9 ng/mL at T Oh, mean +/- SEM) decreased to 35 +/- 5 (T 1.5h) and 40 +/- 6 (T 2h) ng/mL under alteplase, before increasing to 84 +/- 22 (T 3.5h), 130 +/- 30 (T 12h), and 64 +/- 7 (T 24h) ng/mL after therapy, P less than .001. A high baseline PAI-1 activity (18 +/- 3 ng/mL) decreased to 2.0 +/- 0.4 (T 1.5h) and 1.7 +/- 0.2 (T 2h) under alteplase and increased to 32 +/- 5 (T 12h) and 19 +/- 3 (T 24h) ng/mL after therapy (P less than .0001). beta TG levels (339 +/- 105 ng/mL at T Oh) decreased to 203 +/- 48 (T 2h), 154 +/- 51 (T 3.5h), 187 +/- 40 (T 12h), and 142 +/- 32 (T 24h) ng/mL under heparin (P less than .01). FPA levels (34 +/- 9 ng/mL at T Oh) increased to 85 +/- 15 ng/mL under alteplase alone (T 1.5h) and normalized under heparin (11 +/- 4, 6 +/- 2, 4 +/- 2, and 3 +/- 1 ng/mL at T 2h, T 3.5h, T 12h, and T 24h, respectively). A high level of FPA at T 3.5h correlated with reocclusion (33 +/- 12 ng/mL, n = 4 v 2.9 +/- 0.5 ng/mL, n = 21, P less than .005). We conclude that plasma levels of PAI-1 antigen as well as activity markedly increase after alteplase therapy of acute myocardial infarction. The high activity of PAI-1 and decreasing beta TG levels suggest that platelets do not contribute significantly to this phenomenon. The marked increase of FPA levels under recombinant tissue-type plasminogen activator alone and its normalization under heparin emphasize the important role of concomitant anticoagulation in controlling further intravasal fibrin generation under alteplase.

Requirement of heparin for arterial and venous thrombolysis with recombinant tissue-type plasminogen activator.

The effect of concomitant intravenous (IV) heparin (200 U/kg bolus, followed by 100 U/kg/h) on the efficacy of arterial and venous thrombolysis with IV recombinant tissue-type plasminogen activator (rt-PA; 0.5 mg/kg over 1 hour) was investigated in a combined femoral arterial and venous thrombosis model in the dog. The arterial model consisted of a high-grade stenosis, endothelial damage, and a thrombotic occlusion, and the venous model consisted of a 125I-fibrin-labeled blood clot. After a dose-finding pilot study in four dogs, a randomized, prospective, and blind study was performed in 20 animals pretreated with 2.8 mg/kg IV acetyl salicylic acid (ASA). The combination of rt-PA and heparin (group I, n = 10) induced early (less than 30 minutes) arterial reperfusion in seven dogs, late (greater than 30 minutes) reflow in two dogs, and persistent occlusion in one dog. rt-PA alone (group II, n = 10) was associated with early reperfusion in one dog, late reflow in three dogs, and persistent occlusion in six dogs (P = .018). Reocclusion occurred in five of nine reperfused dogs of group I and in one of four reperfused dogs of group II (P = not significant). Venous clot lysis amounted to 81% +/- 4% (mean +/- SEM) for group I and to 49% +/- 7% for group II (P less than .001). Template bleeding times increased moderately, but significantly, in group I (from 2.2 +/- 0.2 minutes at baseline to 7.0 +/- 1.4 minutes at 30 minutes, P = .006), but only marginally in group II (from 2.2 +/- 0.2 minutes to 3.6 +/- 0.7 minutes, P = .09). No systemic fibrinogen depletion was observed. Thus, the concommitant use of heparin with rt-PA accelerates arterial reperfusion and enhances venous thrombolysis in dogs pretreated with ASA. These results, obtained in a randomized prospective study design, add to a growing body of experimental and clinical evidence, indicating that thrombolytic therapy with rt-PA requires concomitant adjunctive IV heparin for optimal efficacy, even in the face of treatment with ASA.

Thrombolytic and pharmacokinetic properties of a conjugate of recombinant single-chain urokinase-type plasminogen activator with a monoclonal antibody specific for cross-linked fibrin in a baboon venous thrombosis model.

Chemical conjugates between recombinant single-chain urokinase-type plasminogen activator (rscu-PA) and a murine monoclonal antibody directed against fragment D-dimer of cross-linked human fibrin (MA-15C5), rscu-PA/MA-15C5, and between rscu-PA and a control monoclonal antibody (MA-1C8), rscu-PA/MA-1C8, were produced by cross-linking with N-succinimidyl 3-(2-pyridyldithio) propionate (SPDP). In an in vitro system composed of a [125 I]fibrin-labeled baboon plasma clot immersed in autologous citrated plasma, dose- and time-dependent lysis was obtained with a ratio of the potencies of free and conjugated rscu-PA similar to that in human plasma: 50% lysis in 2 hours required 4.3 micrograms/ml rscu-PA, 1.0 microgram/ml urokinase-type plasminogen activator (u-PA) equivalent rscu-PA/MA-15C5, or 15 micrograms/ml u-PA equivalent rscu-PA/MA-1C8. The thrombolytic and pharmacokinetic properties of rscu-PA and of rscu-PA/MA-15C5 were compared in baboons with a 0.8-1.0 ml [125 I]fibrin-labeled autologous blood clot produced in a femoral vein. Continuous intravenous infusion of these compounds during a 2-hour period resulted in dose- and time-dependent lysis. The thrombolytic potency of rscu-PA/MA-15C5 was 3.0 +/- 0.5 times higher (50% lysis with 0.3 +/- 0.02 mg u-PA equivalent/kg body wt) than that of rscu-PA measured by ex vivo isotope recovery from the femoral vein segment (p less than 0.001) and was 2.7 +/- 0.5 times higher (50% lysis with 0.35 +/- 0.02 mg/kg rscu-PA/MA-15C5) by external radioisotope counting (p less than 0.001). A dose of 0.5 mg/kg of rscu-PA/MA-1C8 was much less active than rscu-PA. After the end of the infusion, u-PA-related antigen disappeared from plasma in a biphasic manner with an initial half-time of 2.7 +/- 0.5 for rscu-PA, 24 +/- 1.2 for rscu-PA/MA-15C5, and 21 +/- 0.5 minutes for rscu-PA/MA-1C8 with corresponding plasma clearances of 340 +/- 40, 20 +/- 3, and 24 +/- 2 ml/min, respectively. In conclusion, the increased thrombolytic potency of rscu-PA/MA-15C5 is the result of a reduction of the thrombolytic potency due to coupling of rscu-PA to the antibody molecule, which is counter-balanced by an enhancement of the thrombolytic potency due to fibrin targeting by the specific idiotype.

[The prehospital phase of acute myocardial infarct and its significance for thrombolytic therapy]. / Die Vorspitalphase des akuten Myokardinfarktes und ihre Bedeutung für die thrombolytische Therapie.

Early thrombolytic therapy has become the treatment of choice for acute myocardial infarction (AMI). Of 189 patients admitted with AMI to the CCU of Berne University Hospital in 1988, only 17 (9%) underwent thrombolytic treatment. 101 patients (53%) were admitted within 4 hours after onset of symptoms. Early arrival (less than 4 hours) was significantly more frequent among patients admitted without prior medical consultation (76%, p less than 0.001), patients less than 65 years of age (67%, p less than 0.001), patients sustaining AMI outdoors (74%, p less than 0.005) and patients without a history of typical angina (71%, p less than 0.05). In all subgroups analyzed more than half of the prehospital delay (2.8 hours) was due to the patients' indecision whether to seek medical help; prehospital consultation by a general practitioner took 66 minutes and transportation arrangements 30 minutes; in-hospital delay from admission to intensive care treatment amounted to 72 minutes (39 minutes for arrival less than 4 hours; all median times). Overall in-hospital mortality was 16.6%. Mortality during a follow-up period of 4-16 months (overall 8.4%) was higher for patients with reinfarction (15.2%, p less than 0.05) and patients arriving with a delay greater than 4 hours (12.5%, p = 0.08). Combined mortality was 25% among 172 conservatively treated patients vs 0/17 among patients undergoing thrombolytic treatment (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of intravenous bolus injection or continuous infusion of recombinant single chain urokinase-type plasminogen activator (saruplase) for thrombolysis. A canine model of combined coronary arterial and femoral venous thrombosis.

The thrombolytic efficacy of recombinant unglycosylated full length single chain urokinase-type plasminogen activator (rscu-PA, saruplase), applied either as single intravenous bolus or as a continuous infusion over 60 minutes, was studied in 5 randomized blinded groups of 5 dogs with combined copper coil induced coronary artery thrombosis and 125I-fibrin labeled femoral vein clots. Infusion of 1 mg/kg recu-PA (group I) induced coronary recanalization in 4 of 5 dogs and 98 +/- 1% (mean +/- SEM) venous clot lysis. Bolus injection of 1 mg/kg recu-PA (group II) caused reflow in 3 of 5 dogs and 88 +/- 5 percent venous clot lysis. Infusion of 0.5 mg/kg rescu-PA (group III) achieved reflow in 3 of 5 dogs and 52 +/- 6% venous clot lysis. Bolus injection of 0.5 mg/kg rscu-PA (group IV) induced reflow in 4 of 5 dogs and 48 +/- 12% venous clot lysis. Placebo infusion (group V) was associated with late recanalization in 1 of 5 dogs and 18 +/- 8% venous clot lysis. Coronary artery reocclusion after reflow was not observed in groups I and II, but occurred in 2 of 3 animals in group III and in 3 of 4 animals in group IV (P = .02). The time to reflow in responsive animals was 22 +/- 5 minutes with infusion of 0.5 or 1 mg/kg rscu-PA and 14 +/- 1 minute with bolus injection of 0.5 or 1 mg/kg (P = .14). Depletion of fibrinogen and alpha 2-antiplasmin to less than 25% of baseline levels was observed in the 5 dogs given 1 mg/kg rscu-PA by bolus and in 3 of the 5 dogs given 1 mg/kg rscu-PA via infusion, but in none of the dogs that received 0.5 mg/kg rscu-PA (P less than .001). Plasma clearance rates were 170 +/- 44 and 230 +/- 30 mL/minute after bolus injection and 190 +/- 47 and 310 +/- 56 mL/minute during infusion of rscu-PA for the 1 mg/kg and 0.5 mg/kg doses respectively. Thus, intravenous bolus injection of rscu-PA (saruplase) appears to be equipotent to an infusion over 60 minutes for both coronary and venous thrombolysis. This animal model of combined arterial and venous thrombolysis may be useful for the evaluation of new thrombolytic strategies.

Monitoring of fibrin generation during thrombolytic therapy of acute myocardial infarction with recombinant tissue-type plasminogen activator.

Fibrinopeptide A (FPA) is a very sensitive marker of fibrin generation in vivo. Because an imbalance between thrombogenic and thrombolytic forces may be responsible for the failure to recanalize and for reocclusion of coronary arteries, such a marker could be of eminent value during thrombolytic treatment of acute myocardial infarction. Thirty-four consecutive patients with acute myocardial infarction (peak creatine kinase level, 1,869 +/- 1,543 IU/l) were treated with 100 mg recombinant tissue-type plasminogen activator (rt-PA) 3.1 +/- 1.1 hours after onset of chest pain. Angiography 12.5 +/- 6.1 days later revealed an 81% patency rate of the infarct-related vessel. FPA plasma levels (normal, 1.9 +/- 0.5 ng/ml) were 34 +/- 46 ng/ml on admission and 93 +/- 86 ng/ml (538 +/- 674% with respect to each patient's admission level) after 90 minutes of rt-PA infusion (p less than 0.01). In patients without evidence of reocclusion (including three primary failures), FPA levels fell under continuous heparin infusion to 6.7 +/- 9.7 ng/ml (24 +/- 33%, p less than 0.01) within 30 minutes and were 3.1 +/- 2.2 ng/ml (15 +/- 15%, p less than 0.01), 1.6 +/- 1.1 ng/ml (8 +/- 10%, p less than 0.01), and 2.5 +/- 3.0 ng/ml (12 +/- 16%, p less than 0.01) 30 minutes, 9 hours, and 21 hours, respectively, after completion of rt-PA therapy. Five patients sustained intermittent or permanent coronary reocclusion after primary thrombolytic success. Their early postlytic FPA levels (13-51 ng/ml) remained high or increased again despite adequate anticoagulation. FPA allows the monitoring of fibrin generation during acute myocardial infarction and thrombolytic therapy. Despite successful recanalization, fibrin generation is increased under rt-PA administration before anticoagulation. Patients under anticoagulation with postlytic FPA levels less than 5 ng/ml or below their admission value seem to be at low risk of reocclusion for several days. FPA levels that are persistently high or that increase again despite adequate anticoagulation indicate ongoing fibrin generation. However, whether FPA can indeed be considered a useful marker of reocclusion remains to be confirmed in a larger population of patients with acute myocardial infarction.

Fibrin formation and platelet activation in patients with myocardial infarction and normal coronary arteries.

Coronary spasm is the mechanism most often postulated to explain the rare combination of myocardial infarction and angiographically normal coronary arteries, although the reported evidence for its role is circumstantial rather than conclusive. Whereas the importance of thrombosis in myocardial infarction is uncontested in the presence of significant coronary artery disease, there is little in vivo evidence for thrombosis in angiographically normal coronary arteries. Among 11 consecutive patients with acute myocardial infarction undergoing thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) 3.2 +/- 0.7 h after onset of chest pain, and angiography 10.2 +/- 4.5 days later, three young men had normal coronary arteries. Their cases are documented electrocardiographically, enzymatically and angiographically. Mean plasma levels of fibrinopeptide A (FPA) and beta-thromboglobulin (BTG) were clearly elevated before and during rtPA therapy: FPA 52 +/- 41 ng ml-1, BTG 257 +/- 46 ng ml-1. They did not differ significantly from corresponding mean plasma levels in the eight patients with severe coronary artery disease: FPA 67 +/- 66 ng ml-1, BTG181 +/- 75 ng ml-1. We conclude that fibrin formation and platelet activation are probably equally important in the early hours of myocardial infarction, whether or not significant coronary artery disease is present.

Restenosis and its determinants in first and repeat coronary angioplasty.

Restenosis is the main problem limiting long-term success of percutaneous transluminal coronary angioplasty (PTCA) and is most accurately evaluated by follow-up angiography. We compared the primary and long-term results of angioplasty in 268 consecutive patients (293 segments) with first PTCA (PTCA 1, angiographic follow-up 98%) and in 66 patients (76 segments) with repeat PTCA after restenosis (PTCA 2, angiographic follow-up 92%). Forty clinical, angiographic and procedural factors were assessed in relation to outcome. Primary success rate was higher in PTCA 2 (91% vs 67.5%) and major complications were fewer (4.5% vs 16%). Higher inflation pressure (7.9 +/- 2.3 vs 6.8 +/- 1.8 atm, P less than 0.005) and larger balloons (3.5 +/- 0.5 vs 3.2 +/- 0.5 mm, P less than 0.005) were used for PTCA 2, resulting in lesser residual stenosis (33 +/- 16% vs 40 +/- 18%, P less than 0.05). Restenosis rate (greater than or equal to 70%) after PTCA 1 and after PTCA 2 (27% vs 36%, P = NS) and the mean time to recurrence (4.7 vs 5.3 months, P = NS) were similar. Procedural factors were the main determinants of long-term success in primary PTCA. The restenosis risk was independently related to residual stenosis greater than or equal to 45% (P less than 0.001), variant angina (P less than 0.05) and multivessel disease (P less than 0.05) after PTCA 1 and to male sex (P less than 0.001) and higher inflation pressure (P less than 0.05) after PTCA 2. Mild to moderate intimal tearing was associated with less restenosis after PTCA 1, but not after PTCA 2. Including 9 patients (10 segments) with a third PTCA, 70% of the 66 patients with repeat PTCA had a successful long-term outcome. Repeat angioplasty should therefore be considered as an integral part of PTCA therapy. Restenosis however remains a major concern. An optimal primary result with a minimal residual stenosis is decisive for first PTCA, whereas avoidance of a dissection by using lower inflation pressure on a restenosis might improve the long-term outcome of repeat PTCA.

[Thrombolysis in acute myocardial infarct: prerequisites, current experiences and remaining problems]. / Die Thrombolyse beim akuten Myokardinfarkt. Voraussetzungen, bisherige Erkenntnisse und weiterbestehende Probleme.

Left ventricular pump failure is today's main cause of in-hospital mortality from acute myocardial infarction and is directly dependent on infarct size. The first clinical attempts to preserve myocardium after acute infarction and to improve morbidity and prognosis by thrombolysis date from about twenty years ago. Through large multicenter studies and promising new agents, coronary thrombolysis has again attracted increased attention in the past two years. After a brief overview on the preconditions for successful thrombolysis, the efficacy, advantages, complications and problems of different thrombolytic agents and forms of administration are reviewed on the basis of the controlled studies published up to June 1986. They concern streptokinase by intracoronary and intravenous route, urokinase and the "clot specific" agents of the second generation, recombinant tissue-type plasminogen activator (rtPA) and anisoylated plasminogen streptokinase activator complex (APSAC) BRL 26921. Finally, questions that remain open even after successful thrombolysis with myocardial salvage are raised, and in particular the problem of reocclusion and postlytic treatment. In spite of justified hopes and the demonstrable feasibility of reopening a coronary artery, thrombolysis in acute myocardial infarction should not be used routinely as long as the beneficial long term effect is not definitely proven for patients, or at least for a known subgroup of patients, in terms of left ventricular function, mortality and morbidity following myocardial infarction.

Clinical and angiographic assessment 6 months after double vessel percutaneous coronary angioplasty.

Percutaneous transluminal coronary angioplasty is an accepted treatment for selected patients with single vessel disease but has not been rigorously evaluated in patients with double vessel disease. Among 769 patients undergoing transluminal coronary angioplasty between 1980 and 1984, 74 with double vessel stenosis of 50% or more underwent double vessel coronary angioplasty. Primary success was obtained for both lesions in 63 patients (85%), for one lesion in 11 patients (15%) and for 137 (93%) of 148 segments overall. Except for myocardial infarction in one patient, no serious complication occurred. Before coronary angioplasty, 15 patients had unstable angina, 14 had Canadian Cardiovascular Society class III and 32 class I to II effort angina and only 2 were asymptomatic. Six months after coronary angioplasty, 27 were asymptomatic, 27 had class I to II and 5 had class III effort angina and 2 had sustained an episode of unstable angina. During the follow-up study, two patients had an infarction and one had coronary artery bypass surgery. Coronary arteriography was performed at a mean of 5.5 +/- 2.1 months after coronary angioplasty in all but three patients. Restenosis was found in 30 (23%) of 132 segments with angiographic control. Restenosis was present in one vessel in 17 patients and in both vessels in 4; 40 patients (66%) had no restenosis. Of the 34 patients with definite or probable angina, 50% had restenosis and 19% of patients with restenosis were symptom free.(ABSTRACT TRUNCATED AT 250 WORDS)