Rainer von Essen

Impact of early perfusion status of the infarct-related artery on short-term mortality after thrombolysis for acute myocardial infarction : retrospective analysis of four German multicenter studies

OBJECTIVE This study evaluated the impact of early patency of the infarct-related vessel on short-term mortality after thrombolysis for acute myocardial infarction. BACKGROUND Different thrombolytic regimens for acute myocardial infarction proved to be equally effective in large scale mortality trials despite significant differences in their efficacy with respect to early infarct-related vessel patency as shown in smaller angiographic trials. METHODS Patients from four German multicenter studies of thrombolysis in acute myocardial infarction were retrospectively evaluated. Of 939 patients with acute myocardial infarction (duration of symptoms < 6 h) treated with thrombolysis, 907 (96.6%) had an angiogram of the infarct-related artery 90 min after the initiation of thrombolytic therapy. The perfusion status was graded according to the Thrombolysis in Myocardial Infarction (TIMI) study criteria. RESULTS Complete reperfusion (TIMI grade 3) was found in 561 of 907 patients and partial reperfusion (TIMI grade 2) in 122 of 907. Overall, the in-hospital mortality rate was 4.6% (43 patients). In patients with complete reperfusion of the infarct-related vessel, the mortality rate was only 2.7% versus 7.1% in patients with an occluded vessel at the 90-min angiogram. This difference was highly significant in univariate as well as in multivariate analysis. In patients with partial perfusion of the infarct vessel, the mortality rate was 6.6%. CONCLUSIONS The early perfusion status of the infarct-related artery is an independent predictor of short-term survival. However, only complete early reperfusion is associated with a reduced in-hospital mortality rate whereas patients with partial perfusion (TIMI grade 2) have a short-term prognosis similar to that of patients with persistently occluded infarct vessels. Therefore, when used as a surrogate end point for mortality, only TIMI grade 3 perfusion of the infarct vessel should be interpreted as a treatment success of thrombolysis in acute myocardial infarction.

Improved thrombolysis in acute myocardial infarction with front-loaded administration of alteplase: Results of the rt-PA-APSAC patency study (TAPS)

Thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) and anisoylated plasminogen streptokinase activator (APSAC) in myocardial infarction has been proved to reduce mortality. A new front-loaded infusion regimen of 100 mg of rt-PA with an initial bolus dose of 15 mg followed by an infusion of 50 mg over 30 min and 35 mg over 60 min has been reported to yield higher patency rates than those achieved with standard regimens of thrombolytic treatment. The effects of this front-loaded administration of rt-PA versus those obtained with APSAC on early patency and reocclusion of infarct-related coronary arteries were investigated in a randomized multicenter trial in 421 patients with acute myocardial infarction. Coronary angiography 90 min after the start of treatment revealed a patent infarct-related artery (Thrombolysis in Myocardial Infarction [TIMI] grade 2 or 3) in 84.4% of 199 patients given rt-PA versus 70.3% of 202 patients given APSAC (p = 0.0007). Early reocclusion within 24 to 48 h was documented in 10.3% of 174 patients given rt-PA versus 2.5% of 163 patients given APSAC. Late reocclusion within 21 days was observed in 2.6% of 152 patients given rt-PA versus 6.3% of 159 patients given APSAC. There were 5 in-hospital deaths (2.4%) in the rt-PA group and 17 deaths (8.1%) in the APSAC group (p = 0.0095). The reinfarction rate was 3.8% and 4.8%, respectively. Peak serum creatine kinase and left ventricular ejection fraction at follow-up angiography were essentially identical in both treatment groups. There were more bleeding complications after APSAC (45% vs. 31%, p = 0.0019).(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of time to treatment on early infarct-related artery patency after different thrombolytic regimens

BACKGROUND In an in vitro model, recombinant tissue-type plasminogen activator was significantly more effective than streptokinase in dissolving 24-hour-old human blood clots. Therefore there might be a difference in the effect of time to treatment on the efficacy of these fibrinolytics with different fibrin specificity in patients with acute myocardial infarction. METHODS AND RESULTS The effect of the interval between symptom onset and initiation of therapy on the efficacy of 6 different thrombolytic regimens was studied in a retrospective analysis of 6 angiographic trials with similar design. The patency of the infarct-related artery was assessed by angiography 90 minutes after initiation of thrombolysis in patients who were seen within 6 hours after symptom onset. Patency rates of patients with an interval of </=3 hours and >3 hours between symptom onset and start of therapy were compared. There was no difference for Thrombolysis in Myocardial Infarction (TIMI) grade 3 perfusion after front-loaded alteplase (72.5% vs 76. 3%) and reteplase (63.6% vs 63.2% ) between the 2 groups. In contrast, in patients treated with streptokinase (36.8% vs 27.6%, P =.09), anisoylated plasminogen streptokinase activator complex (59. 5% vs 34.8%, P =.004), and urokinase (62.3% vs 41.7%, P =.03), TIMI 3 patency decreased with the increasing interval between symptom onset and initiation of therapy. CONCLUSIONS We conclude from our data that the thrombolytic efficacy of recombinant tissue-type plasminogen activator and reteplase does not decrease with the increasing interval between symptom onset and initiation of therapy. In contrast, after anisoylated plasminogen streptokinase activator complex, streptokinase, and urokinase treatment, a decrease in patency, especially TIMI-3 patency in patients treated after >3 hours after symptom onset, was observed. These results may influence the choice of the thrombolytic agent in patients who are seen >3 hours after symptom onset.

Dose finding with a novel recombinant plasminogen activator (BM 06,022) in patients with acute myocardial infarction: Results of the German recombinant plasminogen activator study

OBJECTIVES The aim of this study was to determine the appropriate dose of a novel recombinant tissue-type plasminogen activator (BM 06.022) for thrombolysis in patients with acute myocardial infarction. BACKGROUND BM 06.022 is a mutant of tissue-type plasminogen activator expressed in Escherichia coli that can be given as a single bolus because of a prolonged half-life, which might obviate the need for complicated regimens. METHODS BM 06.022 given as a single bolus was investigated in 142 patients in a multicenter sequential dose-finding study. Efficacy of the drug was assessed from infarct-related artery patency by coronary angiography. RESULTS With the first dose of 10 MU of BM 06.022, the predefined minimal 90-min patency of 70% was not achieved, as indicated by the sequential probability ratio test after treatment of 42 patients (group A). The second dose of 15 MU of BM 06.022 was given subsequently in the preset maximum of 100 patients (group B). Angiography 30, 60 and 90 min after the bolus injection of BM 06.022 revealed a patent infarct-related artery (Thrombolysis in Myocardial Infarction trial [TIMI] grade 2 or 3) in 65% and 66%, 73% and 74% and 66% and 75% of patients in groups A and B, respectively. Very early reocclusion up to the 90-min angiogram occurred in 17% and 13%, late reocclusion until predischarge angiography occurred in 7% and 5%, and rescue percutaneous transluminal coronary angioplasty after the 90-min angiogram was performed in 6 and 14 patients in groups A and B, respectively. Plasma fibrinogen decreased from 2.79 g/liter (range 0.94 to 4.75) to 1.69 g/liter (range 0.0 to 3.95) in group A and from 2.54 g/liter (range 0.0 to 5.02) to 0.92 g/liter (range 0.0 to 2.68) in group B. Two bleeding complications requiring transfusion or surgical intervention and one nonfatal intracranial hemorrhage were encountered. Eight patients had a reinfarction, and five patients died, all of cardiac causes. CONCLUSIONS With BM 06.022 given as a single bolus, a high early patency rate of the infarct-related coronary artery can be achieved. The speed of thrombolysis seems to be superior to standard thrombolytic drugs. The compound warrants further evaluation with respect to safety and efficacy by clinical end points.

Open, noncontrolled dose-finding study with a novel recombinant plasminogen activator (BM 06.022) given as a double bolus in patients with acute myocardial infarction.

The novel recombinant plasminogen activator (r-PA) (BM 06.022) is a mutant of tissue-type plasminogen activator expressed in escherichia coli which can be given as a bolus because of a prolonged half-life. The primary objective of this trial was to determine the efficacy of an intravenous r-PA double bolus (first bolus of 10 MU followed by 5 MU after 30 minutes) in patients with acute myocardial infarction. All patients received heparin intravenously and acetylsalicylic acid orally. Efficacy was assessed from infarct artery patency by coronary angiography (Thrombolysis in Myocardial Infarction trial perfusion grades 2 or 3) in 50 patients. Ninety minutes after administration of the first r-PA bolus, the infarct-related coronary artery was patent in 39 of 50 patients (78%; 95% confidence interval 64 to 88%). An angiographically confirmed reocclusion occurred in 1 patient between 90 minutes and 24 to 48 hours. The reocclusion rate was influenced by 8 interventions and 1 angiogram missing at 24 to 48 hours. Measurements of hemostatic parameters showed a decrease in fibrinogen to 37% of baseline value. There were 3 clinical reinfarctions before discharge and 2 major puncture site hemorrhages. No further serious bleeding and no serious adverse event with lethal outcome occurred. The 10 + 5 MU r-PA double bolus regimen appears to be effective with regard to patency and the success of thrombolysis. The incidence of reocclusion is very low. From the limited number of patients treated in this study, one need not be concerned about the safety profile of r-PA.

Effects of Octreotide Treatment on Restenosis After Coronary Angioplasty: Results of the VERAS Study

BACKGROUND The VERAS study (VErringerung der Restenoserate nach Angioplastie durch ein Somatostatin-analogon [Prevention of Restenosis Following Angioplasty With a Somatostatin Analogue]) was a placebo-controlled trial to evaluate the effects of octreotide for the prevention of restenosis after coronary angioplasty. Octreotide is a somatostatin analogue with antiproliferative properties on smooth muscle cell growth in vitro that limits myointimal thickening of arteries in balloon injury models. METHODS AND RESULTS Patients received either octreotide or placebo, starting 1 hour before angioplasty and continued for 3 weeks. The minimal luminal diameters before and after angioplasty and at 6-month follow-up were analyzed with a digital quantitative algorithm. Of the initial 274 patients recruited, 217 (108 in the octreotide group and 109 in the placebo group) could be analyzed after a complete 6-month evaluation: the minimal luminal diameters were 1.67+/-0.57 mm in the octreotide-treated group and 1.66+/-0.64 mm in the placebo group (two-paired P=.70), and the relative losses were 0.16+/-0.22 and 0.13+/-0.21 (two-paired P=.27). The restenosis rates were also identical in both treatment groups: final diameter stenosis > or =50% (34.3% versus 33.9%, two-paired P=1.0), loss of > or =50% of the initial gain (34.3% versus 33.9%, two-paired P=1.0), and absolute reduction of minimal luminal diameter >0.72 mm (29.6% versus 24.8%, two-paired P=.45). Likewise, there was no difference with regard to the incidence of clinical events (death, myocardial infarction, bypass operations, reintervention). Octreotide was well tolerated, with the exception of gastrointestinal side effects, which were three times more common than in the placebo group. CONCLUSIONS Octreotide did not reduce the angiographically determined restenosis rate or the incidence of major clinical events after coronary angioplasty.

Spontaneous course of ST-segment elevation in acute anterior myocardial infarction.

The spontaneous course of ST-segment elevation (2ZST) in 24 patients with acute anterior myocardial infarction (AMI) was studied by precordial ST-segment mapping, which was recorded at 2-hour intervals during the first 48 hours after admission. Change of 2ST between two registrations was expressed as mV/hr, and was compared with clinical and hemodynamic parameters, course of MB-CK curve, calculated infarct mass and arrhythmias. After an initial rapid increase, there was a decrease of ZST, which reaches a plateau-like curve approximately 12 hours after the onset of chest pain. A second new increase of ZST exceeding a value of 0.6 mV/hr correlates well with extension of necrosis, verified by re-elevation of MB-CK. During the first 2 days, extension of necrosis could be detected in 50% of our patients. As new ischemic episodes and extension of necrosis in AMI occur frequently and are promptly indicated by an increase of ZST, the physician should, while monitoring therapeutic interventions, concentrate on such a second increase rather than on a decrease of ZST (which may occur spontaneously), as has been suggested in most previous reports

Frequency of achieving optimal reperfusion with thrombolysis in acute myocardial infarction (analysis of four German multicenter studies)

Patients from 4 German multicenter studies on thrombolysis in acute myocardial infarction (AMI) were retrospectively evaluated to assess the incidence of optimal reperfusion, defined as a completely perfused infarct vessel after 90 minutes, without subsequent death or reinfarction, and without reocclusion or deterioration of flow in control angiograms. Of 907 patients with a 90-minute angiogram, 75% had an open infarct vessel by conventional definition (perfusion grade 2 or 3 according to the criteria of the Thrombolysis in Myocardial Infarction [TIMI] study). However, only 62% had TIMI grade 3 complete perfusion. Of the 561 patients with such primary treatment success, 106 (19%) had secondary treatment failure by death, reinfarction, or subtotal or total reocclusion of the infarct vessel. In a subset of 668 patients with a first angiogram after 60 minutes, conventional patency was 70%, complete perfusion 51%, and an optimal perfusion result was achieved in only 42%. The efficacy of thrombolysis in AMI is substantially overestimated by conventional 90-minute patency rates.

Sequential intervention procedures after intracoronary thrombolysis; balloon dilatation, bypass surgery, and medical treatment☆

After successful intracoronary thrombolysis of an acute myocardial infarction in 145 patients subsequent intervention procedures were evaluated. In 48 of 62 patients (43%), percutaneous transluminal coronary angioplasty was performed successfully (success rate 77%), 41 patients (28%) were operated on and 56 patients (39%) were treated only medically. During the hospital phase in the angioplasty group, 4 reinfarctions were noted and 3 repeat angioplasties were required, while 41 of the 48 successfully treated patients (85.4%) remained clinically stable. In the surgical group, one cardiac failure occurred, while 40 patients (97.6%) were without cardiac event. In the medical group, 5 patients died (8.9%), 8 patients (14.3%) had a reinfarction, and 76.8% were clinically stable. During the follow-up period in the surgical group of 6 months 37 patients (90.2%) were clinically stable, all in functional classes I and II. In the angioplasty group 33 patients were stable (68.8%), and in the medical group 26 patients were stable (46.6%). In the whole group of 145 patients the hospital mortality together with that in the 6 months follow-up period was 9.7% with a reinfarction rate of 22.8%.

Frequency of “optimal anticoagulation” for acute myocardial infarction after thrombolysis with front-loaded recombinant tissue-type plasminogen activator and conjunctive therapy with recombinant hirudin (HBW O23)☆

Abstract This retrospective analysis reviewed 183 patients with acute myocardial infarction who were given front-loaded recombinant tissue-type plasminogen activator (rt-PA) and r-hirudin (HBW 023) in 1 of 4 dose groups (bolus dose of 0.07, 0.1, 0.2, or 0.4 mg/kg, followed by an infusion of 0.05, 0.06, 0.1, or 0.15 ma/kg/hour over 48 hours). Activated partial thromboplastin time (aPTT) levels were determined at baseline and at 4, 8, 12, 16, 20, 24, 32, 40, and 48 hours. Of the 178 patients with r-hirudin treatment for ≥12 hours, anti-coagulation was optimal in 55.1% (all aPTTs >2 × baseline), suboptimal in 33.7% (lowest aPTT >1.5 but