Peter Limbourg

More Rapid, Complete, and Stable Coronary Thrombolysis With Bolus Administration of Reteplase Compared With Alteplase Infusion in Acute Myocardial Infarction

BACKGROUND Early restoration and maintenance of normal (TIMI 3) blood flow during acute myocardial infarction is critical for optimal preservation of left ventricular function and survival. Recombinant plasminogen activator (r-PA, reteplase) is a nonglycosylated deletion mutant of wild-type tissue-type plasminogen activator (TPA) that has been shown to achieve more rapid and complete thrombolysis compared with other plasminogen activators in animal models. METHODS AND RESULTS The RAPID Trial was designed to test the hypothesis that bolus administration of one or more dosage regimens of r-PA was superior to standard-dose alteplase (TPA) in achieving infarct-related artery patency 90 minutes after initiation of treatment. Six hundred six patients with acute myocardial infarction were randomized to one of four treatment arms: (1) TPA 100 mg i.v. over 3 hours, (2) r-PA as a 15-MU single bolus, (3) r-PA as a 10-MU bolus followed by 5 MU 30 minutes later, or (4) r-PA as a 10-MU bolus followed by 10 MU 30 minutes later. Coronary arteriography was performed at 30, 60, and 90 minutes after initiation of treatment and at hospital discharge. The 10 + 10-MU r-PA group achieved better 90-minute and 5- to 14-day TIMI 3 flow (63% [CI, 55% to 71%] versus 49% [41% to 57%], P = .019, and 88% [82% to 94%] versus 71% [63% to 79%], P < .001, respectively) than the TPA group. The TIMI 3 flow in the 10 + 10-MU r-PA group at 60 minutes was equivalent to that in the TPA group at 90 minutes (51 versus 49%). Global ejection fraction and regional wall motion in the 10 + 10-MU r-PA group were superior to those of the TPA group at hospital discharge (53 +/- 1.3% versus 49 +/- 1.3%, P = .034; -2.19 +/- 0.12 versus -2.61 +/- 0.13 SD per chord, P = .02, respectively). The 15-MU and 10 + 5-MU r-PA patency and left ventricular function results were similar to those of the TPA and inferior to those of the 10 + 10-MU r-PA group. Bleeding complications were similar between the groups. CONCLUSIONS r-PA given as a double bolus of 10 + 10 MU achieves more rapid, complete, and sustained thrombolysis of the infarct-related artery than standard-dose TPA, without an apparent increased risk of complications. This was associated with improved global and regional left ventricular function at hospital discharge.

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)

Comparison of clinical benefits of Clopidogrel therapy in patients with acute coronary syndromes taking Atorvastatin versus other statin therapies

In clinical practice, we found no significant difference between atorvastatin therapy or other statin therapies in the clinical outcomes of patients with acute coronary syndromes receiving clopidogrel therapy. In patients receiving atorvastatin therapy, clopidogrel therapy was associated with a significant decrease in mortality and stroke during univariate analysis and a moderate trend of reduced mortality and stroke without statistical significance in the multivariate analysis.

Echocardiography in assessing acute pulmonary hypertension due to pulmonary embolism

Eighteen patients with acute pulmonary embolism were studied with right heart catheterization and M mode echocardiography. No patient had evidence of preexisting cardiopulmonary disease; pulmonary embolism was documented with pulmonary angiography. The mean pulmonary arterial pressure correlated with the angiographic severity index of embolic obstruction (r = 0.61, p 2 , p 2 ) and in 5 patients with acute pulmonary embolism and a mean normal pulmonary arterial pressure (10.9 ± 0.4 mm/m 2 ). For all measurements the index size of the right pulmonary artery correlated with the mean pulmonary arterial pressure (r = 0.84, p

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.

Coronary reperfusion studies with pro-urokinase in acute myocardial infarction: Evidence for synergism of low dose urokinase

Pro-urokinase is a single chain precursor of two chain urokinase, which has been shown to induce fibrin-selective plasminogen activation. In the present study, thrombolytic efficacy of 9 million U of glycosylated pro-urokinase administered intravenously was compared with that of a combined regimen utilizing 4.5 million U of pro-urokinase and 0.2 million U of urokinase. Seventy-five patients with a first myocardial infarction were randomized to receive high dose pro-urokinase (n = 40, group A) or the combination therapy (n = 35, group B). Reperfusion of the infarct-related artery was assessed by repeat coronary angiography. Thrombolysis in Myocardial Infarction trial (TIMI) grade II or III reperfusion was achieved in 73% of group A patients compared with 66% of group B patients (p = NS). A trend toward faster reopening of the infarct-related artery was observed in patients in group B. Coronary artery reocclusion occurred in 5 (10%) of 49 patients in whom angiography was repeated within 36 h after the start of therapy. Clot-selective thrombolysis was indicated by a minimal fibrinogen decline (15% and 13%, respectively, in groups A and B). Alpha 2-antiplasmin levels, however, decreased more rapidly in patients in group B (p less than 0.05). This finding and the equivalent reperfusion rate in the combined treatment group strongly suggest synergistic interaction between these two thrombolytic agents. In summary, the high incidence of reperfusion, the low rate of early reocclusion and the paucity of side effects, particularly with regard to bleeding complications, indicate that pro-urokinase possesses the characteristics of an ideal thrombolytic agent.

Effect of diazoxide on left ventricular performance in hypertension

SummaryThe effect of diazoxide on left ventricular performance during rest and isometric exercise (handgrip) was examined in 16 unselected hypertensive patients, 6 of whom had been pretreated with the beta-adrenergic blocking agent pindolol. Diazoxide regularly and promptly produced a fall in left ventricular systolic and end diastolic pressures, and an increase in heart rate and left ventricular dp/dtmax. Haemodynamic changes were maximal 2 minutes after injection of the drug and decreased little over the next 8 minutes. After beta-adrenergic blockade, diazoxide caused a more pronounced reduction in left ventricular systolic pressure and a less marked fall in end-diastolic pressure, whilst the diazoxide-induced rise in heart rate was partially and the increase of dp/dtmax was completely inhibited. The increase in systolic pressure during isometric exercise was not influenced by diazoxide, but the positive inotropic reaction was augmented. The findings appear to show that cardiac stimulation by diazoxide is due to a reflex mechanism transmitted by baroreceptors, and that improvement of cardiac performance is mainly due to a reduction of left ventricular after-load.

Kardiovaskuläre Effekte von Dobutamin

SummaryThe cardiovascular effects of dobutamine, a derivative of dopamine have been investigated in seven patients with chronic left ventricular dysfunction. The patients were either suffering from coronary heart disease or from cardiomyopathy.Dobutamine was administered at doses of 2.5–5.0–7.5–10.0 and 15.0 µg/kg/min. The following parameters were measured: aortic pressure, left ventricular pressure (LVEDP, LVdp/dtmax) by using a Millar tip manometer, pulmonary artery pressure and cardiac output (dy-dilution technique).The positive chronotropic effect of dobutamine was small in the lower dosage range and reached significance only with the highest dose of 15.0 µg/kg/min. Systolic aortic pressure was increased moderately over the whole dosage range (p<0.05). However the increment of mean aortic pressure (+11 mm Hg), of stroke volume (+22%) and of stroke work (+49%) was already maximum (p<0.05) at a dose of 5.0 µg/kg/min.The positive inotropic action of dobutamine caused a dose related increase of cardiac index and of LVdp/dtmax of +53% and of +193% respectively. This effect was accompanied by a continuous and significant decrease of LVEDP and of peripheral resistance. Dobutamine induced arrhythmias have not been observed. 15 min after infusion stop, no dobutamine effect could be detected. These findings demonstrate that the actions of dobutamine are not merely cardioselective. However, in the dose range between 2.5 and 15.0 µg/kg/min a positive inotropic effect is predominant. Further clinical trials with dobutamine on patients with severe myocardial dysfunction and low output syndrome may yield promising results.ZusammenfassungDie kardiovaskulären Effekte von Dobutamin, einem Derivat des Dopamin, wurden an 7 Patienten mit chronischer Funktionsstörung der linken Kammer bei koronarer und myokardialer Herzerkrankung untersucht.Dobutamin wurde in steigenden Dosen von 2,5–5,0–7,5–10,0 und 15,0 µg/kg/min infundiert. Gemessen wurden der Druck in der zentralen Aorta, im linken Ventrikel (Kathetertipmanometer; LVEDP, LVdp/dtmax) und in der Pulmonalarterie sowie das Herzminutenvolumen (Farbstoffverdünnungsmethode).Der positiv chronotrope Effekt von Dobutamin war gering und erst bei 15,0 µg/kg/min statistisch auffällig. Der systolische Aortendruck nahm im gesamten Dosisbereich mäßig stark zu. Dagegen war die Zunahme des mittleren Aortendruckes mit 11 mm Hg, die des Schlagvolumens mit 22% und der Schlagarbeit mit 49% bei 5,0 µg/kg/min am größten (p<0,05).Die positiv inotrope Wirkung von Dobutamin führte dosisabhängig zu einer Zunahme des Herzindex und von LVdp/dtmax um maximal 63 bzw. 193% (p<0,01). Dabei sanken der LVEDP und der periphere Widerstand signifikant ab. Arrhythmien traten unter Dobutamin nicht auf. Nach 15 min war die Wirkung der Substanz abgeklungen.Die Befunde zeigen, daß Dobutamin keine streng kardioselektive Wirkung besitzt. Jedoch überwiegt im Dosisbereich von 2,5–15,0 µg/kg/min die positiv inotrope Wirkung. Weitere klinische Untersuchungen mit dieser Substanz an Patienten mit schwerer Herzinsuffizienz und low output Syndrom erscheinen erfolgversprechend.

Die Bedeutung proximaler und distaler Leitungsverzögerung bei Patienten mit faszikulärem Block

Patienten mit intraventrikularen Leitungsstorungen erscheinen dann besonders gefahrdet, wenn man, ausgehend vom Konzept des faszikularen Blocks, annehmen kann, das 2 der 3 terminalen Leitungsbahnen unterbrochen sind. Bei Patienten mit der haufigsten Form des bifaszikularen Blocks, dem Rechtsschenkelblock (RSB) mit linksanteriorem Hemiblock (LAH) wird eine Entwicklung zu einem kompletten Block bei 15–30 % der Patienten beobachtet (Lasser et al., 1968, Gleichmann et al., 1972). In einer retrospektiven Studie haben wir dieses Phanomen bei 23 von 70 Patienten nachweisen konnen (Lang et al., 1972).

Left ventricular function after acute myocardial infarction

Abstract10 patients with their first AMI were studied within the first 48 hours and again after 3 weeks. Central and peripheral haemodynamics (CI, SV, SW, TPR) were examined, including indices of contractility (dp/dlmax) and wall stiffness (ΔP/ΔV, relation ΔP/ΔV to P) of the left ventricle.In the early phase CI and SW, as well as LV dp/dtmax were depressed in accordance with symptoms of LV failure. ΔP/ΔV was increased. Elevation of LVEDP correlated well with ventricular gallop rhythm, but less consistently with LV functional disturbance.During convalescence CI increased uniformly, both in digitalized and non-digitalized individuals. In contrast heart rate, aortic pressure, LVEDP and dp/dtmax remained unchanged. The increase of CI, SV and SW was accompanied by a fall of TPR and ΔP/ΔV. LV wall stiffness was still elevatedabove normal after 3 weeks. The improvement of cardiac pumping during infarct convalescence may have been effected through a fall of TPR and LV wall stiffness. Recovery of depressed contractile performance was generally not observed, and does therefore not seem to contribute to recuperation.