Wolfgang Mäurer

Safety observations from the pilot phase of the randomized r-Hirudin for Improvement of Thrombolysis (HIT-III) study. A study of the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausärzte (ALKK)

BACKGROUND Adjunctive therapy for thrombolysis in acute myocardial infarction consists of platelet inhibition with aspirin and thrombin inhibition with heparin. Thrombin inhibition may be improved by the use of hirudin as indicated by experimental and phase II clinical studies. The randomized, double-blind phase III r-Hirudin for Improvement of Thrombolysis study (HIT III) compared a recombinant hirudin (HBW 023) with heparin. The primary end point was the incidence of death or reinfarction. METHODS AND RESULTS Seven thousand patients with acute myocardial infarction and a duration of symptoms of less than 6 hours were to be randomized to receive intravenous heparin (70 IU/kg body wt bolus and 15 IU.kg-1.h-1) or hirudin (0.4 mg/kg body wt bolus and 0.15 mg.kg-1.h-1) infused over 48 to 72 hours and adjusted to an activated partial thromboplastin time of 2 to 3.5 times baseline values. In a pilot phase, 1000 patients receiving front-loaded alteplase for thrombolysis were to be recruited by 93 German centers. After enrollment of 302 patients, the trial was stopped after an increased rate of intracranial bleeding was observed in the hirudin group (5 of 148, 3.4%) compared with the heparin group (0 of 154). The overall stroke rate was 3.4% in the hirudin group and 1.3% in the heparin group. Other major bleeding occurred in five versus three patients and ventricular rupture occurred in three versus one patient in the hirudin and heparin groups, respectively. There were 19 in-hospital deaths, with 13 of them from the hirudin group. CONCLUSIONS Although the number of patients was too small for a definite benefit-risk assessment, at the dosage tested, hirudin in combination with front-loaded alteplase and aspirin may be associated with an increased rate of intracranial hemorrhage. Our findings are consistent with the observations of the GUSTO-II and TIMI-9 trials, where higher doses of another recombinant hirudin were used. Therefore, the therapeutic range of hirudin as an adjunct to thrombolysis may be smaller than previously thought, and reappraisal of dose finding should be considered.

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

Inotropic and electrophysiological action of humoral factors released in cardiogenic shock after acute myocardial infarction

SummaryThe inotropic and electrophysiological effects of plasma obtained from patients and experimental dogs during cardiogenic shock following acute myocardial infarction were studied. Changes in the isometric contraction and the intracellular action potential were determined in isolated papillary muscles of rabbits. Control plasma collected from normal subjects produced no significant changes in the contraction or the electrical parameters. Plasma from shock patients decreased peak force by 42% and the maximum rate of force development by 38% in comparison to control values; the time to peak of contraction, the relaxation time and the action potential parameters were not significantly altered. Corresponding results were obtained with plasma from dogs before and during experimental cardiogenic shock. Biochemical determinations failed to identify a single specific “myocardial depressant factor” in the plasma of patients and dogs with cardiogenic shock. The results suggest that (1) various humoral factors released during cardiogenic shock may depress the contractile function of cardiac muscle and (2) that the observed negative inotropic effect is not due to electrical changes in the cell membrane.ZusammenfassungDie Irreversibilität eines kardiogenen Schocks nach Myokardinfarkt soll angeblich wesentlich durch die Freisetzung eines humoralen, negativ inotropen Peptids, des “myocardial depressant factor” (MDF), mibestimmt werden. Bei Patienten und Hunden wurde Plasma während eines kardiogenen Schocks nach akutem Myokardinfarkt gewonnen. Gemessen wurde die Wirkung von Plasmadialysaten auf die isometrische Kontraktion und auf intrazelluläre Aktionspotentiale an isolierten Papillarmuskeln von Kaninchen in vitro. Kontrollplasma von herzgesunden Normalpersonen hatte keinen signifikanten Einfluß auf die Kontraktion und die elektrischen Parameter. Wechsel der Superfusions-flüssigkeit von Kontrollplasma auf Schockplasma verursachte eine signifikante Abnahme von Kontraktionsamplitude und maximaler Kontraktionsgeschwindigkeit um 30–40%; Kontraktionszeit, Relaxationszeit und die elektrophysiologischen Parameter des Aktionspotentials blieben unverändert. Ähnliche Ergebnisse wurden mit Plasmaproben von Hunden beobachtet, die während eines experimentellen kardiogenen Schocks entnommen wurden. Biochemische Untersuchungen mit der Polyacrylamid-Gel-Elektrophorese und der High-Voltage-Elektrophorese ergaben keinen Unterschied zwischen den Peptidfraktionen in Kontrollplasma und Schockplasma. Die Ergebnisse deuten auf eine Beteiligung von unspezifisch negativ inotropen Plasmafaktoren bei der Entstehung eines kardiogenen Schocks hin; dagegen konnte das von mehreren Autoren postulierte spezifische MDF-Peptid mit den angewendeten empfindlichen analytischen Verfahren nicht nachgewiesen werden.

Catecholamine release in myocardial ischemia and its clinical implications

The occurrence of myocardial necrosis (1) and of ventricular tachyarrhythmias (2) has been related to high local concentrations of noradrenaline during ischemia. The positive results of secondary prevention beta-blocker trials after myocardial infarction and of recent studies of beta-blocker treatment in acute moycardial infarction (ISIS I study) may support this concept. Cardiac catecholamine release was, therefore, investigated in patients with ischemic heart disease and in animal experiments.

Lokale Kontraktilitätsstörungen unter isometrischer Belastung bei normaler linksventrikulärer Kinetik in Ruhe

Die hamodynamische Bedeutung einer Koronararterienstenose wird durch Untersuchungen in Ruhe oft unterschatzt (2). Die funktionelle Beurteilung einer Koronarstenose ist aber z. B. fur die Indikationsstellung von koronarchirurgischen Eingriffen besonders wichtig. Es wird daher untersucht, ob durch die technisch einfache isometrische Belastung eine lokale Storung der linksventrikularen Kinetik bei Patienten mit koronarer Herzkrankheit und normalem linksventrikularem Angiokardiogramm in Ruhe provoziert werden kann.