Study objectives: Tezosentan, an IV dual endothelin-receptor antagonist, has demonstrated beneficial hemodynamic effects in patients with advanced heart failure. In addition, no notable differences in safety and tolerability variables were detected between tezosentan-treated and placebo-treated patients when infused over 4 to 6 h. The present study was conducted primarily to assess the safety and tolerability of tezosentan when administered over a prolonged, 48-h treatment period, and secondarily to investigate hemodynamic response.
Design: This randomized, double-blind, active-controlled study of continual IV administration of two dosages of tezosentan (20 mg/h and 50 mg/h; n = 6 each) or dobutamine (5 microg/kg/min; n = 2) over 48 h in patients with advanced heart failure was conducted to assess tolerability, safety, and hemodynamic variables (Doppler echocardiography).
Results: During tezosentan infusion, no episodes of hypotension requiring withdrawal of therapy occurred, and hemodynamic rebound was not observed after abrupt cessation of the infusion. There were no reports of worsening heart failure in tezosentan-treated patients up to 28 days following the infusion. The most common side effect during the infusion was headache (9 of 12 tezosentan-treated patients and both dobutamine-treated patients). Echocardiographic Doppler measurements suggested improvements in cardiac index, pulmonary capillary wedge pressure, and relaxation properties as well as in diastolic and systolic function in all treatment groups.
Conclusions: Prolonged, 48-h IV dual endothelin-receptor antagonism with tezosentan was well tolerated with no new safety concerns emerging. These data further support the potential role of tezosentan in the treatment of patients with acute heart failure.