MDL 17,043 therapy in severe congestive heart failure: Characterization of the early and late hemodynamic, pharmacokinetic, hormonal and clinical response

MDL 17,043, an agent with both inotropic and vasodilator properties, was evaluated in the treatment of chronic severe heart failure. The early and late hemodynamic, hormonal, pharmacokinetic and clinical responses to oral MDL 17,043 were studied in 20 patients. MDL 17,043 acutely increased cardiac output from 3.6 ± 0.9 to 4.6 ± 1.0 liters/min ( + 28%, p < 0.001) and decreased mean pulmonary artery wedge pressure from 24 ± 8 to 13 ± 8 mm Hg (−46%, p < 0.001), mean right atrial pressure from 10 ± 5 to 4 ± 4 mm Hg (−60%, p < 0.001) and mean arterial pressure from 78 ± 9 to 70 ± 11 mm Hg (−10%, p < 0.001). Hemodynamic improvement was sustained for 8 hours. Plasma renin activity tended to increase (0.10 < p > 0.05), plasma norepinephrine tended to decrease (0.10 < p > 0.05) and arginine vasopressin did not show any directional change. Elimination half-life for MDL 17,043 was approximately 20 hours. Hemodynamic responsiveness was maintained in six patients undergoing restudy at 4 weeks. Initial subjective improvement in the 20 patients occurred in 90%, was present at 4 weeks in 50% and continued longer than 3 months in 25%. Side effects occurred in 75% and required cessation of treatment in 10%. Thirteen (93%) of 14 patients on long-term therapy died (median time after start of MDL 17,043 therapy 39 days). Deaths were sudden in 69%. It is concluded that oral MDL 17,043 produces early and late hemodynamic improvement in patients with severe heart failure. The clinical response suggests caution in its use and controlled trials to ascertain whether MDL 17,043 is safe and efficacious in chronic severe heart failure.