PMID- 14734123
OWN - NLM
STAT- MEDLINE
DCOM- 20040506
LR  - 20190922
IS  - 1053-2498 (Print)
IS  - 1053-2498 (Linking)
VI  - 23
IP  - 1
DP  - 2004 Jan
TI  - Neurohumoral and hemodynamic effects of the selective endothelin antagonist 
      darusentan in advanced chronic heart failure.
PG  - 20-7
AB  - BACKGROUND: Endothelin antagonists represent a new approach to neurohumoral 
      treatment in patients with chronic heart failure. In this study, the new 
      selective endothelin-A receptor antagonist, darusentan, was compared with placebo 
      for 3 weeks in patients with severe heart failure on top of standard treatment 
      that included angiotensin-converting enzyme (ACE) inhibitors and beta-blockers. 
      Effects on neurohormones and hemodynamics were evaluated. METHODS: Consecutive 
      patients with severe heart failure (New York Heart Association [NYHA] Grade III) 
      were included in this neurohumoral sub-study of an international, multi-center, 
      double-blind, placebo-controlled study of darusentan, and randomized to 
      darusentan (n = 23) or placebo (n = 8). The mean left ventricular ejection 
      fraction was 19 +/- 6% at the beginning of the study. Patients were randomized to 
      different dosage levels of darusentan (30, 100, or 300 mg) for 3 weeks. 
      Hemodynamics were obtained by right heart Swan-Ganz catheterization at entry and 
      end of study. Serial assessment of plasma brain natriuretic peptide (BNP), 
      big-endothelin, and pro-atrial natriuretic peptide (pro-ANP) was performed. In 
      the active treatment group, 1 patient died due to worsening heart failure, 1 
      patient received elective heart transplantation, and 2 patients stopped taking 
      the medication due to vertigo. In the placebo group, 1 patient was excluded due 
      to non-compliance. RESULTS: Overall, the mean dose of darusentan was 144 +/- 125 
      mg/day (30 mg: n = 8; 100 mg: n = 4; 300 mg: n = 7). Significant benefits in 
      hemodynamic variables were found after 3 weeks only in patients receiving 
      darusentan (baseline vs end of study: cardiac index: 2.0 +/- 0.3 vs 2.6 +/- 0.5 
      liters/min m(2), p < 0.0001; mean pulmonary artery pressure: 35 +/- 9 vs 33 +/- 8 
      mm Hg, p < 0.05; heart rate: 79 +/- 16 vs 71 +/- 10 beats/min, p < 0.01). A 
      significant reduction in mean arterial blood pressure was observed with the 
      endothelin antagonist (baseline 80 +/- 8 vs end 73 +/- 8 mm Hg, p < 0.01). BNP 
      decreased significantly in patients with darusentan (90 +/- 87 at entry vs 63 +/- 
      67 fmol/ml after 3 weeks, p < 0.01), whereas big-endothelin remained unchanged. 
      Pro-ANP tended to decrease in the active treatment group, but did not reach 
      statistical significance. CONCLUSION: Significant hemodynamic and neurohumoral 
      benefits were observed in patients with severe heart failure receiving the 
      selective endothelin antagonist darusentan.
FAU - Bergler-Klein, Jutta
AU  - Bergler-Klein J
AD  - Department of Cardiology University of Vienna, Vienna, Austria. 
      jutta.bergler@akh-wien.ac.at
FAU - Pacher, Richard
AU  - Pacher R
FAU - Berger, Rudolf
AU  - Berger R
FAU - Bojic, Anda
AU  - Bojic A
FAU - Stanek, Brigitte
AU  - Stanek B
LA  - eng
PT  - Clinical Trial
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PL  - United States
TA  - J Heart Lung Transplant
JT  - The Journal of heart and lung transplantation : the official publication of the 
      International Society for Heart Transplantation
JID - 9102703
RN  - 0 (Endothelin A Receptor Antagonists)
RN  - 0 (Endothelin-1)
RN  - 0 (Phenylpropionates)
RN  - 0 (Pyrimidines)
RN  - 114471-18-0 (Natriuretic Peptide, Brain)
RN  - 33JD57L6RW (darusentan)
RN  - 85637-73-6 (Atrial Natriuretic Factor)
SB  - IM
MH  - Atrial Natriuretic Factor/blood/metabolism
MH  - Blood Pressure/drug effects
MH  - Dose-Response Relationship, Drug
MH  - Double-Blind Method
MH  - *Endothelin A Receptor Antagonists
MH  - Endothelin-1/blood/metabolism
MH  - Female
MH  - Heart Failure/*drug therapy/metabolism
MH  - Heart Function Tests
MH  - Hemodynamics/drug effects
MH  - Humans
MH  - Liver Function Tests
MH  - Male
MH  - Middle Aged
MH  - Natriuretic Peptide, Brain/blood/metabolism
MH  - Phenylpropionates/*therapeutic use
MH  - Pyrimidines/*therapeutic use
EDAT- 2004/01/22 05:00
MHDA- 2004/05/07 05:00
CRDT- 2004/01/22 05:00
PHST- 2004/01/22 05:00 [pubmed]
PHST- 2004/05/07 05:00 [medline]
PHST- 2004/01/22 05:00 [entrez]
AID - S1053249803000627 [pii]
AID - 10.1016/s1053-2498(03)00062-7 [doi]
PST - ppublish
SO  - J Heart Lung Transplant. 2004 Jan;23(1):20-7. doi: 10.1016/s1053-2498(03)00062-7.