Meta-analysis of the effects of endothelin receptor blockade on survival in experimental heart failure.
BACKGROUND
Although an initial study of endothelin receptor blockade reported positive findings, subsequent experiments and clinical trials in humans found little or no benefit.


METHODS
We applied meta-analytic methods to assess the methodologic rigor of preclinical studies of endothelin blockade and to quantitatively evaluate the totality of evidence regarding the effect of endothelin receptor blockers in experimental heart failure. A total of 396 animals were assigned to control and 594 were assigned to experimental therapy in the pooled analysis. Of the 9 studies identified, no study reported a priori sample size justification. Although there was a tendency to increased mortality with early administration (relative risk 1.39, P=.15) and decreased mortality with late administration (relative risk 0.85, P=.6), in the overall analysis, there was no significant evidence of benefit or harm (relative risk 1.03, P=.9). Studies with a small sample size had estimated effects that tended to deviate further from the pooled estimate of all studies.


CONCLUSIONS
Consideration of mortality effects in the totality of studies revealed no significant effect of endothelin antagonists in animal models of experimental heart failure. Given the potential for between-study variability, reliance on studies with small sample size may lead to unrealistic expectations when extrapolating preclinical experimental results to future research.
Lee
Douglas S
DS
Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Nguyen
Quang T
QT
Lapointe
Nathalie
N
Austin
Peter C
PC
Ohlsson
Arne
A
Tu
Jack V
JV
Stewart
Duncan J
DJ
Rouleau
Jean L
JL
D000818:Animals; D000077868:Atrasentan; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D065128:Endothelin Receptor Antagonists; D006333:Heart Failure / Q000188:drug therapy*; D010456:Peptides, Cyclic / Q000627:therapeutic use; D010666:Phenylpropionates / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D011759:Pyrrolidines / Q000627:therapeutic use; D051381:Rats; D012306:Risk; D015996:Survival Rate
D002316:Cardiotonic Agents; D065128:Endothelin Receptor Antagonists; D010456:Peptides, Cyclic; D010666:Phenylpropionates; D011743:Pyrimidines; D011759:Pyrrolidines; C107831:darusentan; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D000077868:Atrasentan