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Meta-analysis of the effects of endothelin receptor blockade on survival in experimental heart failure
Douglas S Lee1, Quang T Nguyen, Nathalie Lapointe
1Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
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.
Insights
Endothelin receptor blockade showed no significant benefit in animal models of heart failure. Small studies may overestimate treatment effects, leading to unrealistic expectations in future research.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Experimental Medicine
Background:
- Endothelin receptor blockade initially showed promise for heart failure.
- Subsequent human trials and experiments yielded limited or no benefits.
Purpose of the Study:
- To meta-analytically assess the methodological rigor of preclinical endothelin blockade studies.
- To evaluate the overall evidence for endothelin receptor blockers in experimental heart failure models.
Main Methods:
- Meta-analysis of 9 preclinical studies involving 990 animals (396 control, 594 experimental).
- Assessment of methodological quality, including a priori sample size justification.
- Analysis of mortality effects based on drug administration timing.
Main Results:
- No studies reported a priori sample size justification.
- Overall analysis showed no significant evidence of benefit or harm (RR 1.03, P=.9).
- Small sample size studies tended to show effect estimates deviating from the pooled estimate.
Conclusions:
- Endothelin antagonists demonstrated no significant mortality effect in animal models of experimental heart failure.
- Reliance on small studies may lead to overestimation of treatment effects.
- Caution is advised when extrapolating preclinical findings to future research due to potential variability.
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