Objectives: Two multicenter randomized controlled trials (RCTs) in premature infants (Ment et al, 1994 and TIPP, 2001) found beneficial effects of indomethacin prophylaxis on the incidences of patent ductus arteriosus (PDA), PDA ligation, and severe intracranial hemorrhage (ICH). The Ment trial recommended the use of indomethacin prophylaxis. The TIPP trial failed to find a benefit in its primary outcome (improved survival/neurodevelopmental outcome); this negative result may have discouraged indomethacin prophylaxis use.
Study design: We used the National Institute of Child Health and Development's Neonatal Network Registry to determine the association between the 2 trials and the use of indomethacin prophylaxis. We also statistically assessed the assumptions that led to the TIPP trial's negative results.
Results: Use of indomethacin prophylaxis among network clinicians increased after publication of the Ment trial and decreased after the TIPP trial. Analysis of the TIPP trial showed that the primary outcome's anticipated effect size (> or = 20%) was too large; a smaller effect size (< 3%) would have been more appropriate based on the incidence of ICH in their population and its association with neurodevelopmental outcome.
Conclusions: Two multicenter RCTs were associated with changes in indomethacin prophylaxis. After the Ment trial, the use of indomethacin prophylaxis increased. After the TIPP trial, which reported negative results based on an excessively large anticipated effect size, its use decreased.