Pros and cons of prophylactic indomethacin in very preterm infants - PowerPoint PPT Presentation

Barbara Schmidt, MD, MSc, CM Pros and cons of prophylactic indomethacin in very preterm infants

Based on randomized trials, the relative risk reduction of prophylactic indomethacin on severe IVH is 35% If the average risk of What is the absolute risk severe IVH in your reduction if you use hospital is: indomethacin prophylaxis? 10% ? % 20% ? %

Outline • Effects of prophylactic indomethacin on severe IVH and disability • Relative and absolute effects of indomethacin for different baseline risks of severe IVH • Effects of prophylactic indomethacin on PDA and BPD

Prophylactic indomethacin P Very low birth weight infants Prophylactic indomethacin I No drug therapy C Severe IVH O Before first discharge home T

Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants Comparison: Prophylactic indomethacin vs. control Outcome: IVH Grade 3 and 4 Total (95% CI) 115/1285 177/1303 Favours treatment Favours control

Prophylactic indomethacin P Very low birth weight infants Prophylactic indomethacin I No drug therapy C Disability O At 18 months corrected age T

Canada USA Hong Kong Australia New Zealand

Death or Disability at 18 months Indomethacin Placebo 261 of 569 271 of 574 46% 47% OR = 1.1 95% CI 0.8-1.4 p = 0.61

Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants Outcome: Death or severe neurosensory impairment at 18 – 36 mo corrected age Total (95% CI) 304/743 299/748 Favors treatment Favors control

Evidence-Based Practice Those who prescribe prophylactic indomethacin practice evidence-based medicine. Those who don’t prescribe prophylactic indomethacin also practice evidence-based medicine. Roger Soll, MD

A Riddle? • Prophylactic indomethacin reduces the risk of severe IVH • Severe IVH increases the risk of childhood disability • Why does prophylactic indomethacin not reduce the risk of disability?

Therapies that reduce a serious neonatal morbidity but not disability Therapy Severe IVH BPD Severe ROP ↓ Indomethacin No Diff  No Diff ↓ Vitamin A No Diff No Diff Oxygen ↓ Saturation No Diff No Diff Targeting

Outline • Effects of prophylactic indomethacin on severe IVH and disability • Relative and absolute effects of indomethacin for different baseline risks of severe IVH • Effects of prophylactic indomethacin on PDA and BPD

The relative treatment effects of prophylactic indomethacin on severe IVH are stable across all risk quartiles

A Relative Risk Reduction of 35% will have variable absolute effects of prophylactic indomethacin on severe IVH Baseline Absolute Risk NN Risk Reduction Treat 20% 7.0% 15 10% 3.5% 29 5% 1.8% 58

Relative versus absolute effects • Relative effects (e.g. relative risk, odds ratio) of prophylactic indomethacin on severe IVH do not vary with the baseline or predicted risk of severe IVH • In contrast, absolute treatment effects (e.g. absolute risk reduction, NNT) will depend on baseline risk

Will “targeted” indomethacin prophylaxis reduce death or disability? No! • In TIPP, there was no treatment effect of prophylactic indomethacin on death or disability • This (lack of a) relative treatment effect of prophylactic indomethacin on death or early childhood disability does not change with the baseline risk of severe IVH

Outline • Effects of prophylactic indomethacin on severe IVH and disability • Relative and absolute effects of indomethacin for different baseline risks of severe IVH • Effects of prophylactic indomethacin on PDA and BPD

Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants Comparison: Prophylactic indomethacin vs. control Outcome: Symptomatic PDA Favours treatment Favours control

Prophylactic intravenous indomethacin for preventing mortality and morbidity in preterm infants Comparison: Prophylactic indomethacin vs. control Outcome: Chronic lung disease in surviving infants (36 weeks) Total (95% CI) 496 503 Favours treatment Favours control

Why does prophylactic indomethacin reduce PDA but not BPD? • PDA may just be a marker but not a cause of BPD; or • The benefit of PDA closure may be offset by harm from the therapy

J Pediatr 2006;148:730-4

Proportion of infants treated with prophylactic indomethacin at each of 35 study hospitals

BPD at 36 weeks PMA For Prophylactic Observed Rates: Indomethacin Prophylactic No Prophylactic Adjusted OR Indomethacin Indomethacin (95% CI) 0.9 45% 44% (0.7-1.1)

Conclusions • Prophylactic indomethacin reduces the risk of severe IVH but not the risk of early childhood disability • The absolute effects of indomethacin on severe IVH increase with increasing baseline risk of IVH • Prophylactic indomethacin reduces the risk of PDA but not the risk of BPD