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

Pros and cons of prophylactic indomethacin in very preterm infants

Barbara Schmidt, MD, MSc, CM

Based on randomized trials, the relative risk reduction of prophylactic indomethacin

• n severe IVH is 35%

If the average risk of severe IVH in your hospital is: What is the absolute risk reduction if you use indomethacin prophylaxis?

10% ? % 20% ? %

Outline

• Effects of prophylactic indomethacin
• n severe IVH and disability
• Relative and absolute effects of

indomethacin for different baseline risks of severe IVH

• Effects of prophylactic indomethacin
• n PDA and BPD

Prophylactic indomethacin

P I C O T

Very low birth weight infants Prophylactic indomethacin No drug therapy Severe IVH Before first discharge home

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 I C O T

Very low birth weight infants Prophylactic indomethacin No drug therapy Disability At 18 months corrected age

USA Canada Hong Kong Australia New Zealand

Death or Disability at 18 months Indomethacin Placebo

261 of 569 46%

OR = 1.1 95% CI 0.8-1.4 p = 0.61

271 of 574 47%

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

• f 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 Targeting No Diff No Diff ↓

Outline

• Effects of prophylactic indomethacin
• n severe IVH and disability
• Relative and absolute effects of

indomethacin for different baseline risks of severe IVH

• Effects of prophylactic indomethacin
• n PDA and BPD

The relative treatment effects of prophylactic indomethacin

• n 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 Risk Absolute Risk Reduction NN Treat 20% 7.0% 15 10% 3.5% 29 5% 1.8% 58

Relative versus absolute effects

• Relative effects (e.g. relative risk,
• dds 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
• n severe IVH and disability
• Relative and absolute effects of

indomethacin for different baseline risks of severe IVH

• Effects of prophylactic indomethacin
• n 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

Prophylactic Indomethacin No Prophylactic Indomethacin

For Prophylactic Indomethacin

Adjusted OR (95% CI)

45% 44% 0.9

(0.7-1.1)

Observed Rates:

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