### Systematic Review Scenario

You are asked to provide antenatal counselling to a mother with imminent premature delivery at 26 weeks gestation. Both parents are concerned about the prognosis of their baby. They have read on the Internet that early indomethacin may improve their child’s neonatal course. You are aware of the cautious recommendation by Nehgme et al, based on their systematic review, to use indomethacin prophylaxis in infants with birth weights < 1500 grams (Nehgme RA, O'Connor TZ, Lister G, Bracken MB. Patent ductus arteriosus. In:Sinclair JC, Bracken MB, editors. Effective care of the newborn infant. Oxford: Oxford University Press; 1992. P. 281-324). However, you have remained concerned about the long-term efficacy and safety of this approach and wonder whether more information has since become available. You formulate the question, "In a very premature infant, does indomethacin prophylaxis improve survival without severe disability?" You have a bookmark for the NIH Web Site that publishes all neonatal reviews for the Cochrane Collaboration: silk.nih.gov/silk/cochrane (no longer online). You click on "Collection of Documents and Reviews", then click on "Proceed to Systematic Reviews". On "The Cochrane Neonatal Collaborative Review Group" page, you click on "Search this site" and enter the word "indomethacin". Of the four reviews, one is a perfect match. After reading the abstract, you decide to print the whole document off the web site http://silk.nih.gov/silk/cochrane/fowlie/fowlie.htm (no longer online)

• Is the evidence from this randomised trial valid?
• If valid, is this evidence important?
• If valid and important, can you apply this evidence in caring for your patient?

### Completed Systematic Reviews Worksheet for Evidence-Based Neonatal Medicine

#### Citation

Fowlie PW. Prophylactic intravenous indomethacin in very low birth weight infants (Cochrane Review). In: The Cochrane Library, 1997. Oxford: Update Software.

#### Are the results of this systematic review (systematic review) of therapy valid?

Is it a systematic review of randomised trials of the treatment you’re interested in?
Yes.
Does it include a methods section that describes finding and including all the relevant trials?
Yes.
Does it include a methods section that describes assessing their individual validity?
Yes.
Were the results consistent from study to study?
All trials suggest that prophylactic indomethacin is associated with short-term benefits, namely reduction of Patent Ductus Arteriosus (PDA) and severe Intraventricular Hemorrhage (IVH grade 3 and 4). Whether or not this results in improved survival without disability has not been sufficiently evaluated.

#### Are the valid results of this systematic review important?

Translating odds ratios to NNTs. The numbers in the body of the table are the NNTs for the corresponding odds ratios at that particular patient’s expected event rate (PEER).
Odds Ratios
0.9 0.85 0.8 0.75 0.7 0.65 0.6 0.55 0.5
Patient’s Expected Event Rate (PEER) 0.05 2091 139 104 83 69 59 52 46 412
0.10 110 73 54 43 36 31 27 24 21
0.20 61 40 30 24 20 17 14 13 11
0.30 46 30 22 18 14 12 10 9 8
0.40 40 26 19 15 12 10 9 8 7
0.503 38 25 18 14 11 9 8 7 6
0.70 44 28 20 16 13 10 9 7 6
0.90 1014 64 46 34 27 22 18 15 125

$$qquad text{For all IVH:}\ qquad text{Control Event Rate (CER)} = 221/614 = 0.3599 \ qquad text{Experimental Event Rate (EER)} = 161/598 = 0.2692 \ qquad OR = 0.61 \ qquad text{NNT is approximately 10.}$$

$$qquad text{For IVH Grade 3 and 4:}\ qquad text{Control Event Rate (CER)} = 80/599 = 0.1336 \ qquad text{Experimental Event Rate (EER)} = 46/577 = 0.0797 \ qquad OR= 0.55 \ qquad text{NNT is approximately 18}$$

$$qquad text{For symptomatic PDA:}\ qquad text{Control Event Rate (CER)} = 135/410 = 0.3293 \ qquad text{Experimental Event Rate (EER)} = 46/403 = 0.1141 \ qquad OR = 0.29 \ qquad text{NNT is approximately 5.}$$

#### Can you apply this valid, important evidence from a systematic review in caring for your patient?

##### Do these results apply to your patient?
Is your patient so different from those in the systematic review that its results can’t help you?
No
How great would the potential benefit of therapy actually be for your individual patient?
Method I:
In the table on page 1, find the intersection of the closest odds ratio from the overview and the CER that is closest to your patient’s expected event rate if they received the control treatment (PEER):
See above approximate NNTs.
Method II:
To calculate the NNT for any OR and PEER:

$$NNT = frac{1-[PEER times (1-OR)]}{(1-PEER) times PEER times (1-OR)}$$

##### Are your patient’s values and preferences satisfied by the regimen and its consequences?
Do your patient and you have a clear assessment of their values and preferences?
Yes.
Are they met by this regimen and its consequences?
Yes.
##### Should you believe apparent qualitative differences in the efficacy of therapy in some subgroups of patients?

Not applicable; there have been no subgroup analyses.

Despite the evidence of short-term benefits, indomethacin prophylaxis is not widely used in many countries, due to concerns about drug safety (e.g. the risk of necrotizing enterocolitis and gastro-intestinal perforations) and the lack of convincing data on long-term outcomes after indomethacin prophylaxis in this high-risk population.

Therefore, an international placebo-controlled trial was launched in 1996, to determine whether the prophylactic administration of low-dose indomethacin to infants weighing 500-999 grams at birth improves survival without neurosensory impairment to a corrected age of 18 months. This trial is funded by the Medical Research Council of Canada, and co-sponsored by the National Institute of Child Health and Human Development. Twelve-hundred and two infants have been enrolled between 1996 and 1998 in Canada, the US, Australia, New Zealand and Hong Kong. Follow-up will be completed early in the year 2000. For further information, please contact Barbara Schmidt.

### Premature infants: Prophylactic intravenous indomethacin decreases risk of PDA

#### Clinical Bottom Line

All trials suggest that prophylactic indomethacin is associated with short-term benefits, namely reduction of Patent Ductus Arteriosus (PDA) and severe Intraventricular Hemorrhage (IVH grade 3 and 4).

#### Citation

Fowlie PW. Prophylactic intravenous indomethacin in very low birth weight infants (Cochrane Review). In: The Cochrane Library, 1997. Oxford: Update Software.
Lead author’s name and fax: Fowlie PW. Fax: 01382 645783.

#### Clinical Question

In a very premature infant, does indomethacin prophylaxis improve survival without severe disability?

#### Search Terms

“Indomethacin” in the NIH Web Site that publishes all neonatal reviews for the Cochrane Collaboration: silk.nih.gov/silk/cochrane (no longer online).

#### The Review

• Data Sources: Medline, Embase, Oxford Database of Perinatal Trials.
• Study Selection: Restricted to randomised controlled trials using prophylactic intravenous indomethacin in newborn infants with birth weights <1751 grams.
• Data Extraction: Each of the articles identified by the original literature search was assessed independently, using the inclusion criteria, by the author and a colleague trained in research methodology. Each selected article was reviewed by the author and the outcomes measured were recorded, initially without specific data. Any discrepancies were resolved by a third data extraction. The data from abstracts were compared with those from full manuscripts by the same author(s) to avoid duplicating data.
• Multiple independent reviews of individual reports? No.
• Tested for heterogeneity? No.

#### The Evidence

Outcome Time to Outcome Typical CER Typical OR RRR NNT p Value
All intraventricular hemorrhage (IVH) 0.3599 0.61 29% 10
95% Confidence Intervals 0.47 to 0.79 7 to 19
For IVH Grade 3 and 4 0.1336 0.55 41% 18
95% Confidence Intervals 0.37 to 0.80 13 to 42
For symptomatic PDA 0.3293 0.29 62% 5
95% Confidence Intervals 0.21 to 0.40 4 to 6

Despite the evidence of short-term benefits, indomethacin prophylaxis is not widely used in many countries, due to concerns about drug safety (e.g. the risk of necrotizing enterocolitis and gastro-intestinal perforations) and the lack of convincing data on long-term outcomes after indomethacin prophylaxis in this high-risk population. Therefore, an international placebo-controlled trial was launched in 1996, to determine whether the prophylactic administration of low-dose indomethacin to infants weighing 500-999 grams at birth improves survival without neurosensory impairment to a corrected age of 18 months. This trial is funded by the Medical Research Council of Canada, and co-sponsored by the National Institute of Child Health and Human Development. Twelve-hundred and two infants have been enrolled between 1996 and 1998 in Canada, the US, Australia, New Zealand and Hong Kong. Follow-up will be completed early in the year 2000. For further information, please contact Barbara Schmidt.

#### Appraised By

Barbara Schmidt, MD, MSc, FRCP(C), and Bo Zhang, MPH

#### References

1. The relative risk reduction (RRR) here is 10%
2. The RRR here is 49%
3. For any OR, NNT is lowest when PEER = .50
4. The RRR here is 1%
5. The RRR here is 9%