Evidence map›Paper›PMID 33874894›Full record

SynthesisBMC medical research methodology2021

Intention-to-treat analysis may be more conservative than per protocol analysis in antibiotic non-inferiority trials: a systematic review.

Anthony D Bai, Adam S Komorowski, Carson K L Lo, Pranav Tandon, Xena X Li, Vaibhav Mokashi, Anna Cvetkovic, Aidan Findlater, Laurel Liang, George Tomlinson and 3 more

Open access · goldAbstract readSystematic Review
PubMed Full text at PMC Publisher
In one paragraph

Synthesis in BMC medical research methodology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers, 5 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
19citing papers in PubMed, 5 pooled it
2.1field-weighted citation impact, top 5% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

19 citing papers in PubMed, 5 syntheses or guidelines pooled it, 33 citations in OpenAlex.

  1. Pooled it
  2. Pooled it
  3. Pooled it
  4. Pooled it
  5. Pooled it
  6. Trial
  7. Trial
  8. Trial
  9. Article
  10. Article
  11. Article
  12. Article
  13. Review
  14. Article
  15. Article
  16. Article
  17. Article
  18. Review
  19. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

13 authors at 4 institutions in 1 country.

Anthony D BaiDivision of Infectious Diseases, McMaster University, Hamilton, ON, Canada. anthony.bai@medportal.ca.ORCID 0000-0003-0448-9934
Adam S KomorowskiDivision of Medical Microbiology, McMaster, University, Hamilton, ON, Canada.
Carson K L LoDivision of Infectious Diseases, McMaster University, Hamilton, ON, Canada.
Pranav TandonGlobal Health Office, McMaster University, Hamilton, ON, Canada.
Xena X LiDivision of Infectious Diseases, McMaster University, Hamilton, ON, Canada.
Vaibhav MokashiDivision of Infectious Diseases, McMaster University, Hamilton, ON, Canada.
Anna CvetkovicDivision of Infectious Diseases, McMaster University, Hamilton, ON, Canada.
Aidan FindlaterDivision of Infectious Diseases, McMaster University, Hamilton, ON, Canada.
Laurel LiangLeslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
George TomlinsonDepartment of Medicine, University Health Network and Mount Sinai Hospital, Toronto, ON, Canada.
Mark LoebDivision of Infectious Diseases, McMaster University, Hamilton, ON, Canada.
Dominik MertzDivision of Infectious Diseases, McMaster University, Hamilton, ON, Canada.
McMaster Infectious Diseases Fellow Research Group
McMaster University · CAJuravinski Cancer Centre · CAMount Sinai Hospital · CAUniversity of Toronto · CA

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundIn non-inferiority trials, there is a concern that intention-to-treat (ITT) analysis, by including participants who did not receive the planned interventions, may bias towards making the treatment and control arms look similar and lead to mistaken claims of non-inferiority. In contrast, per protocol (PP) analysis is viewed as less likely to make this mistake and therefore preferable in non-inferiority trials. In a systematic review of antibiotic non-inferiority trials, we compared ITT and PP analyses to determine which analysis was more conservative.

methodsIn a secondary analysis of a systematic review, we included non-inferiority trials that compared different antibiotic regimens, used absolute risk reduction (ARR) as the main outcome and reported both ITT and PP analyses. All estimates and confidence intervals (CIs) were oriented so that a negative ARR favored the control arm, and a positive ARR favored the treatment arm. We compared ITT to PP analyses results. The more conservative analysis between ITT and PP analyses was defined as the one having a more negative lower CI limit.

resultsThe analysis included 164 comparisons from 154 studies. In terms of the ARR, ITT analysis yielded the more conservative point estimate and lower CI limit in 83 (50.6%) and 92 (56.1%) comparisons respectively. The lower CI limits in ITT analysis favored the control arm more than in PP analysis (median of - 7.5% vs. -6.9%, p = 0.0402). CIs were slightly wider in ITT analyses than in PP analyses (median of 13.3% vs. 12.4%, p < 0.0001). The median success rate was 89% (interquartile range IQR 82 to 93%) in the PP population and 44% (IQR 23 to 60%) in the patients who were included in the ITT population but excluded from the PP population (p < 0.0001).

conclusionsContrary to common belief, ITT analysis was more conservative than PP analysis in the majority of antibiotic non-inferiority trials. The lower treatment success rate in the ITT analysis led to a larger variance and wider CI, resulting in a more conservative lower CI limit. ITT analysis should be mandatory and considered as either the primary or co-primary analysis for non-inferiority trials.

trial registrationPROSPERO registration number CRD42020165040 .

Indexed as

Anti-Bacterial AgentsBiasClinical ProtocolsHumansIntention to Treat AnalysisTreatment OutcomeAnti-Bacterial AgentsIntention-to-treatNon-inferiority trialsPer protocolSystematic review

Identifiers

PMID33874894
PMCPMC8054385
OpenAlexW3154127147

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.