PAS 2018 No5: the trial with no name… propranolol for early RoP, a proper trial.

As far as I can see, this trial has no acronym, which isn’t a big deal, but it also doesn’t show up on trial registry searches, which is a big deal. Trials must be registered before starting them, it ensures that protocols, sample sizes, outcomes, analyses, and so on, do not change without explanation. And it ensures that trials don’t end up being hidden and unpublished. The trial may have been registered, I just can’t find it.

I would call this trial PROPER, Pre-threshold RoP, Evaluation of pRopranolol! The authors can have that acronym for free if they want! How generous I am; unfortunately my Spanish is not good enough to generate a Spanish acronym.

In a single center trial, Aldo Bancalari and colleagues from Concepcion in Chile randomized 62 VLBW infants with stage 2 or 3 RoP in zone 2 or 3 (without plus disease) to oral propranolol or control (I am not sure if there was a placebo or not).

Progression to treatment thresholds (laser or intravitreal anti-VEGF treatment) was much less frequent with propanolol, with 28/31 (90%) having a favourable evolution, compared to 17/31 (55%) of controls. Which is a big difference unlikely to be due to chance alone. One of the propranolol babies was hypoglycemic on day 1, and there were no other side effects noted.

As I was creating this post, I realized that it actually looks like the authors have already published the results of this trial at an earlier stage, when they had enrolled 47 babies. That is really not appropriate; repeated analysis and presentation of results as they accumulate inflates risks of bias, dramatically. I was quite excited by this trial when I first saw it, but it looks now that it might not be a good use of my acronym, and perhaps it isn’t that proper!

**UPDATE, I have now received the full text of the previous publication, and that publication seems to refer to a cohort of treated babies that they compared to a historical control group (as mentioned by Ben Stenson in his comment below) and therefore this is probably a PROPER publication after all, I apologize to the authors if I mischaracterized this trial***

I think it is clear that we need… A Large Multicentre Trial of Propranolol in the Early Stages of RoP to Prevent Progression. Which we could call  “PREPARE” the PREvention of the Progression of REtinopathy trial. I claim priority for this acronym. PORKY would work too, if we could work out how to get the k in there.

About keithbarrington

I am a neonatologist and clinical researcher at Sainte Justine University Health Center in Montréal
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8 Responses to PAS 2018 No5: the trial with no name… propranolol for early RoP, a proper trial.

  1. Afif EL Khuffash says:

    Prevention Of Retinopathy in Kidz Yo!

  2. Numan Nafie Hameed says:

    Good morning
    You may add kids Retinopathy

  3. Ben Stenson says:

    It would be a big disappointment if they had previously published this info for the reasons that you have given. Their earlier report descibes historical controls rather than randomisation, so perhaps you are mistaken. Let’s hope it is prospectively registered so that it can get in a good journal.

  4. Brian Darlow says:

    There are important details missing from this trial report, particularly the numbers of infants (and eyes) in both group groups with zone 3 disease at randomisation. Zone 3 disease almost never progresses to need treatment. We need those data to be able to assess the trial overall.

    • I absolutely agree Brian. This study shouldn’t make anyone start using propranolol as routine therapy to prevent progression of retinopathy. I think it (and the 3 other trials in the Cochrane review, which all have significant limitations) gives sufficient support to do further trials.
      The frequency of retinal treatment in the study seems very high, even though the mean gestational age of the babies was just over 26 weeks. In the CNN, and in our NICU, treatment of babies over 25 weeks is quite unusual.
      We are a big cardiac center and often give propranolol (mostly to infants with Tetralogy of Fallot, but sometimes for other indications) they seem to tolerate it very well, but they aren’t small preterms, and those with more aggressive retinopathy also often have BPD, where propranolol might be a much bigger issue!

  5. Namasivayam Ambalavanan says:

    I am rather concerned that people may jump upon the propranolol bandwagon without additional study with larger sample sizes and careful evaluation for other effects. One main concern is that propranolol is anti-angiogenic (hence its relevance to use in ROP and hemangiomas). This would also suggest that use of propranolol would result in a reduction of lung microvascular development, which would increase the risk of inhibiting lung alveolar development (and therefore BPD) or gut vascularity (and hence increase NEC) or kidney glomerular development (and hence oligonephronia and subsequent CKD).

    • I absolutely agree. I don’t think we should be doing this without adequate trials, powered to detect the potential problems you mention. Beta-blockers are, of course, contra-indicated in asthma, for other reasons than anti-angiogenic effect, they trigger bronchospasm. Not a good effect to have in kids with BPD, which is a large proportion of babies who develop retinopathy.
      I hadn’t considered some of the other effects you mention, but they do need to be looked into.

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