In which Pawel Irisik examines a Big Dumb Trial. This one  is exactly the sort of question that needs a BDT: proton pump inhibitors versus placebo in ICU patients. tl;dr they caused about the half the low bleeding risk to which ICU patients are exposed given placebo, but no difference in any other outcome.
In most ICUs in OECD countries we give acid suppression to everybody, either proton pump inhibitors or H2 receptor antagonists. This started in the old days to stop stress ulcers, giant erosive prostaglandin mediated things that covered the whole stomach, of which many bled and with which many died.
Stress ulcers don’t seem to be around much any more, so it’s hard to lavish much resource on investigated their cause, but it was probably a general systemic illness effect, with deprivation of food an important contributor. GI bleeding among ICU patients on PPIs is much rarer now than was GI bleeding among ICU patients on PPIs in days of stress ulcer yore. So the question is, are PPIs as useful as they once seemed, or should the credit go to the overall less brutal ICU practice of the now?
With that hint that routine PPIs are part of the days of cardiac output optimisation and paralysis for “fighting the ventilator”, there are many great plans worldwide to answer the question, “is it better to give acid suppression or not?”. A little late, perhaps, as this trial found that 42% of patients are already on them at home. Still, blanket PPI coverage is a troublesome rock sticking out in the tide of best practice that forms modern ICU, so the question will be answered well.
Because it’s such a routine practice, the silky powers of the ANZICS CTG have been brought to bear, to point out the case for equipoise. Just riding out as an expert or a managerial style research capo, with a banner saying “PPI v placebo”, might not persuade many people that there really is a question. After all, “We give PPIs to everyone. We have no more stress ulcers. People used to die of that shit. Have you run out of topics, you fool?”
The actual sciencey reasons have been WELL dissected by some of the most productive and best communicators of the ANZICS CTG, which means the whole topic is much better dealt with elsewhere. Apparently they’re associated with C difficile infection and myocardial infarction, for misty reasons. What interested me to put this on Journal Club is that very process of building equipoise. It’s one of the strengths of the CTG, convincing all kinds of ICUs that there is a real question, that we don’t know things and that doesn’t make us bad people, that we can answer it and that in doing so we will make things better for patients. It’s nice.
There is a planned pantoprazole-v-placebo trial looking at GI bleeding, REVISE. That’s pausing for thought after this trial. There is a planned pantoprazole-v-ranitidine cluster randomised trial using administrative data (the things that hospitals do to get paid for casemix-based funding in Australia, and to stop their chief executives from getting the sack in other places), PEPTIC. That’s potentially going to change everything, as the first one that will really be able to be run and give a clear answer using hospital-scale resources. The point is, there are people articulating clearly that there might be reasons to stop giving everybody PPIs.
Equipoise is poorly understood. I take it to mean that, extracting emotion and latent preferences and obvious heuristic biases, the person who has equipoise believes that several options may be as good as each other. So one intervention might have more efficacy but less tolerability and so overall be less useful, if the only option is to give it to all the same patients. Or one might be new; or one might be so old that the information on it might as well be new, because the data is all low quality; or there are significant reasons why inference from another population is not transferable (Heterogeneity of treatment effect, differential treatment effect, novel confounders, under-dispersed interactions …). Overall, it means that the deciding person is comfortable with any of the options.
There are those who have a narrow definition of equipoise: one says that you must believe that the interventions are equal but simply lack information, another that you must have exactly equal belief that each one is superior and so on. Because these are almost all entirely foolish, they mostly end up with people denying the existence of equipoise. It’s the same sort of foolishness that expects doctors always to know the right treatment… or at least to say they do. It’s an adversarial courtroom definition and it has no place in science. It denies the possibility that a person can be truly, honestly prepared to be just wrong without defending the wrongness, and intending to come to truth not by an authority informing them of their wrongness but by inquiry and reopening the old facts in light of the new.
So I say personal clinical equipoise can be as far from the zenith as “I sort of prefer this, going on my biases, but I know how often everyone else is wrong when they go by their biases so I’ll ditch my ego and support the research for the sake of patients”. It’s the kind of equipoise in which you could offer orchidectomy patients the three options of prophylactic radiotherapy, prophylactic carb& gem, or watchful waiting as if it’s a normal choice of the kind that humans make about themselves. See, it does exist. It’s the kind of equipoise by which a seasoned anti-Parenteral Nutrition activist might push for their unit to be involved in a supplemental PN trial because look how often people are wrong about nutrition (ICYMI, it’s every time they speak or write anything about it. Every time.). It’s a bit meridional for some, but it’s the way we learn how not to harm patients.
Community equipoise, on the other hand, is when there are camps of opinion where people genuinely believe that their preference is better, yet are happy to randomise to get the answer they expect. How can this be OK? Surely if you have the tablets from the Mount you want to proselytise, not just keep them in your Holy? Well, apart from the fact that some people are happy to have others in error, that’s just not the way scientifically derived opinions are formed. People who believe that they have the true knowledge and others are inferior are dangerous, because that is not a belief that can be tested, challenged, falsified or mitigated. Again, it comes down to the personal responsibility to recognise when you might be wrong and hopefully our ICU community is grown up enough to display that.
Also, on a more jihadi note, when there are camps around certain practices but not a whole monolithic religion yet (say the Righteous Sect of Early Tracheostomy and the Noble Sect of Late), it might not be possible to have your chosen belief dominate, and a trial is the only way, pragmatically, that you will win. So community equipoise is not simply weak will and group think but a principled way to move your whole community to safer, more effective practice through research.
Intention to Treat
So, this is an intervention that is applied across the whole ICU population: you need to know what the effect is to the next admission. So you need an intention to treat analysis (which they did as their primary analysis; I’m just emphasising).
If there were potentially side effects that were dose dependent, or significant proportions of people were unlikely to get it despite being allocated, or heaven forfend if we were somehow capable of giving medicine differentially to the members of externally identifiable segments of the polity (cf Macpherson Report), then other analysis such as Per Protocol or Sensitivity might be more important. It all depends on the intended use of the information, with a strong additional feature that ITT analysis is less susceptible to selection bias on behalf of the analyst.
It’s a large,multicentre product of the Scandinavian Critical Care Trials Group, who as well as being apparently limitlessly pleasant in plenary and discussion, are also methodological ultras, so the randomisation scheme and follow up are presumably faultless and look so from the report. 3298 were randomised to 40mg pantoprazole daily or placebo until ICU discharge and 31.1% versus 30.4% died by day 90, with 2.5% and 4.2% having significant GI bleeding. Oddly, Only 20 of the 3298 withdrew entirely, which in light of the equipoise discussion shows people have a real desire to help to find the answer even if it’s not relevant to their own care.
I find it a little weird that they don’t report more about bleeding in the main paper, but table S8 in the supplements shows “overt” bleeding in 5.4 v 9.0%. “Significant” was bleeding associated with 20mmHg drop in BP, 2 unit drop in Hb, 2 unit transfusion or 20% increase in vasopressors; which is a little loose for most future purposes. Only 16/88 vs 28/148 had endoscopy for their overt bleed; the numerators may be the same or different for the significant bleeds, but the denominators are 41 and 69. Either way, that’s well outside of our usual, or recommended practice. 3 v 5 had surgery and 2 v 4 endovascular haemostatis. Oddly, although 14/41 vs 21/69 were ulcers or gastritis as expected, only 6/41 and 14/69 were “other”, which I suppose means all sorts of things but implies some in the placebo arm were not preventable by PPI.
Also, 32.5 versus 29.6% of patients had a transfusion over the 90 days. Yes, more transfusions in the pantoprazole group. Maddeningly, there’s no total RBC unit count, just a median 0 and range 0 to 1 for each patient. There was no association with C difficile or MI.
The EBM questions:
1. What is equipoise? And what is community equipoise? What are your duties as a doctor, to the institution and science and the patient, when your equipoise conflicts with someone else’s equipoise? Is it OK just not to “believe in high flow” for example?
2. And most importantly, when is a per protocol analysis appropriate, as opposed to an Intention to Treat analysis?
- Krag M, Marker S, Perner A, et al. Pantoprazole in Patients at Risk for Gastrointestinal Bleeding in the ICU. New England Journal of Medicine. October 2018. doi:10.1056/NEJMoa1714919