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PPI for critically ill ICU patients – no benefit?

Thomas Rösch, Hamburg

NEJM 2018; 379: 2199-2208

ORIGINAL ARTICLE Pantoprazole in Patients at Risk for Gastrointestinal Bleeding in the ICU Original Investigation Population-Based Colonoscopy Screening for Colorectal Cancer A Randomized Clinical Trial
M. Krag, S. Marker, A. Perner, J. Wetterslev, M.P. Wise, J.C. Schefold, F. Keus, A.B. Guttormsen, S. Bendel, M. Borthwick, T. Lange, B.S. Rasmussen, M. Siegemund, H. Bundgaard, T- Elkmann, J.V. Jensen, R.D. Nielsen, L. Liboriussen, M-H. Bestle, J.M. Elkjaer, D.F. Palmqvist, M. Bäcklund, J.H. Laake, P.M. Bådstøløkken, J. Grönlund, O. Breum, A. Walli, R. Winding, S. Iversen, I.-L. Jarnvig, J.O. White, B. Brand, M.B. Madsen, L. Quist, K.J. Thornberg, A. Møller, J. Wiis, A. Granholm, C.T. Anthon, T.S. Meyhoff, P.B. Hjortrup, S.R. Aagaard, J.B. Andreasen, C.A. Sørensen, P. Haure, J. Hauge, A. Hollinger, J. Scheuzger, D. Tuchscherer, T. Vuilliomenet, J. Takala, S.M. Jakob, M.L. Vang, K.B. Paelestik, K.L.D. Andersen, I.C.C. van der Horst, W. Diepernik, J. Fjølner, C.K.W. Kjer, C. Sølling, J. Karttunen, M.P.G. Morgan, B. Sjøbø, J. Engstrøm, B. Agerholm-Larsen, and M.H. Møller, for the SUP-ICU trial group*

BACKGROUND

Prophylaxis for gastrointestinal stress ulceration is frequently given to patients in the intensive care unit (ICU), but its risks and benefits are unclear.

METHODS

In this European, multicenter, parallel-group, blinded trial, we randomly assigned adults who had been admitted to the ICU for an acute condition (i.e., an unplanned admission) and who were at risk for gastrointestinal bleeding to receive 40 mg of intravenous pantoprazole (a proton-pump inhibitor) or placebo daily during the ICU stay. The primary outcome was death by 90 days after randomization.

RESULTS

A total of 3298 patients were enrolled; 1645 were randomly assigned to the pantoprazole group and 1653 to the placebo group. Data on the primary outcome were available for 3282 patients (99.5%). At 90 days, 510 patients (31.1%) in the pantoprazole group and 499 (30.4%) in the placebo group had died (relative risk, 1.02; 95% confidence interval [CI], 0.91 to 1.13; P = 0.76). During the ICU stay, at least one clinically important event (a composite of clinically important gastrointestinal bleeding, pneumonia, Clostridium difficile infection, or myocardial ischemia) had occurred in 21.9% of patients assigned to pantoprazole and 22.6% of those assigned to placebo (relative risk, 0.96; 95% CI, 0.83 to 1.11). In the pantoprazole group, 2.5% of patients had clinically important gastrointestinal bleeding, as compared with 4.2% in the placebo group. The number of patients with infections or serious adverse reactions and the percentage of days alive without life support within 90 days were similar in the two groups.

CONCLUSIONS

Among adult patients in the ICU who were at risk for gastrointestinal bleeding, mortality at 90 days and the number of clinically important events were similar in those assigned to pantoprazole and those assigned to placebo. (Funded by Innovation Fund Denmark and others; SUP-ICU ClinicalTrials.gov number, NCT02467621.)

Study Bullet points

PPIs have become routine in ICU units to prevent bleeding in critically ill patients – but are they justified? Data from randomized trials on PPI and H2 blockers (mostly including limited patients, numbering between 60 and 200) have been summarized in quite a few meta analyses, and the most recent ones were not really conclusive with regards to major outcomes, such as survival1-3.

This very large and laudable randomized multicenter study, which included almost 3300 patients, did not show any survival benefit or improved composite outcome with regards to clinically important events. Notably, this was not everybody, but only patients at risk, such as shock, use of anticoagulant agents, renal-replacement therapy, mechanical ventilation (expected to last >24 hours), any history of liver disease, or any history of/or ongoing coagulopathy. Main outcome, mortality at 90 days, was around 30% in both groups, and thus not different in any way.

Was there any benefit of the PPI therapy at all? Only GI bleeding was substantially reduced, namely from 4.2% to 2.5%. Statistical considerations prevented calculation of significance for secondary outcomes, but it could be assumed that with these case numbers there could have been a significant difference (relative risk 0.6, range 0.41-0.87).

Side effects did not frequently differ either. This concerned all infections (around 17%), including pneumonia (16.2%) and clostridium difficile enterocolitis (1.2-1.5%).

What should we conclude? There is no need for PPI, at least routinely and probably not at all, if we look at survival. However, a topic for further discussion should be: What are the (positive) consequences of a bleeding rate reduced by 40% – which is likely to be “significant”.

References

  1. Alhazzani W, Alshamsi F, Belley-Cote E, et al. Efficacy and safety of stress ulcer prophylaxis in critically ill patients: a network meta-analysis of randomized trials. Intensive care medicine 2018;44:1-11.
  2. Marker S, Perner A, Wetterslev J, et al. Stress ulcer prophylaxis versus placebo or no prophylaxis in adult hospitalised acutely ill patients-protocol for a systematic review with meta-analysis and trial sequential analysis. Systematic reviews 2017;6:118.
  3. Alshamsi F, Belley-Cote E, Cook D, et al. Efficacy and safety of proton pump inhibitors for stress ulcer prophylaxis in critically ill patients: a systematic review and meta-analysis of randomized trials. Critical care (London, England) 2016;20:120.

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