Pantoprazole in ICU patients at risk for gastrointestinal bleeding—1‐year mortality in the SUP‐ICU trial

Marker, Søren; Krag, Mette; Perner, Anders; Wetterslev, Jørn; Lange, Theis; Wise, Matt P.; Borthwick, Mark; Bendel, Stepani; Keus, Frederik; Guttormsen, Anne Berit; Schefold, Joerg C.; Rasmussen, Bodil Steen; Elkmann, Thomas; Bestle, Morten H.; Arenkiel, Bjørn; Laake, Jon Henrik; Kamper, Maj K.; Lång, Maarit; Pawlowicz-Dworzanska, Malgorzata B.; Karlsson, Sari; Liisanantti, Janne; Dey, Nilanjan; Knudsen, Heidi; Granholm, Anders; Møller, Morten Hylander; investigators, Sup-Icu trial

doi:10.1111/aas.13436

Cited by 12 publications

(10 citation statements)

References 17 publications

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“…Ninety‐day mortality in ICU patients administered PPIs or H2RAs versus a placebo for GIB prophylaxis was not significantly different 7,32 . However, in a post hoc analysis of the placebo‐controlled Stress Ulcer Prophylaxis‐ICU trial by Marker et al ., pantoprazole was associated with higher 90‐day mortality and fewer days alive without life support than the placebo in patients with high disease severity, 33 while there was no significant difference in 1‐year mortality among the same population 34 . The effects of acid suppressants on mortality in patients with cardiovascular diseases are still unclear.…”

Section: Discussionmentioning

confidence: 99%

“… 7 , 32 However, in a post hoc analysis of the placebo‐controlled Stress Ulcer Prophylaxis‐ICU trial by Marker et al ., pantoprazole was associated with higher 90‐day mortality and fewer days alive without life support than the placebo in patients with high disease severity, 33 while there was no significant difference in 1‐year mortality among the same population. 34 The effects of acid suppressants on mortality in patients with cardiovascular diseases are still unclear. Several studies have reported that the interaction between PPIs and antiplatelet drugs may increase the risks of cardiovascular events and potential infections, such as pneumonia and CDI, which may result in an increased risk of mortality.…”

Section: Discussionmentioning

confidence: 99%

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The efficacy and safety of acid suppressants for gastrointestinal bleeding prophylaxis in cardiac care unit patients

Chen

Liu

Duan

et al. 2021

J of Gastro and Hepatol

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Background and Aim: Concerns regarding adverse events associated with proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) for gastrointestinal bleeding (GIB) prophylaxis in the intensive care unit have increased in recent years. Few studies have focused on acid suppressant use in the cardiac care unit (CCU) setting exclusively. We performed a cohort study to determine the efficacy and safety of acid suppressants for GIB prophylaxis in CCU patients. Methods: This retrospective cohort study included adults who were admitted directly to the CCU for more than 2 days from January 1, 2014, to April 30, 2019. The Crusade score was calculated to evaluate the risk of GIB. The primary outcomes were clinically important gastrointestinal bleeding (CIGIB), hospital-acquired pneumonia (HAP), and in-hospital mortality. Results: Of the 3318 patients enrolled, 2284 (68.8%) patients received PPIs, 515 (15.5%) received H2RAs, and 519 (15.7%) received no acid suppressants. After adjusting for potential confounders, utilization of PPIs (2.69, 95% confidence interval [0.62-11.73]) and H2RAs (1.41, 95% confidence interval [0.19-10.36]) were not associated with a lower risk of CIGIB than the control. Sensitivity analyses revealed that PPI use was an independent risk factor for in-hospital mortality in patients over 75 years old, with an adjusted odds ratio of 4.08 (1.14-14.63). PPIs increased the risk of HAP in patients over 75 years old and in those with heart failure, with adjusted odds ratios of 2.38 (1.06-5.34) and 2.88 (1.34-7.28), respectively. Conclusions: Proton pump inhibitors and H2RAs for GIB prophylaxis in CCU patients were not associated with a lower risk of CIGIB than the controls. PPI therapy is associated with increased risks of HAP and in-hospital mortality in patients over 75 years old. PPIs may increase the risk of HAP in patients with heart failure.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The efficacy and safety of acid suppressants for gastrointestinal bleeding prophylaxis in cardiac care unit patients

Chen

Liu

Duan

et al. 2021

J of Gastro and Hepatol

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“… Assuming a risk of 30% for all‐cause mortality at day 90 after randomisation in the control group 35,36 we have about 37% power to detect a relative risk reduction of 15% at the 1% alpha level. Assuming the same in‐hospital mortality as in the primary outcome 35 and a 10% increase in days alive at day 90 without life support (vasopressor/inotropic support, invasive mechanical ventilation, or RRT) in the intervention group, then we have about 59% power at the 1% alpha level. Assuming a risk of 37% for all‐cause mortality at 1‐year after randomisation in the control group, 37 we have about 52% power to detect a relative risk reduction of 15% at the 1% alpha level. Assuming a control group proportion of participants with one or more SAEs and/or SARs of 30%, 36 we have about 37% power to detect a relative reduction of 15% at the 1% alpha level. …”

Section: Methodsmentioning

confidence: 99%

Goal directed fluid removal with furosemide versus placebo in intensive care patients with fluid overload: A trial protocol for a randomised, blinded trial (GODIF trial)

Wichmann

Itenov

Berthelsen

et al. 2022

Acta Anaesthesiol Scand

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Background: Fluid overload is a risk factor for mortality in intensive care unit (ICU) patients. Administration of loop diuretics is the predominant treatment of fluid overload, but evidence for its benefit is very uncertain when assessed in a systematic review of randomised clinical trials. The GODIF trial will assess the benefits and harms of goal directed fluid removal with furosemide versus placebo in ICU patients with fluid overload.Methods: An investigator-initiated, international, randomised, stratified, blinded, parallel-group trial allocating 1000 adult ICU patients with fluid overload to infusion of furosemide versus placebo. The goal is to achieve a neutral fluid balance. The primary outcome is days alive and out of hospital 90 days after randomisation. Secondary outcomes are all-cause mortality at day 90 and 1-year after randomisation; days alive at day 90 without life support; number of participants with one or more serious adverse events or reactions; health-related quality of life and cognitive function at 1-year follow-up. A sample size of 1000 participants is required to detect an improvement of 8% in days alive and out of hospital 90 days after randomisation with a power of 90% and a risk of type 1 error of 5%. The conclusion of the trial will be based on the point estimate and 95% confidence interval; dichotomisation will not be used. ClinicalTrials. gov identifier: NCT04180397.

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“…There were various degrees of overlap in inclusion periods, with only the HOT‐ICU trial overlapping all other trials. The SUP‐ICU trial was the first trial to be initiated in January 2016 and completed inclusion in October 2017; the results have been published 5,11 . The HOT‐ICU trial was initiated in June 2017 and finished inclusion in August 2020; the results have been published 7 .…”

Section: Methodsmentioning

confidence: 99%

“…The SUP-ICU trial was the first trial to be initiated in January 2016 and completed inclusion in October 2017; the results have been published. 5,11 The HOT-ICU trial was initiated in June 2017 and finished…”

Section: Settingmentioning

confidence: 99%

Interactions in clinical trials: Protocol and statistical analysis plan for an explorative study of four randomized ICU trials on use of pantoprazole, oxygenation targets, haloperidol and intravenous fluids

Schjørring

Lange²,

Krag

et al. 2021

Acta Anaesthesiol Scand

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Background: Intensive care unit (ICU) patients receive numerous interventions, but knowledge about potential interactions between these interventions is limited. Coenrolment in randomized clinical trials represents a unique opportunity to investigate any such interactions. We aim to assess interactions in four randomized clinical trials with overlap in inclusion periods and patient populations.Methods: This protocol and statistical analysis plan describes a secondary explorative analysis of interactions in four international ICU trials on pantoprazole, oxygenations targets, haloperidol and intravenous fluids, respectively. The primary outcome will be 90-day all-cause mortality. The secondary outcome will be days alive and out of hospital in 90 days after randomization. All patients included in the intention-totreat populations of the four trials will be included. Four co-primary analyses will be conducted, one with each of the included trials as reference using a logistic regression model adjusted for the reference trial's stratification variables and for the cointerventions with interactions terms. The primary analytical measure of interest will be the analyses' tests of interaction. A p-value below .05 will be considered statically significant. The stratification variable-and co-intervention-adjusted effect estimates will be reported with 95% confidence intervals without adjustments for multiplicity. | 157 SCHJØRRING et al. 1 | INTRODUC TI ON When accepting co-enrolment in randomized clinical trials, assessment of possible interaction between interventions is important, 1-3 both to establish the possible impact of co-enrolment on the results of each trial, and to identify inconspicuous interactions. Intensive care unit (ICU) patients receive numerous interventions, but the knowledge about any potential interaction between these interventions is limited. Co-enrolment in randomized clinical trials represents a unique option to investigate such interactions. The Centre for Research in Intensive Care (CRIC) has initiated four randomized clinical trials in adult ICU patients. All interventions tested were considered standard of care in everyday clinical practice in ICUs. All trials were generally conducted in the same sites, had overlapping inclusion criteria and inclusion periods, and co-enrolment was allowed. The trials were the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial investigating pantoprazole versus placebo in patients at risk of gastrointestinal bleeding; 4,5 the Handling Oxygenation Targets in the Intensive Care Unit (HOT-ICU) trial investigating a lower versus a higher oxygenation target in patients with acute hypoxaemic respiratory failure; 6,7 the Agents Intervening against Delirium in the Intensive Care Unit (AID-ICU) trial investigating haloperidol versus placebo in patients with delirium 8 and the Conservative versus Liberal Approach to fluid therapy of Septic Shock in Intensive Care (CLASSIC) trial investigating restrictive versus standard intravenous fluid therapy in patient...

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Pantoprazole in ICU patients at risk for gastrointestinal bleeding—1‐year mortality in the SUP‐ICU trial

Cited by 12 publications

References 17 publications

The efficacy and safety of acid suppressants for gastrointestinal bleeding prophylaxis in cardiac care unit patients

The efficacy and safety of acid suppressants for gastrointestinal bleeding prophylaxis in cardiac care unit patients

Goal directed fluid removal with furosemide versus placebo in intensive care patients with fluid overload: A trial protocol for a randomised, blinded trial (GODIF trial)

Interactions in clinical trials: Protocol and statistical analysis plan for an explorative study of four randomized ICU trials on use of pantoprazole, oxygenation targets, haloperidol and intravenous fluids

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