The SUP-ICU Trial: Does It Confirm or Condemn the Practice of Stress Ulcer Prophylaxis?

Abstract

Purpose: Stress ulcer prophylaxis (SUP) is routinely administered to critically ill patients for the prevention of stress ulcer–induced, clinically important bleeding (CIB). Recently, the value of SUP has been questioned due to the perceived decline in CIB and the potential for infectious complications secondary to acid suppressive therapy. The SUP-ICU trial is a large, randomized controlled trial comparing intravenous pantoprazole with placebo for the indication of SUP. It is hoped that this trial would answer many of the questions pertaining to the overall value of SUP. This article will provide an in-depth assessment of the SUP-ICU trial in the context of the overall body of literature in this area. Furthermore, applications for clinical practice and recommendations on the provision of SUP are provided. Summary: The SUP-ICU trial revealed no difference in the primary outcome of 90-day mortality with pantoprazole but lower rates of CIB were noted (which was a secondary outcome). Overall, these data provide important insight into the value of SUP along with other questions related to the provision of SUP such as the relationship between CIB and mortality, infectious complications, and enteral nutrition. Conclusions: The SUP-ICU trial is a landmark trial describing the value of SUP in a modern-day setting of intensive care unit (ICU) practice. The provision of SUP should be continued in high-risk patients. Future studies are ongoing that will add further insight to this routine practice.

Keywords

stress ulcer prophylaxis pantoprazole gastrointestinal hemorrhage critical care

The biological response to “stress” was first introduced by Seyle¹ in a classic Letter to the Editor published in Nature in 1936 where he described a 3-phase syndrome (later referred to as the “stress syndrome”) resulting from the exposure to acute nonspecific nocuous agents. Part of this stress syndrome, occurring 6 to 48 hours after the initial injury, is the formation of acute erosions in the digestive tract, particularly in the stomach, small intestine, and appendix that occur due to tissue ischemia and reperfusion injury. More than 30 years later, the occurrence of these stress erosions were linked to surgical or traumatic stress and specifically found in patients with respiratory failure, hypotension, sepsis, or jaundice.²,³ In 1978, the provision of antacid therapy titrated to maintain gastric pH of 3.5 in high-risk critically ill patients led to a reduction in gastrointestinal bleeding events (3.9% vs 24%,P < .005).⁴ The potential role of acid suppressive therapy for the prevention of gastrointestinal bleeding was recognized, and the concept of stress ulcer prophylaxis (SUP) was born. Over the next 40 years, there have been numerous randomized controlled trials, observational studies, systematic reviews, and practice guidelines addressing various aspects of SUP therapy. Nevertheless, despite the overwhelming body of evidence, there are still questions regarding this widely used and, for the most part, universally accepted practice.

The proton pump inhibitors (PPI) are the most widely used pharmacologic agents for the provision of SUP.^5-7 Over the last decade, though, there has been great concern with their widespread use. Acutely, PPIs have been associated with infectious complications such as nosocomial pneumonia and Clostridium difficile infection.⁸,⁹ Long-term use of PPIs has been linked to kidney disease, dementia, and fractures.¹⁰ While these adverse drug reactions have primarily been reported through observational research, inadvertent continuation upon discharge occurs at rates approaching 25%.¹¹ It remains speculative if the risk of adverse reactions associated with PPIs increases with long-term use, thus emphasizing prudent utilization during transitions of care. In addition to the potential harms with these agents, there is the perception that stress-related gastrointestinal mucosal clinically important bleeding (CIB) is rare due to the advancements with modern day intensive care unit (ICU) care. Some systematic reviews suggest that acid suppression offers no benefit over placebo.¹² Therefore, the potential for clinical equipoise exists due to concerns that the benefits observed with PPI therapy may be overshadowed by their complications.

The SUP-ICU study is the first large, multi-center, international, outcome-based, randomized controlled trial conducted in the modern era comparing PPI therapy with placebo.¹³ Study aims were to assess both the benefits and harms of SUP and provide a clearer picture of the value of PPI therapy for this indication. The remainder of this article will focus on the SUP-ICU trial and provide insight on how clinicians can interpret this trial (while appreciating the complete body of evidence) and optimize SUP use at their respective institutions.

The SUP-ICU trial included adult patients who were admitted to an ICU for an acute condition with at least one risk factor for CIB. Risk factors for CIB were shock, renal replacement therapy, invasive mechanical ventilation, receipt of therapeutic anticoagulants, ongoing or history of coagulopathy (defined as platelets <50 000, international normalized ratio >1.5, or prothrombin time >20 seconds within the past 24 hours or 6 months prior to admission, respectively), and history of chronic liver disease. Enrolled patients were randomized to receive either intravenous pantoprazole 40 mg once daily or matching placebo. Study drug was administered until ICU discharge, death, or a maximum of 90 days. The primary outcome was 90-day mortality while secondary outcomes were rates of at least one clinically important event (defined as CIB, new-onset pneumonia, C. difficile infection, or acute myocardial ischemia), CIB, infectious adverse events, serious adverse reactions, and the percentage of days alive without the use of life support. It was estimated that 3350 patients would be required to have 90% power to detect a mortality difference of 5% assuming a baseline 90-day mortality of 25%. There were 3298 patients enrolled. No difference was reported in the primary outcome of 90-day mortality (pantoprazole, 31.1% vs placebo, 30.4%; P = .76). For secondary outcomes, 21.9% of patients receiving pantoprazole had a clinically important event compared with 22.6% in the placebo group—unadjusted relative risk (RR) (95% confidence interval [CI]) = 0.96 (0.83-1.11). The incidence of CIB was 2.5% versus 4.2% (unadjusted RR [95% CI] = 0.58 [0.4-0.86]); infectious complications were 16.8% versus 16.9% (unadjusted RR [95% CI] = 0.99 [0.84-1.16]); serious adverse reactions were 0% and 0%, and percentage of days alive without the use of life support (median, interquartile range [IQR]) was 92 (60-97) and 92 (65-97) days for the pantoprazole and placebo groups, respectively. P values were not reported for secondary outcomes because of the lack of adjustment for multiple comparisons.

This study represents the largest single randomized controlled trial in the realm of SUP and the first robust study to evaluate clinical outcomes in the era of modern day critical care practice. Thirty-three ICUs from 6 countries contributed to the patient sample representing a vast array of clinical practice patterns. The protocol was pragmatic allowing for routine ICU practice with the exception of SUP medications. The patient population was diverse representing both medical and surgical ICUs and consisted of high-risk patients (approximately 78% were mechanically ventilated, 67% required vasopressors, 20% were coagulopathic) resulting in a high degree of generalizability. Although there was no difference in the primary outcome, there are several noteworthy points to consider when integrating the results of this trial into bedside practice.

We should not abandon SUP even though it did not influence mortality. Historically, SUP has not been shown to affect mortality likely because death as a direct result of CIB is infrequent. In fact, a recent meta-analysis evaluating acid suppression therapy for SUP versus no therapy utilized trial-sequential analysis and demonstrated statistical futility for the outcome of mortality.¹⁴ This suggests an extremely low probability of any clinical trial being capable of demonstrating a significant difference in mortality. A second systematic review identified trials published before March 2013 and the odds ratio (OR) (95% CI) for mortality was 1.00 (0.84-1.2).¹² This is consistent with that reported in the SUP-ICU trial (90-day mortality, OR [95% CI] = 1.02 [0.91-1.13]). Death is an unequivocal endpoint and provides a complete assessment of benefits versus harms, but lack of mortality benefit should not be interpreted as a lack of value. There are many interventions that are routinely used and considered standard-of-care in the ICU despite lacking survival data (eg, invasive mechanical ventilation for respiratory failure, antimicrobials for surgical prophylaxis, hyperosmolar therapy for intracranial hypertension, etc). The provision of SUP to reduce CIB, irrespective of the relationship with mortality, does have benefit. Gastrointestinal bleeding can lead to increased blood transfusions, additional invasive procedures, high-dose PPI therapy, increased monitoring, resource utilization, and cost.

The relationship between CIB and mortality is not clear. Early research has described the association between gastrointestinal bleeding and mortality.³ Later, a large analysis of 2 multicenter databases, which included 1666 patients, evaluated the attributable mortality from CIB using multiple analytic methods.¹⁵ Two of the 3 methods identified a significant increase in mortality (RR increase = 1-4). Most recently, a large international study evaluated the prevalence of risk factors and prognostic implications of gastrointestinal bleeding for mortality.⁶ There were 1034 patients included and the incidence of CIB was 2.6%. The 90-day mortality was 55.6% in patients with CIB compared with 25.4% in those without (crude OR [95% CI] = 3.72 [1.72-8.04]). After adjusting for numerous confounders, however, no association was noted (OR [95% CI] = 1.7 [0.68-4.28]).

The perception that CIB due to stress ulceration no longer exists in high-risk patients has not been validated. Recent advances in critical care practice have led to the perception that the incidence CIB due to stress ulceration is negligible. This belief, however, is not necessarily supported by the bleeding rates reported in clinical studies. In 1994, a landmark study evaluating risk factors for CIB reported bleeding rates of 3.7% (95% CI, 2.5%-5.2%) for high-risk patients (ie, those with respiratory failure and/or coagulopathy) and 0.1% (95% CI, 0.02%-0.5%) for low-risk patients.¹⁶ In 1998, a large, randomized controlled trial conducted in high-risk patients comparing ranitidine with sucralfate reported an overall rate of CIB of 2.8%.¹⁷ Seventeen years later, a large observational study noted an incidence of CIB of 2.6% (95% CI, 1.6%-3.6%).⁶ Seventy-three percent of patients received acid suppressants for at least 1 day. Two feasibility studies comparing pantoprazole with placebo were recently published whereby the reported CIB rates in the placebo group were 0%¹⁸ and 4.8%,¹⁹ respectively. Finally, 2 large observational studies compared SUP with PPI versus H2RAs (histamine-2-receptor antagonists).²⁰,²¹ The first included high-risk patients who were admitted to an ICU between 2003 and 2008.²¹ The incidence of gastrointestinal hemorrhage (identified via International Classification of Diseases, Ninth Revision [ICD-9]) was 4.4%. The second included patients admitted between 2008 and 2012 and reported CIB rates of 0.6%.²⁰ Differences could be due to the definitions used for bleeding (any vs clinically important), the reliance on ICD-9 coding, or the exclusion of patients with an ICU length of stay <72 hours in the latter study. One report found roughly half of CIB events were observed within the first 72 hours of ICU admission which correlates to when mucosal ischemia and reperfusion injury are heightened.⁶

Proton pump inhibitors may provide benefit with reducing CIB. The primary outcome in the SUP-ICU trial was 90-day mortality but CIB was assessed as a secondary outcome. The incidence of CIB was 2.5% and 4.2% for the pantoprazole and placebo groups, respectively (RR [95% CI] = 0.58 [0.4-0.86]). P values were not reported for this outcome because of the lack of adjustment for multiple comparisons. These results are similar to a network meta-analysis evaluating the efficacy and safety of various modalities used for SUP (eg, PPIs, H2RAs, sucralfate).²² Network meta-analyses allow for indirect comparisons of interventions and provide estimates that are more reliable when the number of studies reporting a particular outcome is small. In this analysis, PPIs were significantly associated with a reduction in CIB versus no prophylaxis (OR [95% CI] = 0.24 [0.1-0.6]). This translates to a number needed to treat (to prevent a CIB) of 6. Whether this benefit outweighs the risk of infectious complications is unknown.

The relationship between PPI therapy and infectious complications is complicated. The SUP-ICU trial did not report any differences in infectious adverse events (RR [95% CI] = 0.99 [0.84-1.16]). Specifically, the incidence of pneumonia was 16.2% and 16.2% for the pantoprazole and placebo groups, respectively (RR [95% CI] = 1.00 [0.84-1.19]). Similarly, there was no difference in C. difficile infection (1.2% vs 1.5%; RR [95% CI] = 0.76 [0.42-1.39]). Evidence linking acid suppressive therapy with adverse infectious outcomes has been widely noted.⁸ In the aforementioned network meta-analysis, PPIs increased the risk for pneumonia compared to sucralfate (OR [95% CI] = 1.65 [1.2-2.27]) and placebo (OR [95% CI] = 1.52 [0.95-2.42]).²² The number needed to harm was 3. Similarly, PPIs have been associated with increased risk for pneumonia in observational trials.²¹,²³,²⁴ The absence of this association in the SUP-ICU trial may relate to the relatively short duration of therapy of a median of 4 days relative to most other studies reporting average durations exceeding a week. Risk of infectious complications typically increases over the first 7 to 14 days likely because the microbial distribution requires some time to change composition in response to gastric acid suppression.⁹

Stress ulcer prophylaxis may be of benefit even in patients receiving enteral nutrition. The need for SUP in patients who are receiving enteral nutrition has been debated. Enteral nutrition has been shown to reduce mucosal ischemia through its effect on splanchnic blood flow. Furthermore, enteral nutrition formulations are usually alkaline and can increase gastric pH. In contrast, some studies have shown enteral nutrition may reduce gastric mucosal pH suggesting gastric ischemia is heightened possibly due to blood flow being redirected away from the mucosa.²⁵ The majority of information pertaining to enteral nutrition and CIB originates from subgroup analyses from previously published data. It is not surprising that systematic reviews have produced dichotomous results as to whether the addition of acid suppression infers protection from CIB in the presence of enteral nutrition.¹⁴,²⁶ These polarizing results are likely due to few studies directly comparing enteral nutrition with acid-suppressive therapy.²⁷ The most rigorous systematic review and meta-analysis evaluated randomized controlled trials comparing pharmacologic SUP with placebo where at least 50% of enrolled patients received enteral nutrition.²⁸ Clinically important bleeding was reported in 4 trials which included 725 patients and no difference was noted with SUP (RR [95% CI] = 0.63 [0.29-1.37]). One randomized controlled exploratory study evaluated 102 patients who received enteral nutrition plus pantoprazole versus enteral nutrition plus placebo.²⁷ No difference in the incidence of CIB was noted (1.8% vs 2.1% for the treatment and placebo groups, respectively). In the SUP-ICU trial, a large majority of patients were receiving enteral nutrition. In fact, the percentage of patients receiving enteral nutrition on days 1, 2, and 3 postenrollment was 57%, 75%, and 81%, respectively. Thus, the benefits observed were likely recognized in addition to that provided by enteral nutrition. Further research is required to delineate the role of enteral nutrition in preventing CIB or if SUP can safely be discontinued when patients are tolerating enteral feeds as tolerance may signify the reversal of gastrointestinal ischemia.

Risk factors for CIB are poorly defined. The 2 most commonly quoted risk factors for CIB are mechanical ventilation exceeding 48 hours and coagulopathy. These parameters result from a landmark study of 2252 ICU patients that evaluated risk factors after physicians were encouraged to withhold prophylaxis unless patients had head injury, burns >30% BSA, transplant, or recently a peptic ulcer or gastrointestinal bleed ultimately resulting in 674 patients who received prophylaxis and 1578 who did not.¹⁶ The univariate analyses showed that respiratory failure, coagulopathy, hypotension, sepsis, hepatic failure, renal failure, enteral nutrition, glucocorticoid administration, organ transplantation, and anticoagulant therapy were all associated with CIB. Only mechanical ventilation and coagulopathy were significantly associated with CIB after multivariate regression analyses (although the presence of hypotension resulted in a P value of .08). The majority of patients enrolled had either the primary diagnosis of cardiovascular disease or cardiovascular surgery representing 54.8% of the study cohort. Few patients had central nervous system injury (4%), sepsis (1.6%), head injury (1.2%), or multiple trauma (0.8%). Therefore, the results of this study must be taken into context given the population evaluated and the exclusion of patients with potential risk factors. Moreover, this study was conducted 25 years ago when practices were substantially different (eg, lack of noninvasive ventilation, lack of revascularization procedures for coronary emergencies, etc). It is not surprising that additional risk assessments have shown some of the same risk factors as this landmark trial but also a variety of additional parameters that include nutritional failure, multiple trauma, spinal cord injury, head injury, thermal injury, acute kidney injury, need for renal replacement therapy, liver disease, use of anticoagulants, and the number of comorbid disease states.⁶,^29-32 When assessed as a whole, the risk factors that are frequently quoted are generally delineated into parameters that represent mucosal ischemia (respiratory failure, need for mechanical ventilation, multiple trauma, shock/hypotension, nutritional failure, solid organ transplant), increased bleeding risk (acute or chronic kidney injury, need for renal replacement therapy, acute or chronic liver disease, use of anticoagulants), or heightened gastric acid production or reduced production of protective substances (spinal cord injury, head injury or other intracranial processes, thermal injury, history of gastrointestinal injury, use of corticosteroids). Unfortunately, all these parameters are common across critically ill patients, so definitively delineating risk factors to guide the selection of patients who should receive SUP is challenging. Moreover, studies often focus on medical or surgical patients, so applying findings to a heterogeneous critically ill population is problematic. A recent systematic review found acid suppression provided significant reductions in CIB over placebo in neurosurgical patients but not in surgery/trauma or medical ICU patients with risk factors.¹⁴ This same systematic review, however, found no benefit of SUP in studies conducted after the practice of early goal directed therapy. This further reinforces the concept that therapies have evolved over the past 25 years to the extent that information from the 1990s may no longer apply. Ultimately, risk factors are numerous and the lack of definition of risk means that most critically ill patients will receive SUP. Another concern related to risk is the use of acid suppression prior to admission to the ICU. These patients were excluded from the SUP-ICU trial. Typical practice is to continue outpatient acid suppression therapy during hospitalization irrespective of risk for CIB.

Questions the SUP-ICU Trial Does Not Address

Although the SUP-ICU trial provides insight on numerous dilemmas surrounding SUP, it is important to address the issues that it does not address. First is whether these results would also apply to H2RAs. As there was no H2RA arm in the SUP-ICU trial, it remains unknown if their overall effect (ie, the balance between bleeding and infectious complications) would be similar to that recognized with PPIs. H2RAs inhibit the secretion of histamine-stimulated acid and limit the extent of reperfusion injury by mediating inflammation (perhaps more so than PPIs).⁹ Data examining CIB rates between H2RAs and PPIs though are conflicting as a recent network meta-analysis suggests CIB rates may be lower with PPIs²² while observational studies report CIB rates that are higher.²⁰,²¹ Nevertheless, a conclusion regarding the most appropriate agent (ie, PPI or H2RA), solely based on the SUP-ICU trial, cannot be made. Second pertains to the cost-effectiveness of SUP. Cost-effectiveness accounts for all related costs of a particular therapy including drug acquisition costs, treatment benefits, and adverse effects. Pharmacoeconomic analyses comparing PPI therapy with H2RAs have demonstrated the incidence of pneumonia as one of the primary drivers of incremental costs.^33-35 The fact that no difference in pneumonia rates was recognized in the SUP-ICU trial could impact future pharmacoeconomic analyses. Further studies are needed. Next, the SUP-ICU trial was conducted in ICU patients who were at high risk for stress-related mucosal bleeding. These data should not be extrapolated to patients who are at low risk or those in a non-ICU setting. The practice of providing routine SUP to these patients should be discouraged. A pharmacist-led SUP management program has been shown to reduce inappropriate use of acid suppressing agents.³⁶ Finally, the most appropriate duration for SUP administration remains a clinical controversy. Future trials should evaluate the risk-benefit ratio of SUP as it relates to duration of therapy.

Future Trials

The SUP-ICU trial provides tremendous insight on the provision of SUP. Building on the success of this trial, other ongoing clinical trials will collectively redefine the landscape for SUP. Re-evaluating the Inhibition of Stress Erosions (REVISE) is a large multicenter randomized controlled trial comparing pantoprazole with placebo in high-risk ICU patients.³⁷ The primary outcome measure is CIB. The PEPTIC (Proton Pump Inhibitors versus Histamine-2 Receptor Blockers for Ulcer Prophylaxis Therapy in the Intensive Care Unit) study is a cluster randomized, crossover, registry-embedded trial comparing PPIs with H2RAs in mechanically ventilated patients.³⁸ The primary endpoint will be in-hospital mortality. Finally, SIREN (Sup-Icu RENal) is an observational study evaluating patients included in the SUP-ICU trial that will address the benefits and harms of SUP specifically in ICU patients in need of renal replacement therapy.³⁹

Summary

The SUP-ICU trial is a landmark study describing the provision of SUP in a modern-day setting of ICU practice. It represents the first large-scale trial revisiting the overall value of this widespread intervention. It is important for clinicians to critically evaluate which patients should receive SUP recognizing the benefits and risks associated with acid suppressive therapy. The decision to administer SUP must be individualized and only considered in patients who are at high risk for stress ulcer–related CIB. Although risk cannot be determined based on the presence or absence of a single factor, high-risk patients generally consist of those patients who have a high severity of illness (eg, shock, high organ-failure score), require organ support therapy (eg, mechanical ventilation, renal replacement therapy), and have multiple coexisting disease states, disorders of coagulation (eg, coagulopathy, liver disease), or severe neurologic injury (eg, severe traumatic brain injury). Stress ulcer prophylaxis should be administered for as long as patients remain severely ill. There may be some benefit with SUP even in patients who are receiving enteral feeds particularly during the acute phase of critical illness. As critical illness subsides, it is anticipated that the risk of CIB may also subside; thus, some patients may require only a few days of therapy rather than a prolonged course. It may not be necessary to administer SUP for the entire duration of mechanical ventilation or the complete ICU length of stay. This may lead to a more favorable balance between bleeding avoidance and infectious risk. Future randomized controlled trials are ongoing, and upcoming evidence-based guidelines will provide further insight on the role of acid-suppressive therapy for SUP.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Jeffrey F. Barletta

Mitchell S. Buckley

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