Abstract

Background

Proton pump inhibitors (PPIs) and histamine type 2-receptor blockers (H2Bs) are commonly used for stress ulcer prophylaxis among patients requiring invasive mechanical ventilation (IMV). Recent studies suggest an increased mortality associated with PPIs compared to H2Bs, but these studies poorly represent patients with cardiovascular disease or acute myocardial infarction (AMI).

Objectives

The aim of this study was to compare outcomes related to stress ulcer prophylaxis with PPIs compared to H2Bs in patients with AMI requiring IMV.

Methods

We queried the Vizient Clinical Data Base for adults aged ≥18 years admitted between October 2015 and December 2019 with a primary diagnosis of AMI and requiring IMV. Using multivariable logistic regression, we assessed for the association between stress ulcer prophylaxis and in-hospital mortality.

Results

Including 11,252 patients with AMI requiring IMV, 66.7% (n = 7,504) received PPIs and 33.3% (n = 3,748) received H2Bs. Age, sex, and the proportion of patients presenting with ST-segment elevation myocardial infarction or cardiogenic shock were similar between groups (all, P > 0.05). Compared to PPIs, patients receiving H2Bs had a lower mortality (41.5% vs 43.5%, P = 0.047), which was not statistically significant after multivariate adjustment (odds ratio 0.97; 95% confidence interval: 0.89-1.06, P = 0.49). In unadjusted and adjusted analyses, H2Bs use was associated with fewer ventilator days, less ventilator-associated pneumonia, and lower hospitalization cost but similar Clostridium difficile infections.

Conclusions

Among patients with AMI requiring IMV in this observation cohort study, there was no difference in mortality among patients receiving H2Bs vs PPIs for stress ulcer prophylaxis despite fewer ventilator days and lower ventilator-associated pneumonia in those receiving H2Bs.

Introduction

Stress ulcer prophylaxis is commonly prescribed for critically ill patients to minimize the morbidity related to clinically significant gastrointestinal (GI) bleeding events.¹ Current guidelines recommend stress ulcer prophylaxis for those at high risk of GI bleeding, which commonly includes patients requiring invasive mechanical ventilation (IMV), coagulopathy, sepsis, shock, history of previous GI bleeding, and those on antiplatelet therapy.^2-5 Proton pump inhibitors (PPIs) and histamine-2 receptor blockers (H2Bs) are the most frequently prescribed agents for acid suppression therapy.^6,7 In a meta-analysis of 57 randomized controlled trials, including over 7,000 patients, PPIs were found to be more effective at preventing GI bleeding, but potentially increased the risk of pneumonia compared to H2Bs.⁸ More recently, the PEPTIC (Proton Pump Inhibitors vs Histamine-2 Receptor Blockers for Ulcer Prophylaxis Treatment in the Intensive Care Unit) trial of over 26,000 mechanically ventilated patients similarly found those receiving PPIs had a lower risk of upper GI bleeding compared to those randomized to H2Bs. However, 90-day mortality was nonsignificantly (P = 0.054) higher in the PPI group and significantly increased in those who underwent cardiac surgery.⁹

Patients presenting with acute myocardial infarction (AMI) may be especially vulnerable to GI bleeding due to the use of antiplatelet and antithrombotic medications,^10,11 especially those who are critically ill requiring IMV.¹² In addition, stress ulcer prophylaxis selection may be particularly critical in this group as PPIs generally have more interactions than H2Bs with antiplatelet and antithrombotic therapy.¹³ A recent scientific statement from the American Heart Association currently recommends PPIs for high-risk patients as “reasonable to administer.”⁴ However, the evidence for either option in this patient population is limited and must be balanced with known risks, including Clostridium difficile infections (CDIs) and ventilator-associated pneumonia (VAP).^14,15 Given these gaps in the literature, we aimed to compare outcomes related to PPI and H2B use for stress ulcer prophylaxis among mechanically ventilated patients with AMI.

Discussion

In this multicenter study of stress ulcer prophylaxis, we report several important findings using a largely understudied population of patients presenting with AMI. First, use of H2B compared to PPIs for stress ulcer prophylaxis did not result in a statistically significant difference in mortality after adjustment for markers of acuity. Second, patients who received stress ulcer prophylaxis with H2Bs experienced fewer days of IMV. Third, the use of H2Bs was associated with less VAP compared to those who received PPIs, but CDI was not different. Finally, patients receiving H2Bs were less likely to require postintubation transfusions and undergo endoscopy. Taken together, despite potentially more complications with PPIs, mortality was similar between groups in this patient population with AMI.

To our knowledge, this is the first study to investigate the use of PPIs vs H2Bs for stress ulcer prophylaxis in critically ill, nonsurgical patients with AMI. Patients with cardiovascular disease represent a minority in most landmark trials exploring the clinical implications of stress ulcer prophylaxis. For example, in the SUP-ICU (Stress Ulcer Prophylaxis in the Intensive Care Unit) trial, only 9% and 6% of patients had a pre-existing history of previous AMI or chronic heart failure, respectively.¹⁸ Similarly, in the recent PEPTIC trial, <7% of patients were reported to have a history of chronic cardiovascular disease. In addition, fewer than 10 to 15% of patients were admitted to the ICU with an acute, nonoperative cardiovascular diagnosis, which is not defined further and may represent a heterogenous group with varying management considerations.⁹ The paucity of evidence guiding stress ulcer prophylaxis strategies among critically ill patients with AMI is a gap in literature that this study addresses.

Our results parallel findings of the PEPTIC trial, which did not find a statistically significant difference in mortality among 26,000 general ICU patients receiving H2Bs compared to PPIs for stress ulcer prophylaxis.⁹ A higher mortality was reported among patients receiving PPIs in a prespecified subgroup of cardiac surgery patients, though a secondary analysis found mortality was statistically similar between treatment groups after adjusting for patient- and site-specific factors.¹⁹ Specific to the AMI population, prior observational studies describe an increased risk of adverse cardiovascular outcomes associated with PPI use, thought to be driven by pharmacologic interactions with dual antiplatelet therapy and endothelial dysfunction.²⁰ However, one of the largest prospective randomized trials, COGENT (Clopidogrel and the Optimization of Gastrointestinal Events Trial), concluded there was no increase in major adverse cardiovascular events during a 6-month period among nonsurgical acute coronary syndrome patients coprescribed omeprazole and clopidogrel.²¹ Our findings are consistent with other studies suggesting the pharmacologic interaction between antiplatelet agents and PPIs has limited clinical impact, even in critical illness.

Our study also found that patients receiving PPIs experienced more VAP and days of IMV compared to those receiving H2Bs. PPIs promote bacterial colonization by reducing gastric acidity, which predisposes patients to VAP. By inhibiting H + ATPases, PPIs also impair neutrophil oxidative burst and phagolysosome formation, thereby blunting the immune response.²² Similar to our findings, Bashar et al²³ reported a 3-fold increase in VAP among mechanically ventilated patients randomized to receive stress ulcer prophylaxis with PPIs compared to H2B, though duration of IMV was similar between the groups.

Conclusions

We found that stress ulcer prophylaxis with H2Bs compared to PPIs in patients with AMI requiring IMV was associated with fewer ventilator days and VAP; however, there was no difference in mortality between the 2 groups. Our findings suggest that choice of either stress ulcer prophylaxis, despite potentially more complications with PPIs, is associated with a similar in-hospital mortality.