H2 receptor antagonists associated with lower risk of bleeding and infections vs. PPIs

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1. Histamine-2 receptor antagonists (H₂RAs) were associated with lower risk of developing a secondary gastrointestinal (GI) hemorrhage, pneumonia, and C. Difficle infection (CDI) than proton-pump inhibitors (PPIs).

2. Secondary outcomes, including ICU length of stay, mortality, and ICU and hospital costs were all favorable in the H₂RA group in the unmatched groups. However, the only secondary outcome that was favored in the matched cohort was ICU mortality.

Evidence Rating Level: 2 (Good)

Study Rundown: H₂RAs and PPIs are commonly used for gastrointestinal prophylaxis in critically ill patients undergoing mechanical ventilation. Recent studies indicate that PPIs are associated with lower risk of GI hemorrhage secondary to stronger acid-suppression properties. However, increased acid suppression is speculated to play a role in infectious complications like pneumonia and CDI. The study authors found that H₂RAs were associated with lower risk of GI hemorrhage, pneumonia, and CDI. Secondary outcomes including ICU length of stay, mortality, and ICU and hospital costs were all greater in the PPI group of the unmatched cohort. Upon creating matched cohorts, the lower risk of H₂RAs in terms of primary outcome measures stood ground but the only secondary outcome favored by H₂RAs was ICU mortality. While dose and duration of acid-suppressant therapy did not affect outcomes, the risk for infectious complications was directly related to the duration of mechanical ventilation.

The strengths of the study lie in the large patient population studied across 71 hospitals, and the ability to identify risk factors for various complications in the critically ill that are consistent with previous literature. This study is clinically significant as it concludes favorably towards H₂RAs for GI prophylaxis, veering away from the Surviving Sepsis Campaign recommendations that favor PPIs. Limitations of this study include the fact that it was retrospective with outcomes being assessed on ICD-9 codes, which may not capture the severity of, or reasons for these outcomes. Other limitations include various types of H₂RAs and PPIs used at varied dosages being combined into just two separate groups based on mechanism of action. Large randomized controlled trials of these two acid-suppression agents is needed to further elucidate effect on hemorrhagic and infectious complications.

Click to read the study, published today in JAMA Internal Medicine

Relevant Reading: Proton pump inhibitors versus histamine 2 receptor antagonists for stress ulcer prophylaxis in critically ill patients: a systematic review and meta-analysis

In-Depth [retrospective cohort study]: This pharmacoepidemiological cohort study was conducted over 71 hospitals between Jan, 2003 and Dec, 2008. A total of 35,312 patients who required mechanical ventilation for 24 hours or more and were either administered a H₂RA or PPI for 48 hours or more were included. The primary outcomes assessed were the occurrence of GI hemorrhage, pneumonia, and CDI 48 hours after the initiation of mechanical ventilation. Covariate data was included if it could predict use of acid-suppressing therapies or increase the risk of primary outcomes. To account for confounding secondary to an indication for use of a particular therapy a propensity score was determined using a multivariate generalized estimating equation. The c statistic for the propensity score was 0.81, which indicates a good ability of the model to distinguish admissions receiving H₂RAs or PPIs.

The unadjusted rates of GI hemorrhage (5.9% vs 2.1%), pneumonia (38.6% vs 27.0%) and CDI (3.8% vs. 2.2%) were higher in the PPI group (p<0.001 for all). Secondary outcomes including ICU length of stay, mortality, and ICU and hospital costs all favored the H₂RA group in unmatched cohort. Cohort matching was conducted using the propensity score for groups receiving H₂RAs vs PPIs using a greedy matching technique with the algorithm searching for 1:1 matching at a tolerance level of 0.0005. The cohort matched groups consisted of 8,799 patients each. The rates of GI hemorrhage (4.7% vs 2.4%, p<0.001), pneumonia (34.0% vs 30.7%, p< 0.001) and CDI (3.4% vs 2.6%, p=0.002) were higher in the PPI group in the matched cohort. The only secondary outcome favored by H₂RAs was ICU mortality (12.3% vs 15.3%, p<0.001).

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