In this large cohort, nosocomial gastrointestinal bleeding outside of the ICU was rare, occurring in only 0.29% of admissions. Acid-suppressive medication was associated with a 37% reduction in the odds of nosocomial gastrointestinal bleeding. Despite this protective effect, given the low overall incidence of this outcome, 770 patients would need to be treated with acid-suppressive medication to prevent one episode of nosocomial gastrointestinal bleeding, and 834 to prevent one episode of clinically-significant nosocomial gastrointestinal bleeding.
Our definition of the primary outcome of nosocomial gastrointestinal bleeding is consistent with prior studies done in the ICU population.10, 11
Additionally, the incidence of our outcome is almost identical to that found in the non-ventilated patients in the latter study (0.18%).11
A recent retrospective case-control study in the non-critically ill patient population found a rate of nosocomial gastrointestinal bleed of 0.41%; however, this study included occult gastrointestinal bleeding in the outcome, and only included cases of bleeding that required upper endoscopy. Allowing for these differences, our observed rate of nosocomial gastrointestinal bleeding is remarkably similar to those previously reported.
The use of a propensity score approach has been shown to improve control of counfounding over traditional logistic regression methods in the setting of scarce outcomes, such as the outcome of interest in this study.29
The positive association between acid-suppressive medication and nosocomial gastrointestinal bleeding in the unadjusted analysis suggests confounding by indication; physicians place patients at higher risk for gastrointestinal bleeding on acid-suppressive medication. The reversal of the direction of the relationship between acid-suppressive medication and gastrointestinal bleeding from unadjusted to adjusted analyses - a phenomenon seen in observational studies of drug effects, attributed to control of confounding by indication30, 31
- suggests that we have controlled for a great deal of such confounding. Although residual confounding is possible, our estimate for the association between acid-suppressive medication use and nosocomial gastrointestinal bleeding is consistent with the estimates of relative risk identified in randomized controlled trials of histamine-2 receptor antagonists in ICU patients, which was 0.58 in one large meta-analysis of these trials.12
Although we have not conducted a formal risk-benefit analysis, our finding of a number-needed-to-treat of 730 should be considered in the context of prior studies addressing the risks of acid-suppressive medications in similar patient populations. A recent study by Howell et al., based at the same medical center, found an association between acid-suppressive medication and hospital-acquired Clostridium difficile
infection, with a number-needed-to-harm of 533.19
Another study based at the same medical center identified a number-needed-to-harm of 111 for hospital-acquired pneumonia.1
While some differences exist in cohort inclusion criteria amongst these studies, and the attributable morbidity and mortality of these outcomes differ, the number-needed-to-treat for nosocomial gastrointestinal bleeding is similar to or greater than the number-needed-to-harm for Clostridium difficile
and pneumonia. These findings lend support to the current guidelines which recommend against prophylactic acid-suppressive medication use in patients outside of the ICU.16
Further risk-factor and risk-benefit analyses are warranted to develop more specific guidelines that target these medications to the subset of hospitalized patients in whom the benefits might outweigh the risks.
As with all studies using administrative data, there is concern over the validity of ICD-9-CM coding. Our chart review of all administratively identified cases of gastrointestinal bleeding, coupled with adjudication of unclear cases, assurred 100% specificity of our outcome, making bias from outcome misclassification highly unlikely. Furthermore, we performed a sensitivity analysis to investigate the effect of missed cases of gastrointestinal bleeding on our number-needed-to-treat, which confirmed the robustness of our estimate even in the face of this type of misclassification.
Given that acid-suppressive medication is not expected to affect lower gastrointestinal hemorrhage, we attempted to include only cases of upper gastrointestinal hemorrhage in our outcome definition. However, we could not rule out that some cases of lower gastrointestinal hemorrhage were included, so we performed a sensitivity analysis to address this limitation. The fact that the apparent protective effect of acid-suppressive medication was relatively unchanged when restricting our analysis to more clearly defined cases of upper gastrointestinal bleeding (excluding hematochezia) strengthens the validity of our findings.
The lack of temporal information related to ICD-9-CM discharge codes is a limitation of our analysis. We addressed this concern with respect to the exposure and outcome via our chart review, assuring that exposure preceded outcome and that outcomes occurred beyond the first 24 hours of admission and not in the ICU. Another limitation is our inability to independently investigate histamine-2 receptor antagonists due to insufficient power. Given their less potent acid-suppressive effect, however, it is unlikely that they would be more protective than proton-pump inhibitors for nosocomial gastrointestinal bleeding, and thus, the number-needed-to-treat with these agents is unlikely to be lower than that observed with proton-pump inhibitors. Another limitation relates to our inability to ascertain whether the patient was on acid-suppressive medication prior to hospitalization, which rendered us unable to specifically evaluate the effect of prophylactic use of these medications in patients without other indications for their use. However, it seems likely that patients with preexisting gastrointestinal conditions necessitating acid-suppressive medication use prior to hospitalization would stand to benefit most from continuation of these medications during hospitalization, and yet despite inclusion of this patient population, we found a relatively high number-needed-to-treat. Further studies are necessary to investigate whether effect modification by prior exposure or prior conditions exists. Lastly, although almost 80,000 admissions were studied over a 4-year period, the single-center nature of our study limits generalizability. Our findings should be validated at other institutions.
In conclusion, we found that in a large cohort of non-critically ill hospitalized patients, nosocomial gastrointestinal bleeding was rare. Acid-suppressive medication use was associated with a decreased odds of nosocomial gastrointestinal bleeding; however, because of the low incidence of this complication, the number-needed-to-treat to prevent one case of gastrointestinal bleeding was high at 730. Clinicians should balance the effectiveness of these medications against their cost, their associated risks,1, 17, 18
and the relatively large number-needed-to-treat to prevent one case of nosocomial gastrointestinal bleeding. Our findings support the current recommendations against routine use of prophylactic acid-suppressive medication in patients outside of the ICU.16