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"The use of acid-suppressive medication has been steadily increasing, particularly in the inpatient setting, despite lack of an accepted indication in the majority of these patients," write Shoshana J. Herzig, MD, from Beth Israel Deaconess Medical Center in Boston, Massachusetts, and colleagues. "Recent data in the outpatient setting suggest an increased risk for community-acquired pneumonia in current users of acid-suppressive medication (both proton-pump inhibitors and histamine₂ receptor antagonists)."

The goal of this prospective study was to evaluate the association between acid-suppressive medication and hospital-acquired pneumonia. The study cohort consisted of all patients who were admitted to a large, urban academic medical center in Boston, Massachusetts, from January 2004 through December 2007, who were 18 years or older and hospitalized for 3 or more days without being admitted to the intensive care unit.

Any order for a proton-pump inhibitor or histamine₂ receptor antagonist was considered as use of acid-suppressive medication. Potentially confounding factors were controlled through traditional and propensity-matched multivariable logistic regression. The primary endpoint of the study was the incidence of hospital-acquired pneumonia, defined with codes from the International Classification of Diseases, Ninth Revision, Clinical Modification, in patients using vs not using acid-suppressive medication.

Of 63,878 admissions in the final cohort, hospital-acquired pneumonia developed in 2219 admissions (3.5%). In more than half of admissions (52%), acid-suppressive medication was ordered (27,236 received proton-pump inhibitors and 7548 received histamine₂ receptor antagonists). Most of these medications (89%) were ordered within 48 hours of admission.

Compared with patients not exposed to acid-suppressive medications, those who were exposed had a higher unadjusted incidence of hospital-acquired pneumonia (4.9% vs 2.0%; odds ratio, 2.6; 95% confidence interval [CI], 2.3 - 2.8).

In the group exposed to acid-suppressive medication, the adjusted odds ratio of hospital-acquired pneumonia was 1.3 (95% CI, 1.1 - 1.4), based on multivariable logistic regression. Findings were identical with use of matched propensity-score analyses. Although the association was significant for proton-pump inhibitors (odds ratio, 1.3; 95% CI, 1.1 - 1.4), it was not significant for histamine₂ receptor antagonists (odds ratio, 1.2; 95% CI, 0.98 - 1.4).

"In this large, hospital-based pharmacoepidemiologic cohort, acid-suppressive medication use was associated with 30% increased odds of hospital-acquired pneumonia," the study authors write. "In subset analyses, statistically significant risk was demonstrated only for proton-pump inhibitor use."

Limitations of this study include inability to determine the potential benefits of acid-suppressive medication in preventing gastrointestinal tract bleeding, concerns regarding the validity of International Classification of Diseases, Ninth Revision, Clinical Modification, coding, and lack of information on the temporal association between use of acid-suppressive medication and diagnosis of hospital-acquired pneumonia. Other limitations include possible unmeasured confounders and insufficient power to exclude a small but increased risk associated with histamine₂ receptor antagonists.

"These results occur in the context of an increasing body of literature suggesting an association between acid-suppressive medication and pneumonia," the study authors conclude. "Further scrutiny is warranted regarding inpatient prescribing practices of these medications."

The study authors have disclosed no relevant financial relationships. Dr. Herzig was funded by the Health Resources and Services Administration of the Department of Health and Human Services to support the Harvard Medical School Fellowship in General Medicine and Primary Care. The study contents are solely the responsibility of the authors and do not necessarily represent the official views of the Department of Health and Human Services.

JAMA. 2009;301:2120-2128.

Clinical Context

Study Highlights

• The study population consisted of inpatients from 1 Massachusetts medical center between 2004 and 2007. All study subjects were at least 18 years old and were hospitalized for at least 3 days.
• The main outcome of the study was the effect of the use of acid-suppressive therapy on the rate of hospital-acquired pneumonia, an outcome which was culled from hospital discharge codes. Acid-suppressive therapy could consist of either proton-pump inhibitors or histamine₂ receptor antagonists.
• The main result of the study was adjusted to account for 50 potential covariates.
• 63,878 patients provided data for study analysis. The median age was 54 years, and 37% were men. Approximately 70% of subjects were white.
• 52% of the entire study cohort received acid-suppressive therapy. Patients who received such therapy were more likely to receive a medicine service, have an emergent admission, and receive systemic steroids and anticoagulants vs patients who did not receive acid-suppressive therapy.
• Conversely, patients who received nonsteroidal anti-inflammatory drugs were less likely to receive acid-suppressive therapy.
• 83% of subjects receiving acid-suppressive therapy were prescribed proton-pump inhibitors, and 23% received histamine₂ receptor antagonists.
• Hospital-acquired pneumonia occurred in 3.5% of subjects, including 4.9% of those receiving acid-suppressive therapy and 2.0% of those not receiving such medications.
• The adjusted odds ratio for hospital-acquired pneumonia associated with the use of acid-suppressive therapy was significant at 1.3.
• The risk for aspiration pneumonia was particularly elevated with the use of acid-suppressive therapy.
• On subgroup analysis based on treatment type, only patients receiving proton-pump inhibitors experienced a higher risk for hospital-acquired pneumonia.
• An analysis that minimized characteristics between patients who did and did not receive acid-suppressive therapy failed to alter the main study outcome.
• Researchers performed an analysis of the timing of acid-suppressive medications, and initiation of this therapy within 48 hours of admission was associated with a significant increase in the risk for hospital-acquired pneumonia.

Clinical Implications

• A previous study found that although proton-pump inhibitor therapy did not affect the overall rate of community-acquired pneumonia or pneumonia causing hospitalization, recent initiation of proton-pump inhibitor therapy was associated with a higher risk for pneumonia.
• The current study suggests that proton-pump inhibitors significantly increase the risk for hospital-acquired pneumonia, particularly aspiration pneumonia.

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