June 3, 2009 — Proton-pump inhibitor use is linked to increased risk for hospital-acquired pneumonia, according to the results of a large, hospital-based pharmacoepidemiologic cohort study reported in the May 27 issue of the Journal of the American Medical Association.
"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.
June 4, 2009 (Chicago, Illinois) — A case–control study of nearly 34,000 patients with hip fractures taking proton-pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) shows that the risk for hip fracture is approximately 30% higher than in matched controls not taking these medications, researchers announced here at Digestive Disease Week 2009.
Principal investigator Douglas A. Corley, MD, PhD, MPH, assistant clinical professor of medicine at the University of California at San Francisco (UCSF) and staff gastroenterologist at Kaiser Permanente in San Francisco, and colleagues analyzed the Kaiser Permanente database to quantify hip-fracture risk with these drugs.
They identified 33,752 patients with hip fractures and 130,471 age-, sex-, and race-matched controls. Patients with hip fractures were 30% more likely than controls to have taken PPIs for at least 2 years (odds ratio [OR],1.30; 95% confidence interval [CI], 1.21 - 1.39).
Risk for hip fracture was 18% higher in those taking H2RAs for 2 or more years (OR, 1.18; 95% CI, 1.08 - 1.28).
Higher dosages for longer durations increased risk in a linear fashion. Patients who took more than 1.5 PPIs daily for 8 to10 years had an OR of 2.39 (95% CI, 1.40 - 4.08). Patients who took 0.01 to 0.74 pills a day for 8 to10 years had an OR of 0.99 (95% CI, 1.75 - 1.32; P < .001 for both PPIs and H2RAs).
An increased risk was seen even in people taking medications for only 1 year.
The greatest relative increase in risk for more than 2 years of PPI use was among people 50 to 59 years of age, whose risk was more than doubled (OR, 2.31; 95% CI, 1.67 - 3.18).
The largest number of fractures was among those aged 80 to 89 years and, although the actual number of fractures was greater, "this group had a lower relative risk associated with PPIs," Dr. Corley reported (OR, 1.19; 95% CI, 1.06 - 1.33).
"These findings could be coincidental or confounded, even though we controlled for other risk factors for hip fractures, including use of steroids and thyroid medications, and even thiazide diuretics, which are associated with a decreased risk of hip fracture," Dr. Corley said.
"Risk was increased with increasing duration of use, with larger doses, and with advancing age," Dr. Corley told Medscape Gastroenterology. "But since there was no real dose-response, the relationship is probably not causal."
"These [PPIs and H2RAs] are very effective medications for reflux disease, and there are not a lot of alternatives, but they are not completely without risk."
"Physicians should make sure there is a clear indication for PPIs, and they should not be given in perpetuity," the UCSF physician advised.
Moderator Nicholas J. Shaheen, MD, MPH, associate professor of medicine and epidemiology and director of the Center for Esophageal Diseases and Swallowing at the University of North Carolina at Chapel Hill, told Medscape Gastroenterology that "PPIs are not entirely benign."
"A possible risk of hip fracture is a pretty important question, since these drugs are so widely used. Oftentimes, once a patient is prescribed them, they are on them forever. Since their safety profile is pretty good, physicians may not think to re-evaluate the continued need [for PPIs]."
And as to whether PPIs are overprescribed, the answer is an unequivocal yes!" Dr. Shaheen said.
Dr. Corley's study received no commercial funding. Dr. Shaheen receives some funding from manufacturers of PPIs.
Digestive Disease Week (DDW) 2009: Abstract 414. Presented June 3, 2009.
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