VA Researchers Recommend Against the Practice in Most Cases

By Brenda L. Mooney

ANN ARBOR, MI — In a case where the preventive measure might be worse than the avoided outcome, hospitals at the VHA and elsewhere often routinely provide patients with proton-pump inhibitors (PPIs) to reduce heartburn or prevent stomach or gut bleeding.

In fact, a new study suggests that about half of all patients hospitalized in United States use the drugs at any point in time. The problem, however, is that the drugs might increase the risk for infections which often have higher mortality rates than upper-gastrointestinal bleeding (UGIB).

Using a computer simulation based on real-world risk and benefit data, researchers from the VA Ann Arbor, MI, Healthcare System and the University of Michigan, found that about 90% of hospital inpatients who were first prescribed PPIs in the hospital have a higher risk of dying when they’re taking them, compared with their risk without the drugs.

A small increase in dying also exists for about 80% of patients who were already on PPIs when they were admitted and stayed on them in the hospital, according to the study published recently in the Journal of General Internal Medicine.1

Extra mortality risk exists because reducing stomach acid can increase the risk of infections, especially healthcare associated pneumonia (HCAP) and Clostridium difficile infection (CDI), according to the report.

“Many patients who come into the hospital are on these medications, and we sometimes start them in the hospital to try to prevent gastrointestinal, or GI, bleeds,” explained lead author Matthew Pappas, MD, MPH, a VA Health Services Fellow at the Ann Arbor VAMC. “But other researchers have shown that these drugs seem to increase the risk of pneumonia and C. diff, two serious and potentially life-threatening infections that hospitalized patients are also at risk for.”

For example, the drugs could suppress acid production and increase bacteria in the stomach and throat, which could then cause pneumonia, according to study authors, who called for more research on how PPIs increase the risk of infection.

For the study, the researchers used a computer model. Otherwise, they said, achieving the results would have required an impractically large clinical trial.

Pappas said, while the effect found by the study is not large, it is consistent. He recommended that very few hospital patients should start taking or continue on PPIs as a preventive measure against gastrointestinal bleeding.

“For the majority of medical inpatients outside the ICU, use of PPIs likely leads to a net increase in hospital mortality,” the authors wrote. “Even in patients at particularly high risk of UGIB, only those at the very lowest risk of HCAP and CDI should be considered for prophylactic PPI use. Continuation of outpatient PPIs may also increase expected hospital mortality. Apart from patients with active UGIB, use of PPIs in hospitalized patients should be discouraged.”

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PPIs As Routine Care


Characteristics of the study population. [Click to enlarge]

The researchers concede that might be difficult because the medications are so much a part of routine care. For example, Pappas noted, physicians prescribing high-dose steroids in the hospital often automatically prescribe a PPI to prevent the GI bleeding that the drugs can cause.

“In fact, in running our simulation, we thought we would find some populations such as those on steroids or other medications often prescribed together with PPIs, who would not experience the increased mortality risk,” he recounted. “But that turned out not to be the case.”

The VA’s Pharmacy Benefit Management guidelines say that high dose PPIs can be used to reduce the risk of upper gastrointestinal bleeding in critically ill patients who have documented intolerance, contraindication or insufficient response to intravenous histamine-2 receptor antagonists therapy. A double-dose PPI can be used for up to two weeks, according to the PBM document, which notes that the Food and Drug Administration has approved omeprazole immediate-release power for oral suspension for that purpose.

A 2010 study using the database of the New England Veterans Health Care System from 2003 to 2008 looked at 1,166 inpatients and outpatients with metronidazole- or vancomycin hydrochloride-treated incident CDI. Of those, 527 (45.2%) had received oral PPIs within 14 days of diagnosis and 639 (54.8%) did not.

The Boston Medical Center-led research team found that recurrent CDI was more common in veterans exposed to PPIs than in those not exposed — 25.2% vs 18.5. Results indicated that risks were highest among those older than 80 years and those receiving antibiotics not targeted to C difficile during follow-up.

“Proton pump inhibitor use during incident CDI treatment was associated with a 42% increased risk of recurrence,” authors of that study wrote. “Our findings warrant further studies to examine this association and careful consideration of the indications for prescribing PPIs during treatment of CDI.”

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Broad Applications of Model

Pappas, who has an engineering background and also is a hospitalists at the Michigan hospitals, worked with Sandeep Vijan, MD, MPH, a member of the VA Center for Clinical Management Research and UM’s Institute for Healthcare Policy and Innovation, who sees patients at the Ann Arbor VAMC.

He said their model could be applied to other situations where a treatment or preventive measure might have an unwanted effect. Using such models with observational study data could help tease out important answers in medicine without requiring huge prospective clinical trials, Pappas pointed out.

For example, a clinical trial of more than 64,000 patients randomly assigned to receive PPIs or placebo would be required to determine the predicted increase in mortality risk caused by PPIs in inpatients, he explained. Yet, since PPIs generally are available as generic medications or even over-the-counter medicaitons, finding funding for such a study would be nearly impossible, Pappas added.

“Any time there are complex risk/benefit tradeoffs, without the possibility of a high-quality trial, this kind of simulation can help us come up with answers to inform clinical care,” he suggested.

“Humans aren’t very good at recognizing very rare events, and reacting appropriately to things that are unlikely to happen,” Pappas noted. “Physicians have an instinct to want to prevent very bad, though rare events – but everything we do carries risks. We need to be mindful of the things we are doing to prevent rare outcomes, and keep the risks in perspective. Computers can help.”

  1. Pappas M, Jolly S, Vijan S. Defining Appropriate Use of Proton-Pump Inhibitors Among Medical Inpatients. J Gen Intern Med. 2015 Nov 9. [Epub ahead of print] PubMed PMID: 26553337.
  2. Linsky A, Gupta K, Lawler EV, Fonda JR, Hermos JA. Proton pump inhibitors and risk for recurrent Clostridium difficile infection. Arch Intern Med. 2010 May 10;170(9):772-8. doi: 0.1001/archinternmed.2010.73.