Published in the June 2006 issue of Today’s Hospitalist
As recent studies shed new light on the overuse of proton pump inhibitors (PPIs) in the hospital, some experts are calling on physicians “including hospitalists “to reassess how they prescribe the drugs.
The use of proton pump inhibitors in the inpatient setting has become so pervasive, particularly among housestaff, that some liken it to a runaway train. While the drugs are presumably used to protect against GI bleeding, a number of studies show that the threat of GI bleeds outside the ICU is relatively rare. One study, in fact, found that up to 68 percent of patients in one hospital were receiving PPIs inappropriately.
That’s a problem for several reasons. For one, when patients leave the hospital with a PPI script in hand, their outpatient physicians continue the therapy, thinking that there must have been a good reason they received the drugs while in the hospital. In addition, the therapy has received little scrutiny because few contraindications have emerged in the wake of their widespread use in the outpatient setting,
That approach may be changing. Several recent studies have found a link, albeit a tenuous one, between PPI use and the development of Clostridium difficile, as well as a higher risk of community-acquired pneumonia among patients with a history of using the acid-suppressing drugs.
Cause for concern?
While the relationship between community-acquired pneumonia and PPIs has not been studied extensively, an article in the October 2004 Journal of the American Medical Association caused physicians everywhere to take notice.
The retrospective review of 5,561 cases of first pneumonia found a significantly higher incidence of the infection among patients who received acid-suppressing drugs. For patients using PPIs, the pneumonia rate was 2.45 per 100 person years, compared to 0.6 for non-users. Researchers also found that when patients had been taking PPIs but stopped, the relative risk of developing pneumonia fell to 1.89 per 100 person years.
The data on C. difficile paint a similar picture. One Canadian case-control study found that of 18 patients admitted to the ICU with a primary diagnosis of C. difficile, 64 percent were receiving PPIs. By comparison, only 36 percent of the control group was using the drugs.
Research into the association between PPIs and C. difficile suggest that because acid suppression, like antibiotics, disrupts normal intestinal flora, the decreased gastric acidity that results may create a potentially fertile breeding ground for C. difficile. And while the studies have not established a causal relationship, they’re helping physicians who are concerned about overuse of the drugs make a case for addressing the issue.
“The issues of potential infection risk and C. difficile are providing some evidence that PPIs might not be as harmless as people have thought,” says Daniel Brotman, MD, director of the hospitalist program at Johns Hopkins Hospital in Baltimore.
Success in the ICU
What’s driving the use of PPIs in the hospital setting? Some say it’s simply a matter of too much of a good thing.
Prophylaxis with histamine-receptor antagonists (H2 blockers) or PPIs is well-established in the ICU because the drugs have been proven to reduce the incidence of stress ulcers. Strong data show that the drugs can help patients who have been on mechanical ventilation for more than 48 hours or who have been on anticoagulation.
PPI prescribing took hold on the medicine wards, the thinking goes, when physicians thought the drugs would confer similar benefits for non-critically ill patients.
“Most doctors have not met a therapy they don’t like, and they think they’re being modern if they do these things,” explains California gastroenterologist Ronald Koretz, MD, a professor of clinical medicine at the University of California, Los Angeles. “Our housestaff generally put patients on PPIs, even intravenous PPIs, and if I ask why, they tell me it’s for stress bleeding. But when you look at the data, most people don’t have stress bleeding outside the ICU.”
The reality is that even in ICU patients, stress ulcers are relatively uncommon. Data from studies led by Canadian researcher Deborah Cook, MD, considered the guru of GI bleeding prophylaxis and treatment, put the ICU incidence at less than 3 percent.
And in non-critically ill hospitalized patients, stress ulcers appear to be downright rare. In the January/February 2006 issue of the Journal of Hospital Medicine, Dr. Brotman and colleagues found that only 73 of the more than 17,000 patients admitted to the general medicine unit over a four-year period developed clinically significant gastrointestinal bleeding during hospitalization or within four weeks of discharge. That’s a rate of 0.41 percent.
Disconnect between data, practice
“The important thing to realize is that those high-risk patients are actually the vast minority of patients admitted to the hospital, even in the ICUs,” explains Brooks Cash, MD, chief of gastroenterology at the National Naval Medical Center in Bethesda, Md., and associate professor of medicine at Uniformed Services University of the Health Sciences.
“PPIs are widely overused because people don’t realize the risk factors for stress ulcer prophylaxis,” says Dr. Cash, who frequently writes on the topic. “The mindset is that the patients are in the ICU, they’re sick, and the last thing they need is another illness, so what’s a little acid suppression going to do? Yet the data simply don’t support the breadth of the use of these agents in the hospital.”
Data from a number of studies and surveys have found an estimated 30 percent or more of inpatients who receive the medications have no clinical indications for stress ulcer prophylaxis. And a study published in the June 2003 issue of Alimentary Pharmacology & Therapeutics found that 68 percent of inpatient prescriptions for PPIs were inappropriate.
“In a lot of places, when patients are admitted to the general medicine ward for relatively uncomplicated conditions such as DVT, pneumonia or atrial fibrillation, they are put on acid-suppression therapy as prophylaxis,” Dr. Cash explains. “It’s a significant disconnect when you’re talking about ICU populations and stress ulcer prophylaxis vs. a relatively ambulatory population.”
More data needed
While Dr. Cash says the possible C. difficile association is a “cause for concern,” he and other physicians interviewed for this story don’t think the studies linking PPIs to C. difficile or pneumonia are convincing enough to cause physicians to stop prescribing the drugs. They cite not only concerns about the methodologies used in the studies, but the legitimate benefits of PPI therapy.
Dr. Brotman, for example, notes that he doesn’t take issue with prescribing PPIs for empiric symptom management, as most internists have “made the observation that it does work.” He adds by way of disclosure that he takes Prilosec daily to address severe heartburn problems he has had since high school, and that he would be “very unhappy if you took the therapy away from me.”
While Dr. Koretz says that he wouldn’t stop giving PPIs to a patient with bad heartburn simply because of C. difficile risk, he notes that he has other concerns about PPI overuse. Because the drugs are so effective at shutting off acid secretion, the body’s “G cells” “the enteroendocrine cells that secrete gastrin “effectively go into overdrive trying to produce gastrin. When PPIs are stopped, trouble can result.
“We know that people on PPIs have higher gastrin levels,” he explains, “so when you stop the PPIs, you suddenly have this higher acid stimulus. The heartburn becomes much worse, and patients think they have to go back on PPIs.”
Dr. Koretz acknowledges that this phenomenon has not been studied in randomized controlled trials and is therefore “a theoretical concern,” but he suspects it could lead to patients who never needed PPIs in the first place remaining on the medications.
Lack of guidelines
Despite the emerging body of evidence about the overuse of PPIs and its clinical effects, changing physicians’ prescribing patterns promises to be a challenge. Dr. Brotman, for example, says that some of the factors driving the use of PPIs are subtle and hard to address.
“It’s become kind of like a checklist item where you can be criticized for not starting PPIs,” he explains. “In a scary way, some people have elevated PPI use to the same status as DVT prophylaxis for hospitalized patients.”
Dr. Brotman notes that he has even seen notes written by housestaff that list “GI prophylaxis, Nexium” immediately after the entry for DVT prophylaxis “even when the patient’s main problem is a urinary tract infection.
He adds that one problem is that there are no good guidelines on how to use PPIs appropriately in non-critically ill medicine patients. “We really need a trusted position statement on appropriate and inappropriate empiric use of PPIs,” Dr. Brotman says.
The most recent guidance on the subject came from the American Society of Health-System Pharmacists, in 1999, and the Society of Critical Care Medicine. But even those documents, which Dr. Cash describes as the “best that’s out there,” don’t directly address the less ill populations that hospitalists see on the wards.
The role of hospitalists
Most physicians agree that the overuse of PPIs, at least in teaching hospitals, is perpetuated by residents who start patients on the therapy or refuse to question why their patients are already using the drugs. But Vikas Parekh, MD, assistant professor of internal medicine at the University of Michigan in Ann Arbor, says that hospitalists play a role in the unnecessary continuation of PPIs as patients are discharged.
“The hospitalist part of this is that PPIs are getting started maybe for a good reason and maybe not, but we’re then sending patients home on them regardless,” says Dr. Parekh, assistant director of the university’s hospitalist program. And while the vast majority of patients discharged on PPIs don’t have a clear-cut reason for using the drugs over the long run, he adds, “It’s not in the outpatient doctor’s radar to do much about it.”
Chad Whelan, MD, associate director of the academic hospitalist program at the University of Chicago, sees the same pattern in his institution. “It’s commonly reported that about half the patients started on PPIs are also sent home on them,” he says. “That’s what we saw here.”
He’s referring to a research project coordinated by a former resident in his program. Joshua Liberman, MD, who is now a cardiology fellow at Loyola University Medical Center, published findings last month in the May 2006 Journal of General Internal Medicine.
At baseline, the researchers found an inappropriate PPI prophylaxis rate of 59 percent among the internal medicine residents. Six months after an educational intervention was begun “a one-hour lecture to the medicine housestaff on appropriate indications for stress ulcer prophylaxis “that rate dropped to 33 percent.
“That was after a new group of residents had started, so clearly it was working,” Dr. Liberman says. He notes that his study found that the general medicine service spent approximately $250,000 annually on PPIs and H2 blockers.
Reappraising PPI use
If changing the way physicians initially prescribe PPIs is difficult, perhaps another approach is to encourage them to reassess patients who are already taking the drugs when they reach the wards.
“For people coming in with major risk factors for stress ulcer disease, putting them on some sort of PPI or H2 blocker is extremely appropriate,” says David Gurka, MD, PhD, chief of critical care medicine at Rush University Medical Center in Chicago. “What we fail to do is rethink their utility once the risk factors are gone. And when patients get transferred to the floor, hospitalists often keep them on PPIs and then don’t reassess or reappraise.”
Rush University has created an ICU order set that calls for a daily reappraisal of certain drugs, including PPIs. The hope, according to Dr. Gurka, is that more ICU patients will stop receiving PPIs before they leave the ICU, which should help reduce inappropriate use downstream.
“The idea is to identify the major risk factors, treat only patients at increased risk, and stop the prophylaxis when the risk factors are gone,” he explains. “If there’s no ulcer disease history, the patient is not coagulpathic, there’s no organ failure, and some enteral nutrition has been started, it’s time to back off.”
Dr. Gurka thinks it’s best if “intensivists tackle the issue first.” But he adds that hospitalists can get involved by standardizing order sets that require physicians to indicate why the patient is being started “or continued “on PPIs. That approach, he adds, will help attack the problem at its root.
Another approach: simplified criteria
Dr. Koretz has come up with another solution that uses simplified criteria for PPIs “or any other type of stress ulcer prophylaxis. “Before PPIs were invented, when we had only H2 blockers, if you actually looked at who did bleed you were able to correlate with how many organs were failing,” he says, and the more organs in failure the more likely patients were to bleed.
As a result, he follows a basic rule: Before initiating prophylaxis, the patient must have at least three organs failing’liver, renal failure and heart failure, for example. “Those three together would count,” Dr. Koretz explains. “But if it was just heart failure, I’d say don’t do it.”
An analogy for the wards, Dr. Koretz suggests, is that patients may get subcutaneous heparin when they go in, but they don’t go out on it.
“I think hospitalists ought to think very carefully about whether they want to start PPIs at all, and not just because of the potential C. difficile issue,” he says. “They need to ask if they want to give the patient more medications than they really need.”
Provided the reason patients were started on PPIs was valid, deciding when “or whether “to stop is not always simple, Dr. Brotman suggests, and there’s no real guidance on the subject. If the patient was started on stress ulcer prophylaxis appropriately, he explains, “I’d say somewhat arbitrarily to keep them on PPIs for a month and then take them off, but I don’t have an evidence base for that.” Beyond a month, he adds, “You have to be thinking about treating something that’s real and ongoing.”
Dr. Brotman adds that emerging evidence about potential harm should also be viewed in light of the economic issues associated with inappropriate PPI prescribing.
“Now that we’re seeing a bit of literature regarding these drugs and infectious complications, that certainly bolsters my opinion that we ought to say, ‘May help, may hurt’ rather than, ‘May help, won’t hurt,’ ” he says. “And there’s certainly economic harm. These are expensive medications.”
Bonnie Darves is a freelance writer specializing in health care. She is based in Lake Oswego, Ore.