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'New' ulcer therapy still at the gate

Most clinicians unsure of whom to treat--and what drugs to use

From the October 1995 ACP Observer, copyright 1995 by the American College of Physicians.

By Edward Doyle

In the early '80s, medical science was on the verge of a breakthrough. Two Australian physicians had discovered that bacteria, not stomach acid, is the cause of most ulcers and that by simply using antibiotics, up to 80% of ulcer patients could be permanently cured. For the nearly 10% of the population that suffers from ulcers, the announcement meant potential freedom from years of costly maintenance drugs and painful ulcer relapses.

More than a decade after that initial discovery, only a handful of physicians are actually treating ulcers with antibiotics. Despite dozens of journal articles, efforts from professional societies and even a consensus statement from the NIH confirming that physicians should treat most forms of ulcers with antibiotics, the medical community has failed to change the way it treats ulcers.

Why? An obvious factor is the reluctance of physicians to adopt new therapies. But the slow move to target the Helicobacter pylori bacteria is also due to the fierce conservatism of academic medicine, the sluggish nature of government agencies and the financial interests of big business. Each of these plays a role in setting the pace of change in medicine, and as the discovery of H. pylori illustrates, all can help inform--or confuse--practicing physicians.

A dramatic new approach

First to confront physicians, though, is the dramatic change in thinking that H. pylori has unfurled. Over the past century or so, the old aphorism "no acid, no ulcer" has become so entrenched in medicine that physicians have had a hard time readjusting their views of ulcer disease. "The fall of the acid hypothesis to me is like the fall of communism," explained David F. Ransohoff, FACP, professor of medicine and epidemiology at the University of North Carolina, Chapel Hill. "I never thought it would happen in my lifetime. I never thought it would be challenged, much less toppled."

Why would he? Traditionally, the cause of ulcers and their treatment weren't even issues. Physicians simply prescribed one of several H-2 blockers, giving their patients somewhat effective relief. And although nearly 80% of all ulcer patients would experience a recurrence within a year, the treatment seemed acceptable enough at the time. "We didn't know that we needed anything else," explained Tadataka Yamada, FACP, chairman of the NIH's 1994 consensus conference on ulcers and chairman of the internal medicine department at the University of Michigan Medical Center. "Ulcers would recur, but as long as you have healing and recurrence, the thought was that you were taking care of the problem."

But by the early '90s, a wealth of clinical studies had made it clear that attacking H. pylori, not prescribing maintenance therapies of H-2 blockers, was the way to cure most ulcers. Even today, however, many physicians simply aren't treating ulcers with antibiotics.

Exactly how many physicians have embraced H. pylori eradication therapies? It's not clear. Leaders in the field estimate that about 10% of primary care physicians treat ulcers with antibiotics; gastroenterologists, who consider themselves to be on the cutting edge of ulcer treatment, say that at least half their colleagues look for H. pylori when treating ulcers.

But statistics from services that track physicians' use of drugs show that on average, less than 3% of drugs prescribed for ulcer patients are antibiotics. Similar statistics show that this rate applies not only to primary care physicians, but also gastroenterologists.

Critics point out that because these data did not come from a study of how physicians treat ulcers, they may be skewed. To be fair, these statistics slightly overestimate the percentage of prescriptions written for H-2 blockers because they are normally prescribed more than once for a single patient, compared to antibiotics, which are typically prescribed only once. But even considering that glitch, the numbers still show that the majority of physicians are not treating ulcers with antibiotics. (Similar results were obtained in a study of physicians' prescribing habits commissioned by the American Gastroenterological Association [AGA].)

There has been some progress--government statistics show that just three years ago less than one half of 1% of prescriptions for ulcer diagnoses were antibiotics--but physicians remain deeply disturbed by the low number of colleagues prescribing antibiotics. "I'm shocked," explained David A. Peura, FACP, president of the AGA. "If this is true, we've got an even bigger job of educating physicians than I thought."

Confusion for clinicians

A big part of that job will be to give clinicians solid information on how to treat H. pylori. The 1994 NIH consensus paper recommended that physicians treat ulcers with antibiotics, but it ignored the chief issue for practicing physicians: Which drugs should be used? It left that task to the FDA, which has yet to approve specific drugs to treat H. pylori. (Agency officials say that recommendations are still being worked on and could be released within a year.)

And the pharmaceutical companies, which provide physicians with much of their drug education, are reluctant to downplay the role of H-2 blockers, drugs that gross billions of dollars a year. For several drug manufacturers, the timing couldn't be worse; many are already watching their bottom lines shrink as many of these drugs' patents expire.

Drug company officials, however, are quick to point out that FDA rules don't allow them to talk about alternative uses for drugs, even antibiotics that have been around for years, until they have been approved for specific new therapies. "We can only talk about what's in our labeling for approved drugs," explained Duane D. Webb, ACP Member, director of international gastroenterology clinical research for Glaxo Inc., the maker of Zantac. "We can't even hand a reference out saying you might want to take a look at this if it's not something in our labeling," he said. "It's very restrictive."

As a result, physicians have to do a little work to learn about the latest treatment for H. pylori. "So many physicians get their information about new treatments either through pharmaceutical company representatives or through journal ads, and nobody can talk about it except physicians among themselves," explained Dr. Peura from the AGA. "As soon as the FDA recommends a particular drug therapy, physicians will be bombarded with literature, but until then, they're on their own."

But that hasn't happened yet, and in recognition that both physicians and patients need some help when it comes to treating H. pylori, the AGA has launched an educational campaign to educate both physicians and patients about the link between H. pylori and ulcers. The organization went farther than the NIH report and recommended specific antibiotics that physicians should use to treat ulcers.

Whom to treat?

But Dr. Peura noted that those recommendations are already outdated, so even the AGA's best effort leaves practicing physicians facing as many questions as answers. For example, how should physicians test for H. pylori? They can currently use blood tests, though physicians not affiliated with academic medical centers may have limited access. (Several non-invasive breath tests are currently at the FDA for approval and are expected to be approved in less than a year.) And which infected patients should be treated with antibiotics, just those with documented ulcers or anyone with ulcer-like symptoms?

Even for practitioners who keep up with the medical literature, the answers to these questions are something of a mystery. Most clinical studies focus on how to treat patients with documented ulcers, a scenario that isn't typical for clinicians. "What people come to the doctor for mostly is for dyspepsia, and you don't know if they have an ulcer or not," explained John H. Walsh, FACP, professor of medicine and director of the Center for Ulcer Research in Education (CURE) at UCLA.

So, unless their patients present with a documented ulcer, physicians are left facing some tough choices. Should they refer all their infected patients for endoscopy to confirm an ulcer before treating for H. pylori? For clinicians trying to keep their patients happy, it's not a likely option. "If you're a practitioner and you have a patient before you with a bellyache, the last thing that patient wants to hear is that he or she has to go to a gastroenterologist to get scoped," said R. Brian Haynes, FACP, professor of medicine and clinical epidemiology and chief of the health information research unit at McMaster University in Hamilton, Canada, editor of ACP Journal Club and co-editor of Evidence-Based Medicine.

One alternative is to treat everyone who is infected with the bacteria (up to half of the overall population) and suffering from ulcer symptoms without confirming the presence of an ulcer. But there are questions about the logic of such an approach; one physician compared it to treating all patients who are tired for hypothyroidism. In addition, there are concerns about allergic reactions to some of the antibiotics used to treat H. pylori and worries about creating drug resistant strains of the bacteria. "When you give lots of antibiotics you're increasing the global antibiotic burden on society," explained Julie Parsonnet, MD, assistant professor of medicine and health research and policy at Stanford University School of Medicine. "What does it mean to the rest of the organisms we carry around with us if we start giving all these antibiotics to minimally symptomatic people?"

There is an even bigger problem in requiring physicians to confirm an ulcer before treating with antibiotics: It's getting harder and harder to find patients with readily identifiable ulcers. Treating ulcers with H-2 blockers has done such a good job of keeping ulcers at bay, at least temporarily, that it is difficult to find patients who are actually suffering from an ulcer. "A lot of people with ulcer disease only have episodes every three or four years," Dr. Walsh said.

H. pylori pioneer Barry J. Marshall, MD, clinical associate professor of medicine at the University of Virginia and now president of the Helicobacter Foundation, an educational institution for physicians and patients in Charlottesville, Va., insists that physicians should treat patients suffering from ulcer symptoms. "What are you going to call this guy? Are you going to call him a patient with an ulcer or are you going to call him a patient with non-ulcer dyspepsia?" he said. "My answer is, who cares. If he's got H. pylori, treat it. If he has an ulcer, you'll cure him."

Change in the offing?

Dr. Marshall may advocate treating all symptomatic patients, but the medical establishment maintains that physicians should not treat for H. pylori unless an ulcer is clearly present. The reality is that conventional treatments are still safe and will continue to remain attractive to many physicians. For most people, after all, ulcers are not a life-threatening condition. "You can always give patients H-2 antagonists," Dr. Haynes said. "If they work, the patient won't complain, and if not you can do [a different treatment] later on."

Even so, Dr. Marshall is optimistic that change is on the way. "The gastroenterologists that are graduating or coming through the specialty have known about this since they started medical school," he explained. "When they took microbiology they would hear about H. pylori, so this little light bulb already goes on in their heads whenever they hear about ulcers."

Several drug companies are racing to develop and obtain FDA approval for new ulcer drugs that will complement the role of antibiotics. (Glaxo is working on an agent that is a combination of ranitidine and bismuth.) Dr. Marshall predicts that once the FDA approves these drugs (expected in less than a year), the drug companies' marketing campaigns will raise awareness--and public demand--for new ulcer treatments.

Still other developments may speed this process up. The World Health Organization has established H. pylori as a cause of cancer in man; if researchers determine that stomach cancer can in fact be prevented by treating H. pylori, the demand for new therapies may be unstoppable."If you can link an infection to cancer and it becomes truly legitimized by an NIH consensus statement," said Dr. Yamada, "the public is not going to stand by and watch this go unnoticed."

But the big question is how would physicians react? They have already proved that they found it difficult to bridge the gap between H. pylori and ulcers; how will they accept the idea that a bacteria causes cancer? It's hard to say, but many predict an even longer struggle. "Physicians' ideas about the mechanisms of carcinogens don't by and large involve infection," explained Dr. Ransohoff. "They might involve inflammation, but it's a huge leap to go from bacteria to cancer."

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