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Raising the Bar: New Paradigms in the
Treatment of Acid-Related Disorders


Introduction

Experts who refer to raising the “therapeutic bar” in the treatment of gastroespophageal reflux disease (GERD) and acid-related disorders point to pharmaceutical developments over the past decade that have enabled the majority of patients to achieve healing and often resolution of their symptoms. Proton pump inhibitors (PPIs), first introduced in late 1989, figure prominently in this accomplishment, which continues today with newer, more effective PPIs. The utilization of newer PPIs, with a rapid onset of acid inhibition and metabolic differences from others in the class, along with therapeutic strategies such as aggressive treatment aimed at complete symptom relief, predict a further elevation of the therapeutic bar. Given this level of success, the question arises: “What is left in the field of GERD in 2000”? This question and others were addressed by leading researchers in the field during this program. Seymour M. Sabesin, MD, Professor of Medicine from Rush-Presbyterian St. Luke’s Medical Center and Program Director, described the twofold focus of this CME program: identification of enhanced utilization of antisecretory drugs in the treatment of acid reflux disease and for eradication of H. pylori in peptic ulcer disease, and dissemination of clinical guidance for the practicing physician.


The Past, Present and Bright Future of Acid-Suppression Therapy

M. Brian Fennerty, MD, Professor of Medicine from Oregon Health & Science University, placed the advances in treatment of acid-peptic disorders into context. In the past, he said, the clinical focus was on healing of the esophagitis. Today, many clinicians believe that goal was misplaced—that it should initially have been focused on relief of symptoms. From one-half to two-thirds of patients with complaints of acid reflux or heartburn have non-erosive reflux disease characterized by moderate to severe symptoms. And even for the smaller proportion of patients with erosive disease, symptom relief, often of heartburn, is a central concern. (The exceptions involve severe cases, such as Barrett’s esophagus, and patients with gastrointestinal bleeding or esophageal cancer.)

In the vast majority of patients, PPIs relieve heartburn, the key symptom, far better than H2 blockers or prokinetic agents. This level of efficacy has served to educate clinicians about the disease state itself. According to Dr. Fennerty, “PPIs effectively allow for the delineation between erosive GERD and common heartburn with a sensitivity as high as 80%, thus reinforcing the correlation between acid control and GERD treatment” (Schenk BE, et al. Am J Gastroenterol 1997;92:1997-2000; Fass R et al. Arch Intern Med 1999;159:2161-2168). The role of PPIs today also extends to treatment, in conjunction with antibiotics, to eradicate helicobacter pylori, a major cause of peptic ulcer disease. Thus the therapeutic bar, a decade-plus after the launch of the first PPI, is raised to the extent that the remaining challenges concern only about 15% of patients with erosive esophagitis whose healing rates are less than
optimal.

In 2002, experts speak of the future in terms of such strategies as on-demand and intermittent therapy in GERD, and chemoprevention of Barrett’s esophagus. In peptic ulcer disease, experts are considering what might be the optimal
PPI regimen with antibiotics.


Pharmacology of PPIs: Some are More Equal than Others

All proton pump inhibitors share a drug class, but possess differences that translate into significant clinical distinctions. According to John R. Horn, PharmD, Professor of Pharmacy from the University of Washington, the question of whether all PPIs are equal can be answered by referencing George Orwell, in “Animal Farm.” All farm animals were said to be equal, as the story went, except that some were more equal than others.

Differences in the pharmacology of individual PPIs translate into differences in onset and extent of pH control and symptom relief, and ultimately into the length of required therapy. PPIs, all prodrugs, are taken in an inactive form. Following administration, a two-step activation process renders the drugs therapeutically available. This process begins with protonation of the parent compound. The pH at which half of the molecules of a compound are protonated— the pKA—determines the range of pH values over which the PPI will become activated, a necessary step prior to binding with the proton pump on the gastric parietal cell. Among the available PPIs, the pKA ranges from about 5 with rabeprazole, to about 3.9 with pantoprazole.” “The higher the pKA,” said Dr. Horn, “the wider the range of pH values over which it will activate.”

This effect has been substantiated in studies such as one to evaluate median 24-hour gastric pH after initial administration of one of several proton pump inhibitors (lansoprazole, omeprazole, pantoprazole), compared to placebo (Pantoflickova D et al. Gastroenterology 2000;118(4):A1290). According to results from this study, Dr. Horn said, and virtually every study to look at this response, rabeprazole was statistically superior to other PPIs in producing a rapid inhibition of acid secretion, partially due to its rapid activation.

Metabolism is another area for clinical PPI differentiation. With the exception of lanzoprazole and rabeprazole, most proton pump inhibitors are metabolized predominantly via the 2C19, cytochrome P450 enzyme pathway. (Lansoprazole is metabolized equally by 3A4 and 2C19 enzymes. Rabeprazole is metabolized primarily via a non-cytochrome P450 branch, with 2C19 a minor pathway.) Additionally, omeprazole and esomeprazole inhibit 2C19 activity, effectively inhibiting their own metabolism. As a result “…they will have altered bioavailability with continuous dosing,” according to Dr. Horn.

Individual genetic variability or the “genotype effect” produces between-person differences in clinical response to PPIs. 2C19 activity is determined by two genes. Most persons possess both genes (homozygotes), or one working gene and one nonfunctional gene (heterozygotes). About 3% of Caucasians have neither gene and as a result are poor metabolizers of 2C19. These genetic differences result in variable PPI kinetics and patient response to PPI therapy. As Dr. Horn explained, with omeprazole, “There was a roughly 10-fold difference between the very fast and very slow metabolizers…[accounting for the fact that] some people require double dosing.”

Rabeprazole, on the other hand, produces a more consistent response across the population because it does not depend to a great degree on 2C19 for its metabolism, and at the clinical level, fewer individuals require double dosing.
PPIs play a role in therapy for peptic ulcer disease that researchers are continuing to optimize. While PPIs are not bactericidal, they interfere with H. pylori by several mechanisms. In addition, PPIs participate in what Dr. Horn described as a complex interplay with antibiotics that are used in combination regimens to eradicate H pylori. In one scenario, some proton pump inhibitors are metabolized by CYP3A4. This enzyme is inhibited by clarithromycin. When used together, the result is an increase in the concentration of the PPI along with a boost in overall antibiotic activity. Amoxicillin and clarithromycin are very sensitive to acid; at the normal gastric pH of 1.2, they undergo rapid degradation. But at higher pH levels, such as those associated with some PPIs, notably rabeprazole, antibiotics are more stable. In clinical terms, this results in a lengthening of the duration of therapeutic effect. Clinical differences in H. pylori eradication rates among different PPIs illustrate the influence of pH over bacterial eradication rates (Figure 1).


Evaluating Symptom Control and the Impact of PPIs on Heartburn Relief

Peter J. Kahrilas, MD, Marquardt Professor of Medicine, Northwestern University Medical School summarized the state of the art in treatment of reflux disease today. “It is now well accepted that PPI therapy is very effective in resolving erosive esophagitis. However, the same cannot be said for symptomatic control. As esophagitis has become less of a problem, the issue of symptom control has become a more substantial one. Thus, whether it be in cases of healed esophagitis or endoscopy-negative reflux disease, the frontier has shifted to symptom control.”

In recent clinical trials, symptom control has become more variable across PPIs than has healing of esophagitis. This finding may follow from the very recent concept that erosive GERD appears to be pathophysiologically distinct from nonerosive disease, and, especially in endoscopic-negative reflux disease (ENRD), evidence suggests that there is a heterogeneous group of patients. Dr. Kahrilas described three distinct patient subpopulations:

• those with esophagitis who are either in remission or fail to meet endoscopic criteria under use
• patients with hypersensitivity to esophageal stimuli, exhibiting both acid and mechano-sensitivity to stimuli below the threshold of a normal population, and
• patients with “functional heartburn”, whose symptoms are not clearly related to reflux despite being characterized as heartburn, regurgitation, chest pain, and so forth.

Without objective endoscopic evidence, the evaluation of symptom control in endoscopy-negative patients has posed a challenge that experts have met by establishing new definitions. Complete resolution of symptoms they define as “no heartburn in the seven days prior to the current clinic visit.” Adequate resolution is defined as “one or fewer episodes of heartburn in the last seven days prior to the clinic visit, and no episodes of severe heartburn.” As study endpoints, these definitions may be too stringent, Dr. Kahrilas suggested, asking whether it should be necessary to eliminate the disease—to effectively bring the heartburn episodes to zero—in order to achieve a level of symptomatology that does not compromise quality of life? He suggested that, in the study of PPIs, perhaps “we’ve set the bar at an unreasonable level.”

When they are evaluated according to their effect on quality of life (QOL), PPIs are indeed having a positive impact on patients. In one of only a few studies to use quality of life as an endpoint, on-demand PPI therapy translated into significant improvements in perceived quality of life. The study, using two doses of omeprazole, showed that symptom control (adequate control) was proportional to the dose of antisecretory therapy (Lind T, et al. Scand J Gastroenterol 1997;32:974).

Where antisecretory therapy is less than effective, it may be that the symptoms are not acid-mediated. In one study of a large population of persons with dyspepsia, in Scotland, only 8% reported heartburn as the dominant symptom (Jones, et al. Eur J of Gen Practice1996). In 25% of the population, upper abdominal symptoms were most prominent. But the majority of patients reported mixed symptoms. These are among the factors that have confounded the establishment of guidelines for the diagnosis of ENRD, Dr. Kahrilas said.

Heartburn Relief in ENRD:Rabeprazole vs Placebo
In a study reported at the 2002 Digestive Diseases Week by Dr. Kahrilas and colleagues, rabeprazole was evaluated for the primary endpoint of speed of heartburn symptom resolution in highly symptomatic patients (Kahrilas PJ et al. Gastroenterology 2002. In press). The time to the first 24-hour heartburn-free day or night was, predictably, very significant for rabeprazole. (Figure 2)

Impressive therapeutic gains were also seen in complete heartburn relief at 4 weeks with active treatment, satisfactory heartburn relief at 4 weeks, and antacid-free days or night or global satisfaction. “An interesting additional finding from this study was that regurgitation and belching was significantly improved in the rabeprazole-treated group.” No difference in bloating was seen, nor effects on nausea, but patients reported an improvement in symptoms of early satiety.

These data help to make the points that the endoscopic-negative patient population suffering with heartburn is a
heterogeneous group and most often has a complex of symptoms, only some of which are acid-mediated. “Symptom control can be achieved by antisecretory therapy,” Dr. Kahrilas concluded, “providing the symptoms are acid-
mediated, and reasonable therapeutic objectives are utilized.”


Setting the Standard for H. pylori Eradication

PPIs play an important role in combination antimicrobial regimens for peptic ulcer disease (PUD) with H. pylori. As it was explained by Nimish B. Vakil, MD, Clinical Professor of Medicine at the University of Wisconsin Medical School, PPIs are not bacteriocidal, but have a “bacteriostatic” effect, causing lysis of H. pylori at neutral pH in the presence of urea.
Treatment strategies for PUD with H. pylori involving PPIs have evolved rapidly in the past decade, but there is still uncertainty as to the optimal duration of therapy, and less than ideal patient compliance is a concern, especially with longer-term regimens. Effective short-term treatment is needed, and in Europe, studies have shown such efficacy, Dr. Vakil remarked. “In Europe, 7-day courses of triple therapy with a PPI, clarithromycin and amoxicillin are widely used and have been shown to have high eradication rates (Mach 2 Clinical Trial).” In the United States, however, studies with 7-day regimens, and even shorter regimens of 3-, 5- and even 1-day, have led to poor results thus far, and current guidelines recommend treatment for 10 to 14 days (Howden C et al. Am J Gastroenterol 1998;93:359-366; Laine L et al. Aliment Pharmacol Ther 1997; 11:913-917).

Studies with newer PPIs have shown an increasingly important role in combination regimens with antibiotics for patients with peptic ulcer disease and H. pylori infection. Rabeprazole has been shown to have a rapid onset of action both in vitro and in vivo (Kromer et al. Pharmacology 1998;56:57-70). And, a number of European studies have shown it to be associated with a high H pylori eradication rate (Stack W et al. Am J Gastroenterol 1998;93:1909-1913). These prior findings provided the conceptual foundation for a recently completed study by Dr. Vakil and co-researchers, who hypothesized that a rapid increase in intragastric pH could result in high eradication rates with shorter duration therapy. Results of their study were reported in abstract form at the 2002 DDW meetings (Vakil NB et al. Gastroenterology 2002;122(4):A551). The goal of the trial was to determine the efficacy and safety of 3-day, 7-day, and 10-day therapy with rabeprazole, amoxicillin and clarithromycin compared to standard 10-day therapy with omeprazole, amoxicillin and clarithromycin. The results clearly demonstrated that both 7-day and 10-day rabeprazole triple therapies have equivalent eradication rates to those of 1-day omeprazole triple therapy, representing a potential advance over currently approved regimens in the United States.

For clinicians treating patients with erosive and non-erosive GERD, and peptic ulcer disease, advances such as those outlined by speakers at this symposium promise to further extend the therapeutic successes that were started with
the introduction of PPIs as treatment options.


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