Gastroesophageal Reflux Disease Newsletter                      Series 1, Issue 1, 2007

MEDICAL MANAGEMENT OF GASTROESOPHAGEAL REFLUX DISEASE

Nikolaos T Pyrsopoulos, MD, PhD
University of Miami School of Medicine

Xaralambos Zervos, DO
Mount Sinai Medical Center

The severity of gastroesophageal reflux disease (GERD) varies from person to person, but the potential of long-term complications, including esophageal adenocarcinoma, make it a formidable disease entity. The annual cost for patients who have symptoms of GERD is in excess of $15 billion. GERD accounts for 2-5% of all primary care office visits, and 40% of Americans experience the symptoms of GERD. Treatment for these patients is aimed at symptom relief, with a targeted goal of improved quality of life, as most patients report that quality of life is negatively affected by the symptoms of GERD.

GERD is widely accepted as chronic symptoms or mucosal damage produced by an abnormal reflux of gastric contents into the esophagus. Heartburn is not only the cardinal symptom of GERD but is also the most common symptom of the condition that brings patients into the physician’s office. In the initial evaluation of patients with GERD, a screen with a more aggressive approach to evaluation is appropriate for patients with "alarm" symptoms (eg, recent weight loss, dysphagia, blood in the stool) or for patients in high-risk categories (eg, male, aged ≥45 y).

For patients who do not have symptoms that may be alarming for associated complications and who are not in any high-risk category, the initial interventions should consist of lifestyle modification, which includes raising the head of the bed, encouraging weight loss, eating small meals, eating low-fat meals for dinner, eating dinner at least 3 hours prior to bedtime, stopping smoking, and limiting alcohol consumption. Antacids and over-the-counter histamine 2 (H2)–antagonists should be tried before other medication is prescribed.

Recent guidelines for the management of GERD from the American College of Gastroenterologists advocate that relief from heartburn alone is indicative of healing esophageal lesions. The clinical management guidelines for patients with GERD recommend initiation of the most effective treatment as early as possible. The severity of symptoms does not correlate well with disease severity. Acid suppressive therapy should be targeted at symptom resolution and should be the primary concern for empirically treating patients with GERD. Sufficient duration to heal unrecognized esophagitis should be considered when treating patients for GERD.

The pharmacologic treatment of GERD is primarily with H2-receptor antagonists and proton pump inhibitors (PPIs). Large randomized studies have been done in many centers worldwide to study the efficacy of H2-antagonists and PPIs. In general, patients with endoscopic evidence of esophagitis show a 50% healing rate with H2-antagonists and an 80-95% rate with PPIs. The superiority of PPIs to H2-antagonists has been well demonstrated over the last 10 years.

H2-receptor antagonists compared with PPIs

In 1998, Mason and colleagues examined 725 patients who were randomized to therapy with either omeprazole or antacid-alginate/ranitidine in a step-up therapy approach. Complete relief at 16 weeks was seen in 61% of the PPI group compared to 40% of the antacid-alginate/ranitidine group (P < .0001). Forty-six percent of the patients treated with omeprazole were free of symptoms after the first 10 mg step compared to only 17% in the group treated with antacid-alginate/ranitidine (P = .0001). Total relief of heartburn was achieved by more patients in the omeprazole treatment group than the antacid-alginate/ranitidine treatment group (62% vs 36%, respectively, at 4 weeks; 81% vs 60%, respectively, at 16 weeks [P = .0001]).

The Canadian Adult Dyspepsia Empiric Treatment – Helicobacter pylori Negative (CADET-HN) study evaluated 512 patients (from 35 centers) who were randomized to receive a 4-week trial of omeprazole 20 mg once daily, ranitidine 150 mg twice daily, cisapride 20 mg twice daily, or placebo. At 4 weeks, symptom relief was achieved at the following rates:

• Omeprazole - 51% (69/135 patients; 95% CI, 43-60%)
• Ranitidine - 36% (50/139 patients; 95% CI, 28-44%)
• Cisapride - 31% (32/105 patients; 95% CI, 22-39%)
• Placebo - 23% (31/133 patients; 95% CI, 16-31%)

The outcome with omeprazole was significantly better than all other treatments (P < .05). Similar results were also obtained by Jones and colleagues, who found, at 4 weeks, 69% symptom relief in patients receiving lansoprazole 30 mg daily compared to 44% relief in patients taking ranitidine 150 mg twice daily (P = .001).

PPIs compared with PPIs

Many head-to-head trials have studied which PPI is more effective in symptom relief. The EXPO trial looked at 2,766 patients who were randomized to receive daily doses of esomeprazole 40 mg or pantoprazole 40 mg for up to 8 weeks. Following the 8-week course, these patients then received 6 months of maintenance therapy at 20 mg daily of their respective medications. At the completion of 6 months of treatment, the proportion of patients with endoscopic and symptomatic remission was significantly greater in the esomeprazole group than in the pantoprazole group (87.0% vs 74.9%; P < .0001). The esomeprazole group also had more patients free of moderate to severe GERD symptoms and fewer discontinuations because of symptoms than did the pantoprazole group (92.2% vs 88.5%; P < .001).

Similar results regarding the use of esomeprazole have been reported by both Richter and colleagues and Castell and colleagues. In Richter’s randomized double-blind trial, esomeprazole 40 mg was compared with omeprazole 20 mg once daily in 2,425 patients (H pylori–negative by serology) with erosive esophagitis from 163 US centers over 8 weeks. The primary end point looked at the number of patients with healed esophagitis at the end of week 8. Secondary end points were the number of patients with resolution of heartburn symptoms at week 4, time to first resolution, sustained resolution of heartburn symptoms, and number of heartburn-free days and nights. At week 4, more patients were healed with esomeprazole than with omeprazole (81.7% vs 68.7%); by week 8, significantly more patients were healed (93.7% vs 84.2%; P < .001). Esomeprazole was superior to omeprazole for all secondary measures and had a similar safety profile. The most common adverse events in both treatment groups were headache, diarrhea, and nausea.

In Castell’s randomized double-blind multicenter trial, 5,241 adult patients with endoscopically documented erosive esophagitis were randomized to receive daily doses of either esomeprazole 40 mg or lansoprazole 30 mg for 8 weeks. The primary end point was healing of erosive esophagitis at week 8. Secondary end points were the number of patients healed at week 4, resolution of heartburn symptoms, time to first resolution, sustained resolution of heartburn symptoms, and number of heartburn-free days and nights. Patients taking esomeprazole had significantly higher healing rates than those taking lansoprazole at week 8 (92.6% vs 88.8%; P = .0001). Patients treated with esomeprazole also had faster resolution of sustained heartburn symptoms as well as nocturnal heartburn symptoms.

European trials have looked at head-to-head comparisons of pantoprazole 40 mg versus esomeprazole 40 mg and pantoprazole 40 mg versus omeprazole 40 mg. Gillessen and colleagues randomized patients into double-blind groups; 113 patients received pantoprazole and 114 patients received esomeprazole. They concluded that similar efficacy existed between the studied PPIs in healing esophageal lesions and symptom relief from GERD. Korner and colleagues randomized 669 patients into a pantoprazole group (n = 337) and an omeprazole group (n = 332). They reported similar efficacy between the studied PPIs in treating patients for GERD, especially in patients who were compliant with the drug regimen.

Onset of action

More recent attention has been paid to the onset of action of PPIs. Bytzer and colleagues studied rabeprazole, a known fast-acting PPI, and omeprazole to compare the onset of heartburn control during the first 7 days of treatment in patients with erosive esophagitis. They randomized 717 patients with endoscopically confirmed erosive esophagitis into double-blind groups to receive once-daily treatment with rabeprazole 20 mg or omeprazole 20 mg for 7 days. Median time to reach heartburn control was 1.5 days for both groups (P < .43).

About 2 thirds of pregnant patients develop heartburn due to anatomic changes or lower esophageal relaxation caused by progesterone. Information about the safety of taking PPIs during pregnancy mostly relates to omeprazole, the oldest PPI in this group. However, some notable new information is available on the use of pantoprazole and lansoprazole in pregnant women.

A multicenter prospective study of the Motherisk group in Canada looked at the outcomes among 113 mothers exposed to omeprazole during pregnancy. They were compared to a group of women receiving H2-antagonists and to a second group of women who were exposed to known nonteratogenic medications. Rates of major malformations, spontaneous abortions, preterm deliveries, cesarean deliveries, neonatal health problems, birth weight, and gestational age at delivery were similar in all 3 groups. The Motherisk program also conducted a meta-analysis on the use of PPIs during pregnancy. All exposures to PPIs (593 cases) had a relative risk of 1.18 (95% CI, 0.72-1.94) and exposures to omeprazole only (534 cases) had a relative risk of 1.05 (95% CI, 0.59-1.85). These statistics indicate no increase in risk of malformations.

The Swedish Medical Birth Registry reported on 955 infants whose mothers used omeprazole during pregnancy. In this report, 863 of the infants were exposed at least during the first trimester, and 92 were exposed only after the first trimester. Rates of congenital malformations, birth weights, perinatal death, and low Apgar scores in the exposed group were comparable to rates of those conditions observed in the general Swedish population.

A recent multicenter prospective study reported on 295 pregnancies in which the mothers were exposed to PPIs. Among these women, 233 mothers were exposed to omeprazole during the first trimester, 62 mothers were exposed to lansoprazole (55 of these in the first trimester), and 53 mothers were exposed to pantoprazole (47 of these in the first trimester). The pregnancy outcomes of these mothers were compared with those of 868 control subjects. In the omeprazole group, 3.6% (9/249) of neonates were born with malformations; in the lansoprazole group, 3.9% (2/52); and, in the pantoprazole group, 2.1% (1/48). These rates were similar to the control group rate of 3.8% (30/792).

As data continue to emerge, studies suggest that the use of PPIs during pregnancy does not indicate an increased risk of teratogenicity and that PPIs are probably safe to use during pregnancy. Most of the medications in this class are category B. Omeprazole, though available now in an over-the-counter formulation, continues to be category C. The manufacturer of omeprazole has received several reports of congenital abnormalities in infants born to women who took omeprazole during pregnancy; a definitive cause-and-effect relationship has not been confirmed.

Opinions on the role of H pylori infection in patients with GERD are conflicting. The decision to eradicate the bacteria in this patient population remains debatable. Nordenstedt and colleagues randomly selected 472 patients with GERD and 472 control patients with no symptoms to evaluate the effect of H pylori infection and its association with GERD. The presence of H pylori did increase the risk of gastric atrophy, a condition that reduces reflux symptoms, but so few patients had atrophy that no association could be established between H pylori infection and patients with GERD. At the moment, the presence of H pylori appears to be an independent factor in the severity of and ability to treat patients with GERD.

Long-term (>10 y) use of PPIs has been shown to be safe and effective, although the dose requirement may increase over time. Klinkenberg-Knol and colleagues studied patients with refractory reflux esophagitis who were undergoing maintenance therapy with omeprazole daily for a mean period of 6.5 years (range, 1.4-11.2 y). These patients had severe reflux esophagitis that was resistant to long-term therapy with H2-antagonists and were not appropriate surgical candidates. The patients were evaluated annually for endoscopic changes. In 230 patients, 158 relapses of esophagitis occurred, with no significant difference in relapse rates between patients who were positive or negative for H pylori infection. All patients rehealed during continued therapy with omeprazole at the same or higher dose.

Patients with GERD commonly also experience extraesophageal manifestations. Chronic cough, hoarseness, throat clearing, and a lump in the throat are some of the more frequently reported symptoms. Efforts to prospectively evaluate this theory have been attempted by both Noordzij and colleagues and El-Serag and colleagues using groups of 53 and 22, respectively. Both of these studies were randomized double-blind placebo studies. Noordzij found that treatment with omeprazole 40 mg twice daily compared to placebo showed statistically significant improvement for hoarseness and throat clearing only. El-Serag did not achieve any statistical differences between treatment with lansoprazole 30 mg twice daily and treatment with placebo.

In general, twice daily dosing of PPIs has been widely accepted as treatment for GERD, though no significant large-scale trials have been completed to indicate that this treatment is correct.

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