Rabeprazole versus ranitidine for the treatment of erosive gastroesophageal reflux disease: A double-blind, randomized clinical trial

THE AMERICAN JOURNAL OF GASTROENTEROLOGY © 2000 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.

Vol. 95, No. 8, 2000 ISSN 0002-9270/00/$20.00 PII S0002-9270(00)01025-X

Rabeprazole Versus Ranitidine for the Treatment of Erosive Gastroesophageal Reflux Disease: A Double-Blind, Randomized Clinical Trial Alain Farley, M.D., Lawrence D. Wruble, M.D., and Thomas J. Humphries, M.D., for the Rabeprazole Study Group Centre De Gastro-Enterologie et D’Endoscopie de Montreal, Montreal, Quebec, Canada; Memphis Gastroenterology Group, Memphis, Tennessee; and Eisai Ltd., London, England

OBJECTIVE: The objective of this study was to compare the efficacy and safety of the proton pump inhibitor rabeprazole to that of the histamine-2 (H2)–receptor antagonist ranitidine in the treatment of erosive gastroesophageal reflux disease. The primary indicator of efficacy was the absence of esophageal erosions or ulcerations as determined by posttreatment endoscopy. Secondary indicators of efficacy included improvement in frequency and severity of daytime and nighttime heartburn. METHODS: A total of 338 patients were enrolled and randomly assigned to therapy with rabeprazole 20 mg once daily in the morning or to ranitidine 150 mg four times daily. At baseline and at 4 wk, patients underwent endoscopy for evaluation of esophageal lesions. Patients whose lesions healed by wk 4 had therapy discontinued; others remained on therapy and had repeat endoscopy at 8 wk. Also recorded at study visits were patients’ ratings of heartburn symptoms and overall sense of well being, patients’ reports of time lost from daily activities, antacid use, and adverse events. Serum gastrin levels were measured and argyrophil enterochromaffin-like cell histology evaluated at baseline and when the patient ended therapy. RESULTS: At wk 4, healing was observed in 59% (98/167) of patients assigned to rabeprazole therapy, compared with 36% (60/169) of those receiving ranitidine (p ⬍ 0.001). By 8 wk, healing was seen in 87% (146/167) and 66% (112/ 169) of patients in the rabeprazole and ranitidine groups, respectively (p ⬍ 0.001). There were also significant differences between the two groups favoring rabeprazole with respect to resolution or improvement of heartburn symptoms and improvement in sense of well-being. No drugrelated serious adverse events were seen with either therapy; fewer patients assigned to rabeprazole had treatment-emergent signs and symptoms. Serum gastrin levels increased over baseline in the rabeprazole group, but the mean value remained within normal limits.

Participating members of the Rabeprazole Study Group are listed in the Appendix.

CONCLUSIONS: Rabeprazole was superior to ranitidine in esophageal healing and symptom relief in patients with erosive gastroesophageal reflux disease, and was equally well tolerated. (Am J Gastroenterol 2000;95:1894 –1899. © 2000 by Am. Coll. of Gastroenterology)

INTRODUCTION It is estimated that between 10% and 20% of adults experience significant symptoms of gastroesophageal reflux disease (GERD) (1– 4). Although most symptomatic patients have a benign, nonprogressive course, serious complications such as esophageal stricture or ulceration or Barrett’s esophagus develop in up to 20% (2, 5). Duration and frequency of contact of the esophagus with refluxed fluid, as well as the characteristics of the fluid, influence the extent of esophageal injury. Therapy may include standard or high doses of histamine-2 (H2)–receptor antagonists or proton pump inhibitors (PPIs) (5). PPIs, of which omeprazole is the prototypical agent, suppress acid secretion through inactivation of H⫹, K⫹ATPase on the secretory membrane of the parietal cell (5, 6). This “acid pump” is the final pathway for all mechanisms of stimulating acid secretion (5). Numerous clinical trials have shown PPIs to be superior to H2-receptor antagonists in the acute treatment of erosive GERD and the prevention of GERD relapse (5–9, 11–14). Healing rates with PPIs average about 75% within 4 – 6 wk, and the rate of symptom relief approaches 100% (11). The safety profile for PPIs is comparable to that for H2-receptor antagonists (15). In the early experience with the class, concerns were expressed regarding elevated serum gastrin levels, and the possibility that hypergastrinemia may result in enterochromaffin-like (ECL) cell hyperplasia and gastric carcinoids. However, the current accumulated evidence suggests that hypergastrinemia associated with PPI therapy is of little clinical significance (15). The new PPI rabeprazole has proven effective in treating a variety of acid-related diseases, including GERD, duodenal ulcer, and gastric ulcer (16 –19). We conducted an 8-wk,

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double-blind trial to test the hypotheses that rabeprazole 20 mg once a day in the morning (q.a.m.) is superior to ranitidine 150 mg four times a day (q.i.d.) in healing erosive GERD and relieving GERD symptoms, and is equally well tolerated. In addition, serum gastrin levels and ECL cell histology were evaluated.

MATERIALS AND METHODS This multicenter, double-blind, randomized, parallel-group study was conducted at 63 sites throughout the United States and Canada. The study was conducted in compliance with institutional review board (IRB) regulations. All patients enrolled were required to sign informed consent documents, which were approved by the IRBs. Patients A total of 338 outpatients (231 men and 107 women) age ⬎18 yr were enrolled. To be eligible, patients had to have a history of GERD during the 3 months before enrollment and erosive GERD diagnosed through endoscopy. Women of childbearing potential were required to use an acceptable method of birth control. Patients were excluded if they had a normal esophagus or grade 1 esophagitis (as defined by the modified Hetzel-Dent rating scale) (20), esophageal stricture or motility disorders, or medical conditions that would prevent endoscopy. Other standard exclusion criteria included treatment with an H2-receptor antagonist or PPI within 2 wk of enrollment and concurrent serious systemic disorders. Each patient was randomly assigned to one of two treatment groups. Distribution of esophagitis grades were comparable for both treatment groups at baseline. Patients in one group received 20 mg rabeprazole q.a.m. and placebo matching ranitidine q.i.d., whereas those in the other received 150 mg ranitidine q.i.d. and placebo matching rabeprazole q.a.m. Antacid tablets (Mylanta) were provided to all patients for use as needed. Patients, investigators, and staff were blinded to treatment assignments until analyses of the study results were completed. Assessments At baseline (visit 1, week 0), patients provided a detailed medical history and underwent physical examination, endoscopy, argyrophil ECL cell biopsy, and laboratory evaluation (hematology panel, chemistry panel, fasting serum gastrin, urinalysis, serum pregnancy test where applicable, and electrocardiogram). Eligible patients received a 4-wk supply of study medication. At visit 2 (wk 4), patients had another detailed clinical evaluation that included endoscopy, and patients who were healed (defined as absence of erosion or ulceration) were removed from the study. Patients who were not healed at visit 2 received additional medication and continued treatment until visit 3 (wk 8), at which time they had another endoscopy and repeat ECL cell biopsy, laboratory tests, and physical evaluations.

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The primary efficacy variable in this study was endoscopically confirmed healing of erosive GERD (a score of 0 or 1 on the modified Hetzel-Dent scale). Secondary efficacy variables included patients’ ratings of symptoms, which were recorded on diary cards. Severity of daytime and nighttime heartburn pain was rated on a scale of 0 (“none”) to 4 (“terrible”). Frequency of symptoms was also rated on a scale of 0 (“none”) to 4 (“continual,” occurring on ⱖ75% of days), as was overall physical well-being (0 ⫽ “very good” to 4 ⫽ “very poor”). Improvement in GERD symptoms or well-being was defined as an on-therapy evaluation grade lower than the baseline evaluation grade, whereas complete resolution in GERD symptoms was defined as an on-therapy evaluation grade of 0 (provided the baseline grade was not 0). In addition, patients were asked at each visit how many days or parts of days they had lost from daily activities (e.g., work, housework, or child care) because of GERD-related symptoms. Antacid use was calculated as mean number of doses per day. Tolerability and safety were determined from analyses of adverse events, clinical laboratory evaluations, fasting serum gastrin levels, physical examination findings, body weight, and electrocardiograms. Argyrophil ECL cell histology was assessed at baseline and at discontinuation of therapy. Statistical Analysis The study was designed to include approximately 310 patients divided between the two groups. This sample size was calculated to provide ⱖ80% power to detect a significant difference (p ⬍ 0.05, two-tailed test) between the two treatment groups, assuming 8-wk healing response rates of 70% for rabeprazole and 54% for ranitidine. Comparability of the two treatment groups with regard to demographic and baseline characteristics was tested by means of a two-way analysis of variance (ANOVA) with investigator and treatment as factors for the continuous variables (e.g., age), and by the Cochran-Mantel-Haenszel (CMH) test stratified by investigator for the categorical variables (e.g., gender and GERD heartburn frequency). Two methods of analysis were used to evaluate efficacy: intent-to-treat (ITT), which carried forward endoscopy results to the next scheduled time point if data for that time point were missing, and the ENDO approach, based upon completed visits or endoscopies performed. The significance of differences in healing rates between the two treatment groups was assessed using the stratified CochranMantel-Haenszel statistic. Differences were considered significant at p values of 0.05. For analysis of safety, differences between the groups in the incidence of treatment-emergent signs and symptoms (TESS) reported by at least two patients in one of the two groups were assessed using Pearson’s ␹2 statistic.

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RESULTS Demographic and Baseline Characteristics A total of 338 patients were enrolled, 169 in each treatment group. The two treatment groups were comparable in all demographic and baseline characteristics (p ⫽ NS), as shown in Table 1. The mean age of the patients was 51 yr (range, 19 – 86 yr), and 68% were male. Overall, 24% were smokers; 34% consumed alcohol and 79% caffeine. At baseline, 52% of patients had grade 2, 38% had grade 3, and 10% had grade 4 esophagitis. The severity of daytime heartburn was mild or moderate for 62% of patients and severe for 13%. The severity of nighttime heartburn was mild or moderate for 52% and severe for 19%. There were no significant differences between treatment groups with regard to the distribution of modified Hetzel-Dent esophagitis grades or baseline GERD heartburn frequency grades. Of the 338 patients, 27 (8%) dropped out of the study (15 in the rabeprazole group and 12 in the ranitidine group). The percentages of patients who completed the study were comparable (p ⫽ 0.539) in the rabeprazole group (91%, 154/ 169) and ranitidine (93%, 157/169) group. Four patients from each group dropped out because of mild to severe adverse events. Two patients (1%) in the rabeprazole group and one patient (1%) in the ranitidine group discontinued treatment because of lack of efficacy. Other reasons for discontinuation included protocol violation (six [4%] rabeprazole, two [1%] ranitidine); patient lost to follow-up (one [1%] rabeprazole, two [1%] ranitidine); and patient decision to discontinue (two [1%] rabeprazole, three [2%] ranitidine). Efficacy HEALING. The numbers and percentages of patients who were healed at wk 4 and 8 for both the ITT and ENDO analyses are shown in Table 2. The rabeprazole-treated patients achieved 59% healing at wk 4, versus 36% for ranitidine (ITT), for a between-group difference of 23% (95% CI: 13%, 23%). After 8 wk of treatment, rabeprazole achieved 87% healing, versus 66% for ranitidine, for a between-group difference of 21% (95% CI: 12%, 30%). Healing rates were significantly higher in the rabeprazole group than in the ranitidine group at each time point (p ⬍ 0.001 for both comparisons). HEARTBURN FREQUENCY. The proportion of patients who reported improvement in the frequency of heartburn was also significantly higher in the rabeprazole group than in the ranitidine group (Table 3), for both wk 4 (p ⬍ 0.001) and wk 8 (p ⫽ 0.032). Similarly, the proportion of patients with complete resolution of heartburn symptoms was higher with rabeprazole than with ranitidine at wk 4 (p ⬍ 0.001) and wk 8 (p ⬍ 0.001) (Table 3). HEARTBURN SEVERITY. There were no significant differences between the two treatment groups in the proportion of patients with improvement in GERD daytime heartburn

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Table 1. Summary of Demographic and Baseline Characteristics Characteristic Gender Male Female Race White Black Other Age (yr): mean ⫾ SD Range Tobacco consumption No Yes Alcohol consumption No Yes Caffeine consumption No Yes Data missing Antacid use No Yes Data missing Antacid doses per day (average of previous 3 days) n Mean ⫾ SD Baseline endoscopy Modified Hetzel-Dent esophagitis grade* n 0 1 2 3 4 5 Baseline GERD heartburn frequency grade n 0 ⫽ none 1 ⫽ few 2 ⫽ several 3 ⫽ many 4 ⫽ continual Missing value

Rabeprazole (n ⫽ 169)

Ranitidine (n ⫽ 169)

Total (n ⫽ 338)

118 51

113 56

231 107

146 16 7 51.4 ⫾ 14.9 21–85

156 302 7 23 6 13 50.4 ⫾ 14.2 50.9 ⫾ 14.5 19–86 19–86

134 35

122 47

256 82

104 65

119 50

223 115

40 126 3

32 137 0

72 263 3

59 108 2

55 111 3

114 219 5

167 2.7 ⫾ 3.6

166 2.7 ⫾ 3.4

333 2.7 ⫾ 3.5

167 0 (0%) 0 (0%) 95 (55%) 60 (36%) 15 (9%) 0 (0%)

169 0 (0%) 0 (0%) 81 (48%) 69 (41%) 19 (11%) 0 (0%)

336 0 (0%) 0 (0%) 173 (52%) 129 (38%) 34 (10%) 0 (0%)

167 5 (3%) 13 (3%) 25 (15%) 32 (19%) 91 (54%) 1 (1%)

169 9 (5%) 9 (5%) 24 (14%) 34 (20%) 91 (54%) 2 (1%)

336 14 (%) 22 (7%) 49 (15%) 66 (20%) 182 (54%) 3 (1%)

* 0 ⫽ normal mucosa; 1 ⫽ no macroscopic erosions, but presence of erythema, hyperemia, or friability of the esophageal mucosa; 2 ⫽ superficial ulceration or erosions involving ⬍10% of the mucosal surface area of the last 5 cm of the esophageal squamous mucosa; 3 ⫽ superficial ulceration or erosions involving ⱖ10% but ⬍50% of the mucosal surface area of the last 5 cm of the esophageal squamous mucosa; 4 ⫽ deep ulceration anywhere in the esophagus or confluent erosion of ⬎50% of the musocal surface area of the last 5 cm of the esophageal squamous mucosa; 5 ⫽ stricture. GERD ⫽ gastroesophageal reflux disease.

severity at either wk 4 or 8. The proportion of patients with complete resolution of daytime heartburn severity, however, was significantly higher in the rabeprazole group both at wk 4 (p ⫽ 0.017) and wk 8 (p ⫽ 0.025) (Table 3). Similar

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Table 2. Summary of GERD Healing Rates: Rabeprazole Versus Ranitidine Analysis

Week

Rabeprazole 20 mg q.a.m.

Ranitidine 150 mg q.i.d.

p Value*

Intent to treat Intent to treat ENDO ENDO

4 8 4 8

98/167 (59%) 146/167 (87%) 98/163 (60%) 146/158 (92%)

60/169 (36%) 112/169 (66%) 60/162 (37%) 112/158 (71%)

⬍0.001 ⬍0.001 ⬍0.001 ⬍0.001

* Treatment p value is adjusted for investigator; obtained using Cochran-Mantel-Haenszel statistic. GERD ⫽ gastroesophageal reflux disease; Healed ⫽ Modified Hetzel-Dent endoscopy evaluation grade 0 or 1; q.a.m. ⫽ once daily in the morning; q.i.d. ⫽ four times daily.

results were obtained for GERD nighttime heartburn severity. There was no significant difference between the two treatment groups in the proportion of patients with improvement in nighttime heartburn severity, but the proportion of patients with complete resolution was significantly higher in the rabeprazole group (p ⫽ 0.012 and (p ⫽ 0.002 for wk 4 and 8, respectively). In all of these measures, the results from the ENDO analysis were very similar to those from the ITT analysis. WELL-BEING AND ANTACID USE. The proportion of patients with improvement in overall well being at wk 4 was significantly higher in the rabeprazole group (p ⫽ 0.02) than in the ranitidine group; at wk 8, there was a trend (p ⫽ 0.056) favoring the rabeprazole group (Table 4). The proportion of patients with normalization in overall well-being was significantly higher for rabeprazole at both wk 4 (p ⫽ 0.021) and wk 8 (p ⫽ 0.007). At wk 8, twice as many patients (or their caregivers) in the ranitidine group reported time lost from daily activities because of the patient’s disease (23 [13%] of 169, vs 11 [6%] of 167 for rabeprazole). Patients in both groups tended to use fewer doses of antacid during treatment. However, there were no significant differences between groups (p ⫽ 0.442). SUBSET ANALYSES. Relationships between wk 8 healing rates and baseline characteristics (sex, age, race, tobacco

use, alcohol use, caffeine use, antacid use, Hetzel-Dent esophagitis grade, GERD heartburn frequency grade, daytime/nighttime heartburn severity grades, and patients’ overall well-being grades) were analyzed. These subset analyses revealed significant factor-by-treatment interaction for two baseline characteristics (being male and antacid use). Among men, the healing rate was significantly (p ⬍ 0.001) higher in those assigned to rabeprazole than in those receiving ranitidine. Among women, the difference in healing rates between the two treatments was not significant (p ⫽ 0.242). Similarly, among patients who were using antacids at baseline, the healing rate was significantly higher in those assigned to rabeprazole than in those receiving ranitidine (p ⬍ 0.001); but among those not using antacids, there were no significant differences (p ⫽ 0.236). Plasma Gastrin and ECL Cell Histology The mean changes from baseline to endpoint in fasting serum gastrin were 36.9 pg/ml (baseline 63.3 pg/ml, endpoint 100.7 pg/ml) in the rabeprazole group and 6.2 pg/ml (baseline 58.2 pg/ml, endpoint 64.5 pg/ml) in the ranitidine group (p ⬍ 0.001). Mean values at endpoint, however, remained well within the normal range (0 –149 pg/ml) in both groups. In all, 21 patients in the rabeprazole group and three patients in the ranitidine group who had normal serum gastrin levels at baseline had values above the upper limit of

Table 3. Summary of Improvement in GERD Heartburn Frequency and Severity (Intent to Treat)*

Frequency evaluation Improvement Complete resolution Daytime severity evaluation Improvement Complete resolution Nighttime severity evaluation Improvement Complete resolution

Week

Rabeprazole 20 mg q.a.m.

Ranitidine 150 mg q.i.d.

p Value†

4 8 4 8

121/161 (75%) 127/161 (79%) 72/161 (45%) 81/161 (50%)

91/158 (58%) 108/158 (68%) 42/158 (27%) 45/158 (28%)

⬍0.001 0.032 ⬍0.001 ⬍0.001

4 8 4 8

95/135 (70%) 102/135 (76%) 79/135 (59%) 92/135 (68%)

84/124 (68%) 99/124 (80%) 53/124 (43%) 67/124 (54%)

0.674 0.409 0.017 0.025

4 8 4 8

101/127 (80%) 110/127 (87%) 84/127 (66%) 94/127 (74%)

107/131 (82%) 113/131 (86%) 67/131 (51%) 74/131 (56%)

0.536 0.937 0.012 0.002

* Patients with normal baseline values (grade 0) were excluded from analysis. † Treatment p value is adjusted for investigator; obtained using Cochran-Mantel-Haenszel statistic. Complete resolution ⫽ evaluation grade 0 (none); GERD ⫽ gastroesophageal reflux disease; Improvement ⫽ evaluation grade lower than baseline evaluation; q.a.m. ⫽ once daily in the morning; q.i.d. ⫽ four times daily.

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Table 4. Summary of Improvement in Patients’ Overall Well-Being Grades (Intent to Treat)* Well-Being Evaluation Improvement Normalization

Week

Rabeprazole 20 mg q.a.m.

Ranitidine 150 mg q.i.d.

p Value†

4 8 4 8

80/135 (59%) 86/135 (64%) 57/135 (42%) 62/135 (46%)

63/138 (46%) 73/138 (53%) 40/138 (29%) 42/138 (30%)

0.020 0.056 0.021 0.007

* Patients with normal baseline values (grade 0) were excluded from analysis. † Treatment p value is adjusted for investigator; value obtained using Cochran-Mantel-Haenszel statistic. Improvement ⫽ evaluation grade lower than baseline evaluation; Normalization ⫽ evaluation grade 0 (very good); q.a.m. ⫽ once daily in the morning; q.i.d. ⫽ four times daily.

normal (⬎149 pg/ml) at endpoint. No significant ECL changes occurred in either treatment group. Tolerability Rabeprazole 20 mg q.a.m. administered for up to 8 wk was generally well tolerated. Three patients in the rabeprazole group and two in the ranitidine group reported serious adverse events, none of which were related to treatment. At least 1 TESS was reported by 61% of patients in the rabeprazole group and 66% of patients in the ranitidine group. Overall, the most frequently reported TESS were headache (17%), diarrhea (13%), nausea (9%), abdominal pain (8%), and rhinitis (7%). No TESS occurred at a significantly higher frequency in the rabeprazole group than in the ranitidine group, with the exception of flatulence (9% vs 4%; p ⫽ 0.043). Dyspepsia (4% vs 0%), nausea (13% vs 6%), vomiting (9% vs 3%), rhinitis (11% vs 2%), and eye disorders (2% vs 0%) were all reported by a significantly higher percentage of patients in the ranitidine group (p ⬍ 0.044, overall). None of the mean changes in hemoglobin, red blood cell count, or ALT/SGPT were clinically meaningful. All values were within normal limits.

DISCUSSION Our study compared the efficacy of rabeprazole 20 mg administered q.a.m. for up to 8 wk with that of ranitidine 150 mg q.i.d. in patients with erosive or ulcerative GERD. We evaluated both endoscopically assessed esophageal healing, employing a scale previously used in studies of omeprazole (12), and patient-reported symptom improvement. All patients who enrolled in this multicenter trial had grade 2 (51%), grade 3 (38%), or grade 4 (10%) esophagitis. Ranitidine, at the US-approved dose for esophagitis, produced quite good results in this trial. However, rabeprazole was still numerically and statistically superior in terms of healing and symptom relief. These efficacy results were validated by a trial of identical design except for the comparator (omeprazole) (17). Subset analyses at wk 8 showed significant factor-bytreatment interaction for two baseline characteristics. Healing rates were significantly higher among male subjects and antacid users at baseline randomized to the rabeprazole group versus the ranitidine group (p ⬍ 0.001). There was a

trend toward higher healing rates in female subjects and non–antacid users at baseline randomized to the rabeprazole group versus the ranitidine group. These differences were not statistically significant, possibly because there were fewer women and non–antacid users in the study. In our study, serum levels of gastrin were increased to a greater extent in patients receiving rabeprazole than in those receiving ranitidine. The change in mean serum gastrin levels in rabeprazole patients represented an approximately 59% increase over baseline. Seven patients receiving rabeprazole had endpoint gastrin levels greater than twice the upper limit of normal. Plasma gastrin concentrations are increased by drugs and surgical procedures that reduce gastric acid secretion (21), and so can serve as a marker of pharmacological suppression of acid secretion. Consistent with previously published reports, both rabeprazole and ranitidine were well tolerated. Routine laboratory test results were not significantly affected by either drug. The ranitidine dosage used in this study, 150 mg q.i.d., is the recommended dosage for erosive esophagitis in the US but would be considered a high dose in other countries. This dose is twice that used in many studies comparing ranitidine with omeprazole (150 mg b.i.d.) (22). The higher dose used in the current study resulted in a somewhat higher rate of healing for ranitidine than has been observed. On the basis of these findings, we conclude that rabeprazole 20 mg q.a.m. is superior to ranitidine 150 mg q.i.d. in the treatment of erosive GERD.

APPENDIX: THE RABEPRAZOLE STUDY GROUP The Rabeprazole Study Group members are as follows: Richard Aaronson, M.D., Chicago Heights, IL; Andre Archambault, M.D., Montreal, Quebec; Richard Baerg, M.D., Tacoma, WA; Robert Bailey, M.D., Edmonton, Alberta; David Ballard, M.D., Cincinnati, OH; Tom Bianchi, M.D., Tallassee, AL; Charles Birbara, M.D., Worcester, MA; Philip Bird, M.D., Norman, OK; Milan Brandon, M.D., San Diego, CA; William Bray, M.D., Charlotte, NC; Jeffrey R. Breiter, M.D., Manchester, CT; Jacques Caldwell, M.D., Daytona Beach, FL; Donald Campbell, M.D., Kansas City, MO; Antonio Caos, M.D., Ocoee, FL; Ian Cleator, M.D., Vancouver, British Columbia; Charles L. Colip, M.D., Port-

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land, OR; Dale Collins, M.D., Arvada, CO; Donald Daly, M.D., Montreal, Quebec; Margaret Drehobl, M.D., San Diego, CA; Theodore Durbin, M.D., Long Beach, CA; Mark Eisner, M.D., Zephyrhills, FL; Alain Farley, M.D., Montreal, Quebec; Ronald Fogel, M.D., Detroit, MI; Norman Gitlin, M.D., Atlanta, GA; Daniel Gremillion, M.D., Nashville, TN; Vernon G.K. Hee, M.D., Vancouver, WA; Samuel Ho, M.D., Minneapolis, MN; David Johnson, M.D., Norfolk, VA; Jeffrey Kaine, M.D., Sarasota, FL; Neil Kassman, M.D., Statesville, NC; Seymour Katz, M.D., Great Neck, NY; Thomas Kovacs, M.D., Los Angeles, CA; Daniel Kruss, M.D., Oakpark, IL; Frank Lanza, M.D., Houston, TX; Desmond Leddin, M.D., Halifax, Nova Scotia; Arthur McCullough, M.D., Cleveland, OH; Aubrey McElroy, M.D.; Johnson City, TN; Gary May, M.D., Calgary, Alberta; Morry Moskovitz, M.D., Beaver, PA; Nicholas Nickl, M.D., Lexington, KY; Howard Offenburg, M.D., Gainesville, FL; Michael Oravec, M.D., Oshawa, Ontario; Daniel Pambianco, M.D., Charlottesville, VA; Francisco Ramirez, M.D., Phoenix, AZ; Dennis Riff, M.D., Anaheim, CA; Peter Rossos, M.D., Toronto, Ontario; Walter Roufail, M.D., Winston-Salem, NC; Seymour Sabesin, M.D., Chicago, IL; Shariar Safavi, M.D., Irving, TX; Michael Safdi, M.D., Cincinnati, OH; Howard Schwartz, M.D., Miami, FL; Barry Scott, M.D., Baton Rouge, LA; David Scott, M.D., Shreveport, LA; Nayan Shah, M.D., Leonardtown, M.D.; Bavikatte Shivakumar, M.D., Davenport, IA; Manuel Sklar, M.D., Bingham Farms, MI; Stephen Sontag, M.D., Hines, IL; Lewis Strong, M.D., Loveland, CO; Z. Vlahcevic, M.D., Richmond, VA; Roger Soloway, M.D., Galveston, TX; Richard White, M.D., Sacramento, CA; Randal Willis, M.D., Harrogate, TN; Lawrence D. Wruble, M.D., Memphis, TN.

ACKNOWLEDGMENT Research supported by Eisai Inc., Teaneck, NJ. Reprint requests and correspondence: Thomas J. Humphries, M.D., 4 Monterey Drive, Princeton Junction, NJ 08550-1318. Received Aug. 12, 1999; accepted Mar. 31, 2000.

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