Sucralfate Versus Cimetidine in the Treatment of Reflux Esophagitis, with Special Reference to the Esophageal Motor Function FRANK JORGENSEN,M.D., Copenhagen,
Denmark,
*LARS
ELSBORG,M.D., Wernd,
Sixty patients entered a double-blind clinical trial comparing the effect of 1 g of sucralfate granulate given four times daily and cimetidine, 400 mg twice daily. Twenty-six patients treated with sucralfate and 26 treated with cimetidine were examined with short-term pH monitoring before and after 12 weeks of treatment. Thirty patients, 19 treated with cimetidine and 11 treated with sucralfate, had esophageal motility studied by a radionuclide test before and after 12 weeks of treatment. The efficacy of the treatments was judged by symptoms and endoscopic response after 4, 8, and 12 weeks of treatment. The endpoint healing rate was approximately 60% in both groups and symptoms were relieved in half of the patients in both groups (difference not significant). The effect of the treatments on pH and number of spikes reflected the different pharmacodynamic profiles of the drugs, whereas the mean transit time (M’lT) was not changed by the treatments. The residual activity after radionuclide transit in the sitting position was significantly increased after treatment with cimetidine. The data support the hypothesis that primary dysmotility might be involved in the pathogenesis of reflux esophagitis in about 33% of the patients. Possibilities for a combination therapy with sucralfate and cimetidine are stressed.
From the Department Frederiksberg Universrty
of Internal Medicine and Gastroenterology B, Hospital of Copenhagen, and *Department of Internal
Internal Medrcihe and Gastroenterology
2A-114s
August 8, 1991
B, Fredenksberg Unrversrty Hospital of Co-
The American Journal of Medicine
Denmark
ymptomatic gastroesophageal reflux is a very common problem in daily medical practice [l]. The reflux episodes are considered to occur because of an insufficient anti-reflux barrier at the gastroesophageal junction, The most important part of the anti-reflux barrier is the lower esophageal sphincter (LES) [2]. Other anatomic factors improve the barrier, i.e., the angle of the His bundle, compression by the oblique muscle fibers of the gastric fundus, and the i&a-abdominal position of the lower esophagus. Reflux episodes occur because of a transient relaxation of the LES, an increase in intraabdominal pressure, or because of extremely low resting pressure of the LES [31. The purpose of this investigation was to monitor the esophageal motility and pH before and after treatment with sucralfate or cimetidine, to explain the effects on motility, and to evaluate the efficacy of the treatments.
S
PATIENTSAND METHODS Patients Sixty patients (age 18-75 years) admitted for endoscopy because of dyspepsia, with endoscopitally verified esophagitis grades II-III according to Savary and Miller [4], entered a randomized double-blind controlled study with two parallel groups. A double dummy technique was used. Exclusion criteria were age below 18 and above 75 years, concomitant peptic ulcer, pregnancy, lactation, previous esophageal or gastric surgery, severe concomitant cardiac, hepatic, or renal disease, malignancy, and treatment with sucralfate and/or cimetidine within 2 months. Methods A general medical history was obtained before entry to the study and details on alcohol and tobacco consumption were obtained by the same investigator in nearly all patients. At the visits (every 4th week) the patients were asked about presence and severity of symptoms (heartburn, regurgitation, dysphagia, odynophagia, nausea, and vomiting). The severity of symptoms was scored from 0 to 3. Endoscopically verified healing was defined as complete macroscopic epithelializa-
Volume 91 (suppl 2A)
SYMPOSIUM
tion of all esophageal lesions. When the symptom score and endoscopy score after 12 weeks of treatment both were ‘1, the patients were considered as cured. Patients were randomly allocated to treatment with 1 g of sucralfate granulate four times a day, taken before meals and before bedtime, or 400 mg of cimetidine twice daily. The patients were treated for 12 weeks with endoscopic control every 4th week. All patients were asked to participate in pH measurements and motility studies. Fifty-two patients were examined with short-term pH monitoring and 30 patients agreed to have their esophageal motility evaluated by radionuclide transit measurements (Table I shows data on patients’ ages). A reference group for the radionuclide measurements consisted of 60 healthy volunteers and 14 young volunteers as controls for pH measurements. Esophageal motility was evaluated using a radionuclide technique presented in an earlier report [5], examining the patients in the supine and sitting positions, using single swallows of 15 mL of water containing 5 MBq of ggmtechnetium-pertechnetate. A gamma-camera (GE-Maxi) and a computer (Digital-PDP-11) were used to handle data. By a computer program the mean transit time (MTT) for the rapid part of the bolus was calculated, and the residue of the bolus remaining in the esophagus after the swallow was estimated from the activity curves. The MTT and the residual activity in the supine and sitting positions were measured twice and the values used were the average of two measurements. The pH monitoring was performed in fasting patients on a separate day, starting at 8 AM and using an antimony pH-electrode (Radiometer GK 28X, Copenhagen, Denmark. The electrode was placed 5 cm above the lower esophageal sphincter and the position was controlled by fluoroscopy. The data from the electrode were stored in a portable recording system. The pH measurements have been used and described previously [6]. Statistical Methods The endoscopic data were analyzed in two ways: (a) “intention-to-treat,” including all patients entering the study, except patients withdrawn because of esophageal malignancy, and, (2) “per protocol,” including all patients who completed the study without violation of the protocol. When paired motility and pH data were compared before and after treatment, the Wilcoxon test for paired data was used, whereas the Mann Whitney U test was used for unpaired data. The chi-square test was used to compare the outcome of treatment in all patients.
ON SUCRALFATE / JBRGENSEN
and ELSBORG
TABLE I Age in 52 Patients Evaluated by pH Monitoring and in 30 Patients Evaluated by Radionuclide Transit Cimetidine Number (pH monitoring] Age, mean (range) Number (motility studies) Age, mean (range)
Sucralfate
Controls
53 ,&2)
43 ,$-79,
50 ,&3, 49 ,&31
The time period in remission after endoscopic healing and remission of symptoms of the two groups was compared by actuarial life-table method. The study was approved by the Regional Ethic Committee and registered by The National Danish Board of Health. Each patient gave informed written and verbal consent before inclusion in the study.
RESULTS Sixty patients were withdrawn noncompliance, endoscopy, and dress to another
entered the study. Three patients from the study, one because of one because of refusal of further the last because of change of adregion.
Mean Transit Time (MTT) In the supine position 33% of the patients had prolonged MTT before treatment, and after treatment few were normalized; 23% still had prolonged MTT after both treatments. No differences were found within the groups before, or after treatment, and compared to healthy volunteers, the MTT was prolonged before and after treatment. In the sitting position no differences were found between groups before or after treatment, and also in this position, both groups had significantly prolonged MTT before and after treatment. Residual Activity In the supine position the residual activity was not different in healthy volunteers and patients before and after treatment (Figure 1). In the sitting position the residual activity increased significantly in the patients treated with cimetidine (p
Denmark,
*LARS
ELSBORG,M.D., Wernd,
Sixty patients entered a double-blind clinical trial comparing the effect of 1 g of sucralfate granulate given four times daily and cimetidine, 400 mg twice daily. Twenty-six patients treated with sucralfate and 26 treated with cimetidine were examined with short-term pH monitoring before and after 12 weeks of treatment. Thirty patients, 19 treated with cimetidine and 11 treated with sucralfate, had esophageal motility studied by a radionuclide test before and after 12 weeks of treatment. The efficacy of the treatments was judged by symptoms and endoscopic response after 4, 8, and 12 weeks of treatment. The endpoint healing rate was approximately 60% in both groups and symptoms were relieved in half of the patients in both groups (difference not significant). The effect of the treatments on pH and number of spikes reflected the different pharmacodynamic profiles of the drugs, whereas the mean transit time (M’lT) was not changed by the treatments. The residual activity after radionuclide transit in the sitting position was significantly increased after treatment with cimetidine. The data support the hypothesis that primary dysmotility might be involved in the pathogenesis of reflux esophagitis in about 33% of the patients. Possibilities for a combination therapy with sucralfate and cimetidine are stressed.
From the Department Frederiksberg Universrty
of Internal Medicine and Gastroenterology B, Hospital of Copenhagen, and *Department of Internal
Internal Medrcihe and Gastroenterology
2A-114s
August 8, 1991
B, Fredenksberg Unrversrty Hospital of Co-
The American Journal of Medicine
Denmark
ymptomatic gastroesophageal reflux is a very common problem in daily medical practice [l]. The reflux episodes are considered to occur because of an insufficient anti-reflux barrier at the gastroesophageal junction, The most important part of the anti-reflux barrier is the lower esophageal sphincter (LES) [2]. Other anatomic factors improve the barrier, i.e., the angle of the His bundle, compression by the oblique muscle fibers of the gastric fundus, and the i&a-abdominal position of the lower esophagus. Reflux episodes occur because of a transient relaxation of the LES, an increase in intraabdominal pressure, or because of extremely low resting pressure of the LES [31. The purpose of this investigation was to monitor the esophageal motility and pH before and after treatment with sucralfate or cimetidine, to explain the effects on motility, and to evaluate the efficacy of the treatments.
S
PATIENTSAND METHODS Patients Sixty patients (age 18-75 years) admitted for endoscopy because of dyspepsia, with endoscopitally verified esophagitis grades II-III according to Savary and Miller [4], entered a randomized double-blind controlled study with two parallel groups. A double dummy technique was used. Exclusion criteria were age below 18 and above 75 years, concomitant peptic ulcer, pregnancy, lactation, previous esophageal or gastric surgery, severe concomitant cardiac, hepatic, or renal disease, malignancy, and treatment with sucralfate and/or cimetidine within 2 months. Methods A general medical history was obtained before entry to the study and details on alcohol and tobacco consumption were obtained by the same investigator in nearly all patients. At the visits (every 4th week) the patients were asked about presence and severity of symptoms (heartburn, regurgitation, dysphagia, odynophagia, nausea, and vomiting). The severity of symptoms was scored from 0 to 3. Endoscopically verified healing was defined as complete macroscopic epithelializa-
Volume 91 (suppl 2A)
SYMPOSIUM
tion of all esophageal lesions. When the symptom score and endoscopy score after 12 weeks of treatment both were ‘1, the patients were considered as cured. Patients were randomly allocated to treatment with 1 g of sucralfate granulate four times a day, taken before meals and before bedtime, or 400 mg of cimetidine twice daily. The patients were treated for 12 weeks with endoscopic control every 4th week. All patients were asked to participate in pH measurements and motility studies. Fifty-two patients were examined with short-term pH monitoring and 30 patients agreed to have their esophageal motility evaluated by radionuclide transit measurements (Table I shows data on patients’ ages). A reference group for the radionuclide measurements consisted of 60 healthy volunteers and 14 young volunteers as controls for pH measurements. Esophageal motility was evaluated using a radionuclide technique presented in an earlier report [5], examining the patients in the supine and sitting positions, using single swallows of 15 mL of water containing 5 MBq of ggmtechnetium-pertechnetate. A gamma-camera (GE-Maxi) and a computer (Digital-PDP-11) were used to handle data. By a computer program the mean transit time (MTT) for the rapid part of the bolus was calculated, and the residue of the bolus remaining in the esophagus after the swallow was estimated from the activity curves. The MTT and the residual activity in the supine and sitting positions were measured twice and the values used were the average of two measurements. The pH monitoring was performed in fasting patients on a separate day, starting at 8 AM and using an antimony pH-electrode (Radiometer GK 28X, Copenhagen, Denmark. The electrode was placed 5 cm above the lower esophageal sphincter and the position was controlled by fluoroscopy. The data from the electrode were stored in a portable recording system. The pH measurements have been used and described previously [6]. Statistical Methods The endoscopic data were analyzed in two ways: (a) “intention-to-treat,” including all patients entering the study, except patients withdrawn because of esophageal malignancy, and, (2) “per protocol,” including all patients who completed the study without violation of the protocol. When paired motility and pH data were compared before and after treatment, the Wilcoxon test for paired data was used, whereas the Mann Whitney U test was used for unpaired data. The chi-square test was used to compare the outcome of treatment in all patients.
ON SUCRALFATE / JBRGENSEN
and ELSBORG
TABLE I Age in 52 Patients Evaluated by pH Monitoring and in 30 Patients Evaluated by Radionuclide Transit Cimetidine Number (pH monitoring] Age, mean (range) Number (motility studies) Age, mean (range)
Sucralfate
Controls
53 ,&2)
43 ,$-79,
50 ,&3, 49 ,&31
The time period in remission after endoscopic healing and remission of symptoms of the two groups was compared by actuarial life-table method. The study was approved by the Regional Ethic Committee and registered by The National Danish Board of Health. Each patient gave informed written and verbal consent before inclusion in the study.
RESULTS Sixty patients were withdrawn noncompliance, endoscopy, and dress to another
entered the study. Three patients from the study, one because of one because of refusal of further the last because of change of adregion.
Mean Transit Time (MTT) In the supine position 33% of the patients had prolonged MTT before treatment, and after treatment few were normalized; 23% still had prolonged MTT after both treatments. No differences were found within the groups before, or after treatment, and compared to healthy volunteers, the MTT was prolonged before and after treatment. In the sitting position no differences were found between groups before or after treatment, and also in this position, both groups had significantly prolonged MTT before and after treatment. Residual Activity In the supine position the residual activity was not different in healthy volunteers and patients before and after treatment (Figure 1). In the sitting position the residual activity increased significantly in the patients treated with cimetidine (p
