Comparable Efficacy of Pantoprazole and Omeprazole ... - Zdravie.sk
Comparable Efficacy of Pantoprazole and Omeprazole ... - Zdravie.sk
Comparable Efficacy of Pantoprazole and Omeprazole ... - Zdravie.sk
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Original Paper: Esophageal Disorders<br />
Digestion 2003;67:6–13<br />
DOI: 10.1159/000070201<br />
<strong>Comparable</strong> <strong>Efficacy</strong> <strong>of</strong> <strong>Pantoprazole</strong> <strong>and</strong><br />
<strong>Omeprazole</strong> in Patients with Moderate to Severe<br />
Reflux Esophagitis<br />
Results <strong>of</strong> a Multinational Study<br />
T. Körner a K. Schütze b R.J.M. van Leendert c I. Fumagalli d<br />
B. Costa Neves e M. Bohuschke f G. Gatz f<br />
a Zentralklinikum Suhl gGmbH, Suhl, Germany; b Hanusch-Krankenhaus, Vienna, Austria;<br />
c Albert Schweitzer Ziekenhuis, Zwijndrecht, The Netherl<strong>and</strong>s; d Medical Centre, Locarno, Switzerl<strong>and</strong>;<br />
e Hospital de Pulido, Lisbon, Portugal; f ALTANA Pharma AG, Konstanz, Germany<br />
Key Words<br />
Acid-related Disease W Esophagitis W Gastroesophageal<br />
reflux disease W <strong>Omeprazole</strong> W <strong>Pantoprazole</strong> W Proton<br />
pump inhibitor<br />
Abstract<br />
Aim: To compare the efficacy <strong>and</strong> tolerability <strong>of</strong> pantoprazole<br />
40 mg <strong>and</strong> omeprazole MUPS 40 mg in patients<br />
with moderate to severe gastroesophageal reflux disease<br />
(GERD). Methods: In this r<strong>and</strong>omized, double-blind,<br />
parallel-group, multicenter study conducted in Austria,<br />
Germany, Portugal, Switzerl<strong>and</strong> <strong>and</strong> The Netherl<strong>and</strong>s,<br />
patients with endoscopically confirmed moderate to severe<br />
GERD (Savary/Miller esophagitis grade II/III) were<br />
enrolled. They received a once-daily dose <strong>of</strong> either 40 mg<br />
pantoprazole or 40 mg omeprazole MUPS. Healing was<br />
determined by endoscopy after 4 weeks <strong>of</strong> treatment. If<br />
patients were not healed, treatment was extended for<br />
another 4 weeks. An additional endoscopy was performed<br />
in these cases after 8 weeks <strong>of</strong> treatment. Healing<br />
was determined by endoscopy after 4 <strong>and</strong> 8 weeks. In<br />
addition, treatment effect on symptoms was evaluated<br />
by the investigator using a questionnaire assessing<br />
heartburn, reflux regurgitation <strong>and</strong> pain on swallowing<br />
at each visit, as well as by a self-administered question-<br />
ABC<br />
Fax + 41 61 306 12 34<br />
E-Mail karger@karger.ch<br />
www.karger.com<br />
© 2003 S. Karger AG, Basel<br />
0012–2823/03/0672–0006$19.50/0<br />
Accessible online at:<br />
www.karger.com/dig<br />
Received: August 26, 2002<br />
Accepted: February 20, 2003<br />
naire comprising further 24 gastrointestinal symptoms.<br />
Analyses were performed for the intention-to-treat (ITT)<br />
<strong>and</strong> the per-protocol (PP) population. In addition, patients<br />
with high compliance (HC: 90% ^110%) were considered<br />
in a separate group. Adverse events <strong>and</strong> the<br />
influence <strong>of</strong> the Helicobacter pylori status were investigated.<br />
Results: A total <strong>of</strong> 669 outpatients were enrolled in<br />
the study, with 337 patients receiving pantoprazole <strong>and</strong><br />
332 omeprazole MUPS. The PP population consisted <strong>of</strong><br />
552 patients, 282 treated with pantoprazole <strong>and</strong> 270 with<br />
omeprazole MUPS. The healing rates in both treatment<br />
groups were shown to be equivalent <strong>and</strong> were higher in<br />
patients who adhered closely to the administration protocol<br />
(HC). According to ITT (ITTHC) analyses, healing<br />
rates were 65.3% (77.4%) in the pantoprazole <strong>and</strong> 66.3%<br />
(74.7%) in the omeprazole group after 4 weeks. Furthermore,<br />
patients infected with H. pylori had slightly but not<br />
significantly higher healing rates than those with a negative<br />
test result. The safety pr<strong>of</strong>ile <strong>of</strong> both treatments was<br />
comparable. Conclusion: <strong>Pantoprazole</strong> 40 mg <strong>and</strong> omeprazole<br />
MUPS 40 mg were equivalent with respect to<br />
healing after 4 <strong>and</strong> 8 weeks <strong>of</strong> treatment in patients with<br />
reflux esophagitis grade II/III. Overall, HC patients had<br />
higher healing rates than the regular compliant patients.<br />
Both drugs were well tolerated <strong>and</strong> safe.<br />
Copyright © 2003 S. Karger AG, Basel<br />
PD Dr. Thomas Körner<br />
Zentralklinikum Suhl gGmbH<br />
Albert-Schweitzer-Strasse 2<br />
D–98527 Suhl (Germany)<br />
Tel. +49 3681 355440, Fax +49 3681 355441, E-Mail thomas.koerner@zs.srh.de
Introduction<br />
Gastroesophageal reflux disease (GERD) is widely<br />
spread <strong>and</strong> has a great impact on patients’ quality <strong>of</strong> life<br />
[1, 2]. In the Western population, approximately 7% <strong>of</strong> all<br />
patients consulting a physician because <strong>of</strong> gastrointestinal<br />
complaints are suffering from heartburn [3]. The therapeutically<br />
most easily influenced pathogenetic factor in<br />
the development <strong>of</strong> GERD <strong>and</strong> its complications is gastric<br />
acid. Control <strong>of</strong> gastric acid secretion is the major key<br />
factor in healing the disease <strong>and</strong> numerous studies demonstrated<br />
the close correlation between the extent <strong>of</strong> acid<br />
secretion <strong>and</strong> therapeutic success [3, 4]. In most cases proton<br />
pump inhibitors (PPIs) achieve the desired acid suppression<br />
when given once daily, they are widely accepted<br />
to be the best treatment option. It is generally accepted<br />
that PPIs are significantly superior to H2-receptor antagonists<br />
[5–8], prokinetics [9] <strong>and</strong> placebo [for review see 10–<br />
12]. Further, it was previously shown that pantoprazole<br />
<strong>and</strong> omeprazole are highly efficacious in the treatment <strong>of</strong><br />
mild [13] <strong>and</strong> moderate to severe GERD [14, 15]. However,<br />
a direct comparison <strong>of</strong> equal doses <strong>of</strong> pantoprazole<br />
<strong>and</strong> omeprazole in patients with moderate to severe<br />
GERD has not been performed so far.<br />
Dose-finding studies <strong>and</strong> comparative trials demonstrated<br />
pantoprazole 40 mg to be the optimal dose for the<br />
treatment <strong>of</strong> moderate to severe reflux esophagitis <strong>and</strong><br />
20 mg for mild disease [16–18]. For omeprazole a st<strong>and</strong>ard<br />
dose <strong>of</strong> 20 mg has been recommended for the treatment<br />
<strong>of</strong> GERD, but in practice 40 mg are <strong>of</strong>ten used [19,<br />
20]. Our aim was to directly compare the once-daily dose<br />
<strong>of</strong> pantoprazole 40 mg with omeprazole MUPS 40 mg in<br />
the treatment <strong>of</strong> reflux esophagitis grade II <strong>and</strong> III as<br />
defined by Savary <strong>and</strong> Miller [21]. Outcome criteria were<br />
the efficacy <strong>and</strong> tolerability <strong>of</strong> both drugs with regard to<br />
endoscopically proven healing <strong>and</strong> symptom relief after 4<br />
<strong>and</strong> 8 weeks <strong>of</strong> treatment <strong>and</strong> a possible effect <strong>of</strong> the bacterium<br />
Helicobacter pylori on treatment outcome.<br />
Patients <strong>and</strong> Methods<br />
Design <strong>and</strong> Ethical Considerations<br />
This study was conducted as a r<strong>and</strong>omized, double-blind, multicenter,<br />
parallel-group study involving 5 centers in Austria, 53 in Germany,<br />
3 in Portugal, 12 in Switzerl<strong>and</strong> <strong>and</strong> 8 in The Netherl<strong>and</strong>s.<br />
The study was conducted according to good clinical practice <strong>and</strong> the<br />
Declaration <strong>of</strong> Helsinki. Furthermore, independent local ethics committees<br />
in the respective countries approved the protocol <strong>and</strong> all<br />
patients gave their written informed consent prior to participation.<br />
<strong>Comparable</strong> <strong>Efficacy</strong> <strong>of</strong> <strong>Pantoprazole</strong> <strong>and</strong><br />
<strong>Omeprazole</strong> in Reflux Esophagitis<br />
Patient Populations<br />
A total <strong>of</strong> 669 male <strong>and</strong> female patients, aged 618 years (for Austria<br />
619 years, 1 patient was ! 18 years for whom the parents gave<br />
their written consent), were enrolled in this study between May 2000<br />
<strong>and</strong> February 2001. They had endoscopically confirmed reflux<br />
esophagitis grade II or III (Savary/Miller classification) <strong>and</strong> had suffered<br />
from at least moderate heartburn during the 3 days prior to<br />
inclusion (for grading <strong>of</strong> symptoms see Medical Assessment below)<br />
[21]. Main exclusion criteria were the following: any other gastrointestinal<br />
disease, i.e. GERD grades other than II or III, florid peptic<br />
ulcer, history <strong>of</strong> Zollinger-Ellison syndrome, pyloric stenosis, esophageal<br />
or gastric surgery, <strong>and</strong> severe diseases <strong>of</strong> other body systems.<br />
Patients were excluded if they took PPIs, H2-receptor antagonists,<br />
prokinetics for more than 10 days, systemic glucocorticosteroids,<br />
anti-inflammatory drugs for more than 3 consecutive days or had<br />
had PPI-based tribple therapy during the previous 28 days.<br />
Intake <strong>of</strong> sucralfate during the 3 days prior to study start also led<br />
to exclusion. Regular intake <strong>of</strong> acetyl salicylic acid <strong>of</strong> dosages up to<br />
150 mg/day was allowed.<br />
Treatment <strong>and</strong> Conduct<br />
Patients were r<strong>and</strong>omized to one <strong>of</strong> two treatment groups receiving<br />
either 40 mg pantoprazole or 40 mg omeprazole MUPS once daily.<br />
R<strong>and</strong>omization was performed by means <strong>of</strong> a computer-generated<br />
r<strong>and</strong>omization list. Patients received their patient number in ascending<br />
order corresponding to the order <strong>of</strong> inclusion. This number corresponded<br />
to a r<strong>and</strong>omized medication. Treatment was extended to 8<br />
weeks for patients not healed after 4 weeks.<br />
For blinding purposes, both pantoprazole <strong>and</strong> omeprazole tablets<br />
were encapsulated. Encapsulation did not change the dissolving or<br />
absorption properties <strong>of</strong> the omeprazole MUPS formulation [22].<br />
At study start patients were assessed endoscopically to determine<br />
the grade <strong>of</strong> GERD. The presence <strong>of</strong> H. pylori was proven directly<br />
after the endoscopy at the initial examination by means <strong>of</strong> a st<strong>and</strong>ardized<br />
<strong>and</strong> validated, commercially available H. pylory rapid urease<br />
test (RUT; CLOtest ® , Ballard Medical Products, USA) kit. For<br />
this test, at least 1 biopsy specimen from the antrum <strong>and</strong> 1 from the<br />
corpus were taken. A patient was considered H. pylori-negative if the<br />
result was negative from both parts <strong>of</strong> the stomach. The investigator<br />
questioned patients about leading symptoms (heartburn, acid eructation,<br />
pain on swallowing), medical history, concomitant medication<br />
<strong>and</strong> clinical symptoms. A physical examination was performed <strong>and</strong> a<br />
blood sample was taken for st<strong>and</strong>ard laboratory investigation. Two<br />
weeks after the initial examination a first follow-up visit was carried<br />
out, at which the investigator assessed symptoms <strong>and</strong> patients filled<br />
in a symptom questionnaire. Further follow-up visits were scheduled<br />
after 4 <strong>and</strong>, if necessary, 8 weeks <strong>of</strong> treatment. Endoscopies were performed<br />
at baseline, after 4 <strong>and</strong>, if necessary, 8 weeks <strong>of</strong> treatment to<br />
ascertain the extent <strong>of</strong> healing.<br />
During the initial endoscopy 1 biopsy each was taken from the<br />
antrum <strong>and</strong> from the corpus for H. pylori testing. Concomitant medication<br />
<strong>and</strong> adverse events were documented at each follow-up visit.<br />
Compliance was checked by counting returned tablets. Patients were<br />
considered non-compliant if they took less than 80% <strong>of</strong> the medication.<br />
Patients were considered to be highly compliant (HC) if they<br />
took between 90 <strong>and</strong> 110% <strong>of</strong> the study medication, i.e. if they strictly<br />
adhered to the administration instructions.<br />
Digestion 2003;67:6–13 7
Medical Assessment<br />
Endoscopy. Healing was defined as complete epithelialization <strong>of</strong><br />
the lesions as confirmed by endoscopy. Healing rates were determined<br />
after 4 <strong>and</strong> 8 weeks <strong>of</strong> treatment for both treatment groups.<br />
Leading Symptoms. The presence <strong>and</strong> intensity <strong>of</strong> the leading<br />
symptoms <strong>of</strong> reflux heartburn, acid regurgitation <strong>and</strong> pain on swallowing,<br />
were assessed at each visit <strong>and</strong> documented as either mild,<br />
moderate or severe by the investigator on a 4-point scale (from 0 =<br />
absent to 3 = severe). A patient with at least mild symptoms at baseline<br />
was defined symptom-free if no symptoms were reported at the<br />
respective visit.<br />
GI Symptoms. In addition to the symptom questioning by the<br />
investigator, patients were requested to fill in a self-administered<br />
questionnaire about further 24 GI symptoms. Frequency <strong>and</strong> intensity<br />
<strong>of</strong> each symptom were assessed on a 6-point scale (from 0 = not at<br />
all to 5 = every day <strong>and</strong> 0 = absent to 5 = very severe, respectively).<br />
For each patient a sum score was calculated as the sum <strong>of</strong> frequency<br />
! intensity/(5 ! 5), divided by the number <strong>of</strong> reported symptoms in<br />
order to normalize the sum score values to the range 0–1.<br />
In addition, a factor analysis <strong>of</strong> the self-reported gastrointestinal<br />
(GI) symptoms was carried out in order to identify a symptom pattern<br />
in moderate to severe esophagitis. The parameters severity, frequency,<br />
<strong>and</strong> symptom load (frequency ! severity) were analyzed by<br />
use <strong>of</strong> VARIMAX. Items to be retained in the groups required item<br />
loadings <strong>of</strong> 10.4. Groups comprised items with the largest load on<br />
one factor, since for several items multiple assignments to different<br />
factors were seen.<br />
Safety<br />
At every follow-up visit patients were a<strong>sk</strong>ed about occurrence <strong>of</strong><br />
adverse events. The investigator assessed the causal relationship <strong>of</strong><br />
the event to the intake <strong>of</strong> the study medication as either unrelated,<br />
unlikely, likely, or definitely related.<br />
Statistical Analysis<br />
The sample size evaluation was performed on the basis <strong>of</strong> healing<br />
rates after 4 weeks <strong>of</strong> treatment. A difference <strong>of</strong> 15% between both<br />
treatment groups was considered as clinically relevant. Two hundred<br />
<strong>and</strong> fifty-six patients per group were required to detect this difference<br />
on a 5% level <strong>of</strong> significance <strong>and</strong> a power <strong>of</strong> 80%.<br />
The primary efficacy variable was the endoscopically confirmed<br />
healing after 4 weeks. Healing rates were calculated for both groups<br />
<strong>and</strong> compared. The null hypothesis <strong>of</strong> this study, that there is no<br />
difference between the drugs, was tested by Cochran-Mantel/Haenszel<br />
method on a 5% level. The 95% confidence intervals (CIs) were<br />
calculated for the odds ratios. Equivalence was concluded if the 95%<br />
CIs were completely within the interval 0.33–3. Secondary criteria<br />
were healing rates after 8 weeks <strong>and</strong> symptom relief rates concerning<br />
the 3 leading symptoms <strong>and</strong> the other GI symptoms after 2, 4 <strong>and</strong> 8<br />
weeks. Symptom relief rates <strong>of</strong> the leading symptoms were only evaluated<br />
descriptively. The pre- <strong>and</strong> posttreatment differences between<br />
GI symptoms baseline values <strong>and</strong> those after 2, 4 <strong>and</strong> 8 weeks were<br />
calculated for the sum score <strong>of</strong> the GI leading symptoms as well as for<br />
the sum score <strong>of</strong> the self-assessed GI symptoms as measured by the<br />
patient questionnaire. The obtained values <strong>of</strong> both treatment groups<br />
were compared two-sided on a 5% level using the Wilcoxon ranksum<br />
test. In addition, the main parameter was evaluated taking the<br />
H. pylori status into account. Furthermore, the correlation between<br />
endoscopic <strong>and</strong> symptomatic healing was calculated by means <strong>of</strong><br />
Cramer’s V.<br />
Table 1. Demography <strong>and</strong> medical history (ITT)<br />
Patient<br />
characteristics<br />
<strong>Pantoprazole</strong><br />
40 mg<br />
(n = 337)<br />
<strong>Omeprazole</strong><br />
MUPS, 40 mg<br />
(n = 332)<br />
Age, years B SD 53.7B14.3 53.8B14.6<br />
Height, cm B SD 171.7B8.7 170.4B9.3<br />
Weight, kg B SD 78.9B13.7 78.0B14.4<br />
Body mass index, kg/m 2 B SD 26.8B4.0 26.8B4.2<br />
Men/women 216/121 186/146<br />
Non-smokers, n (%) 264 (78.3) 253 (76.2)<br />
Alcohol consumers, n (%) 23 (6.8) 22 (6.6)<br />
Esophagitis grade II, n (%) 283 (84.0) 281 (84.6)<br />
Esophagitis grade III, n (%) 54 (16.0) 51 (15.4)<br />
H. pylori positive, n (%) 72/337 (21.4) 82/332 (24.7)<br />
H. pylori negative, n (%) 257/337 (76.3) 241/332 (72.6)<br />
Dichotomous parameters were compared by Fisher’s exact twotailed<br />
test <strong>and</strong> ordinal variables by the Wilcoxon rank-sum test.<br />
Populations<br />
Protocol violators were defined before unblinding. The statistical<br />
analyses <strong>of</strong> the primary <strong>and</strong> secondary parameters were performed<br />
by intention-to-treat (ITT) <strong>and</strong> per-protocol (PP) analysis. Symptoms<br />
assessed by the patient questionnaire were analyzed only PP.<br />
The ITT population comprised all patients included. The PP analysis<br />
excluded protocol violators. In addition, all parameters were analyzed<br />
in subgroups comprising HC patients, i.e. patients that took<br />
between 90 <strong>and</strong> 110% <strong>of</strong> the study medication <strong>and</strong> therefore adhered<br />
closely to the administration protocol (ITTHC <strong>and</strong> PPHC).<br />
Results<br />
Study Populations<br />
Overall, 669 patients were included in the study (ITT<br />
population). All patients who completed the study without<br />
protocol violations were included in the PP population,<br />
which comprised 552 patients, 282 in the pantoprazole<br />
<strong>and</strong> 270 in the omeprazole MUPS group. The most<br />
prominent protocol violations were violation <strong>of</strong> the inclusion<br />
criteria, poor compliance, intake <strong>of</strong> not permitted<br />
concomitant medication, or deviations from the first follow-up<br />
visit dates. The subgroup <strong>of</strong> HC patients within<br />
the PP population comprised 452 patients, 233 in the<br />
pantoprazole <strong>and</strong> 219 in the omeprazole MUPS group.<br />
The populations are described in figure 1.<br />
No clinically relevant differences in the demographic<br />
characteristics between the treatment groups were observed<br />
(table 1). The ratios <strong>of</strong> H. pylori-positive <strong>and</strong><br />
-negative patients as well as the percentage <strong>of</strong> patients<br />
8 Digestion 2003;67:6–13 Körner/Schütze/van Leendert/Fumagalli/<br />
Costa Neves/Bohuschke/Gatz
Fig. 1. Study populations <strong>and</strong> patient flowchart.<br />
Table 2. Comparison between treatment groups<br />
Population Odds ratio 95% CI<br />
4 weeks ITT 0.957 0.696–1.318<br />
ITTHC<br />
1.1620.759–1.718<br />
PP 0.921 0.636–1.334<br />
PPHC 1.111 0.718–1.720<br />
8 weeks ITT 0.950 0.624–1.446<br />
ITTHC 1.148 0.541–2.436<br />
PP 0.814 0.435–1.523<br />
PPHC 1.068 0.469–2.430<br />
Equivalence was concluded if the 95% CI ranged between 0.33<br />
<strong>and</strong> 3.<br />
with reflux esophagitis grade II or III were similar in both<br />
groups. At baseline, reflux esophagitis grade II was diagnosed<br />
in 85.0% <strong>of</strong> patients in the PP population (242<br />
patient in the pantoprazole, 227 in the omeprazole MUPS<br />
group), <strong>and</strong> grade III in 15.0% <strong>of</strong> patients.<br />
<strong>Efficacy</strong><br />
The primary parameter was endoscopically confirmed<br />
healing <strong>of</strong> the esophageal lesions after 4 weeks <strong>of</strong> treat-<br />
<strong>Comparable</strong> <strong>Efficacy</strong> <strong>of</strong> <strong>Pantoprazole</strong> <strong>and</strong><br />
<strong>Omeprazole</strong> in Reflux Esophagitis<br />
Fig. 2. Healing rates <strong>of</strong> GERD grade II/III after 4 <strong>and</strong> 8 weeks <strong>of</strong><br />
treatment with 40 mg pantoprazole or 40 mg omeprazole MUPS.<br />
ment. After this first treatment period healing rates were<br />
similar for both drugs <strong>and</strong> statistically equivalent for all<br />
populations (table 2, fig. 2). Overall, 70.9% <strong>of</strong> patients<br />
were healed in the pantoprazole <strong>and</strong> 72.6% <strong>of</strong> patients in<br />
the omeprazole MUPS group after 4 weeks <strong>of</strong> treatment<br />
(PP). The healing rates after 8 weeks <strong>of</strong> treatment were<br />
also similar in both treatment groups. Only a few patients<br />
in both groups remained unhealed, but in most <strong>of</strong> them<br />
the reflux esophagitis improved to grade I. As expected, in<br />
all subgroups comprising HC patients, healing rates were<br />
higher than in patients with regular compliance, with<br />
slightly but not significantly higher values in the pantoprazole<br />
than in the omeprazole MUPS group for ITT <strong>and</strong><br />
PP populations both after 4 <strong>and</strong> 8 weeks <strong>of</strong> treatment (table<br />
3; p 1 0.05).<br />
Influence <strong>of</strong> the H. pylori Status on Esophagitis Healing.<br />
Additionally, the influence <strong>of</strong> the H. pylori status on<br />
treatment outcome was examined. H. pylori was present<br />
Digestion 2003;67:6–13 9
Table 3. Healing rates (%) <strong>of</strong> reflux esophagitis in HC patients after<br />
4 <strong>and</strong> 8 weeks <strong>of</strong> treatment with pantoprazole or omeprazole MUPS<br />
once daily<br />
<strong>Pantoprazole</strong> 40 mg<br />
ITTHC<br />
PPHC<br />
<strong>Omeprazole</strong> MUPS 40 mg<br />
ITTHC<br />
PPHC<br />
4 weeks 77.4 77.7 74.7 75.8<br />
8 weeks 94.1 94.8 93.3 94.5<br />
Table 4. Symptom relief rates (%) after 2, 4 <strong>and</strong> 8 weeks <strong>of</strong> treatment<br />
with pantoprazole <strong>and</strong> omeprazole MUPS in the PP population<br />
<strong>Pantoprazole</strong> <strong>Omeprazole</strong> MUPS<br />
2 weeks<br />
Heartburn 70.274.4<br />
Acid eructation 73.7 75.6<br />
Pain on swallowing 74.3 74.1<br />
4 weeks<br />
Heartburn 83.7 88.1<br />
Acid eructation 83.5 90.6<br />
Pain on swallowing 83.1 91.9<br />
8 weeks<br />
Heartburn 91.1 92.6<br />
Acid eructation 89.0 94.4<br />
Pain on swallowing 94.1 96.3<br />
Table 5. Symptom sum score values <strong>of</strong> leading GI symptoms after 2,<br />
4 <strong>and</strong> 8 weeks in the PP population<br />
Symptom sum score <strong>Pantoprazole</strong> <strong>Omeprazole</strong> MUPS<br />
Baseline 5.04B1.825.12B2.01<br />
2 Weeks 0.80B1.420.75B1.35<br />
4 Weeks 0.44B0.94 0.28B0.81<br />
8 Weeks 0.33B0.78 0.24B0.71<br />
Table 6. Correlation between endoscopic healing <strong>and</strong> symptom<br />
relief after 4 weeks <strong>of</strong> treatment in the ITT population (n = 669)<br />
Endoscopically healed but<br />
no symptom relief (%)<br />
after 4 weeks after 8 weeks<br />
Heartburn 20.8 42.1<br />
Acid eructation 25.5 47.9<br />
Pain on swallowing 17.9 36.7<br />
in 22.8% <strong>of</strong> PP patients at baseline as tested by RUT. It<br />
could be shown that the overall healing rates after 4 weeks<br />
<strong>of</strong> treatment in patients infected with H. pylori were higher<br />
(ITT: 68.2%, PP: 77.0%) than in those with a negative<br />
H. pylori test result (ITT: 65.3%, PP: 70.3%). However,<br />
this difference did not reach statistical significance (p 1<br />
0.05). After 8 weeks <strong>of</strong> treatment the effect <strong>of</strong> H. pylori on<br />
healing was less prominent <strong>and</strong> patients had similar healing<br />
rates, irrespective whether they were H. pylori positive<br />
(ITT: 85.1%, PP: 93.7%) or negative (ITT: 85.0%, PP:<br />
92.2%). Therefore, H. pylori status did not influence the<br />
healing <strong>of</strong> esophageal lesions in this study.<br />
Symptom Relief. After 2 weeks <strong>of</strong> treatment, relief <strong>of</strong><br />
all 3 symptoms (complete absence <strong>of</strong> heartburn, acid eructation,<br />
<strong>and</strong> pain on swallowing) was achieved in more<br />
than 70% <strong>of</strong> patients in both treatment groups (PP population).<br />
The relief rates increased during further treatment<br />
to over 83% after 4 weeks <strong>and</strong> 89% after 8 weeks in both<br />
groups (table 4).<br />
At baseline, the mean symptom sum score <strong>of</strong> the GI<br />
leading symptoms was 5.04 in the pantoprazole <strong>and</strong> 5.12<br />
in the omeprazole MUPS group (PP population). In both<br />
groups this score value decreased strongly during treatment<br />
(to 0.33 in the pantoprazole <strong>and</strong> to 0.24 in the omeprazole<br />
MUPS group after 8 weeks, table 5). The differences<br />
between the treatment groups regarding the sum<br />
score after 2, 4 <strong>and</strong> 8 weeks were not statistically significant<br />
(p 1 0.05).<br />
In addition, the correlation between endoscopic <strong>and</strong><br />
symptomatic healing was calculated in order to identify<br />
the proportion <strong>of</strong> those patients who still had symptoms<br />
but were healed according to endoscopy (table 6). The<br />
proportion <strong>of</strong> patients that were endoscopically healed<br />
but not symptom-free increased from more than 17.9%<br />
after 4 weeks to more than 36.7% after 8 weeks <strong>of</strong> treatment.<br />
Results were similar for the 2 treatment groups <strong>and</strong><br />
comparison between them did not yield any statistically<br />
significant difference (p 1 0.05).<br />
Patient Questionnaire. Patients were a<strong>sk</strong>ed to fill in a<br />
patient questionnaire at each visit. Mean sum scores<br />
decreased from 0.163 <strong>and</strong> 0.175 at baseline to 0.025 <strong>and</strong><br />
0.033 within 8 weeks in the pantoprazole <strong>and</strong> omeprazole<br />
MUPS group, respectively (PP population). Differences<br />
between treatment groups were not statistically significant<br />
(p 1 0.05).<br />
In addition, a factor analysis <strong>of</strong> the gastrointestinal<br />
symptoms was performed in order to identify an underlying<br />
symptom pattern, considering frequency <strong>and</strong> intensity<br />
<strong>of</strong> the reported symptoms. Factor analyses were consistent<br />
<strong>and</strong> 5 symptom clusters were isolated: Each cluster<br />
10 Digestion 2003;67:6–13 Körner/Schütze/van Leendert/Fumagalli/<br />
Costa Neves/Bohuschke/Gatz
contains the symptoms that occurred most <strong>of</strong>ten together:<br />
(1) acid-related symptoms (heartburn at day/night, acid<br />
eructation, burn in throat, burning behind the breastbone,<br />
dysphagia); (2) upper-epigastric-pain-related symptoms<br />
(pain, malaise, pressure, cramps, <strong>and</strong> burn in the epigastrium);<br />
(3) typical symptoms <strong>of</strong> irritable bowel syndrome<br />
(pain, cramps <strong>and</strong> pressure in the lower abdomen, alternating<br />
diarrhea <strong>and</strong> constipation); (4) meteroism-related<br />
symptoms (feeling <strong>of</strong> inflation, satiety feeling, uncomfortable<br />
deflation, bad breath, feeling <strong>of</strong> incomplete defecation,<br />
eructation/burping), <strong>and</strong> (5) vomiting-related symptoms<br />
(vomiting, retching, nausea). The symptoms with<br />
the highest correlation coefficient in each cluster were<br />
(1) heartburn at day; (2) pain in the epigastrium, (3) pain<br />
in the lower abdomen; (4) feeling <strong>of</strong> inflation, <strong>and</strong><br />
(5) vomiting.<br />
Compliance. Compliance was similar in both groups<br />
for the first treatment period (4 weeks) as well as for the<br />
second period (further 4 weeks). In the pantoprazole<br />
group mean compliance was similar with 98.1% for the<br />
first <strong>and</strong> 97.7% for the second treatment period; in the<br />
omeprazole group compliance was 97.1 <strong>and</strong> 96.2%, respectively.<br />
The percentage <strong>of</strong> HC patients, i.e. those who<br />
took 90–110% <strong>of</strong> the study medication, were 70.9% (239/<br />
337) in the pantoprazole <strong>and</strong> 67.8% (225/332) in the omeprazole<br />
MUPS group (ITT).<br />
Adverse Events<br />
Safety data were analyzed for the 669 patients <strong>of</strong> the<br />
ITT population, 86 patients (13%) reported a total <strong>of</strong> 128<br />
adverse events, 40 patients in the pantoprazole <strong>and</strong> 46<br />
patients in the omeprazole MUPS group. The most frequently<br />
reported adverse event in the pantoprazole group<br />
was headache (1%) <strong>and</strong> in the omeprazole MUPS group<br />
diarrhea (2%). However, adverse events were mostly <strong>of</strong><br />
mild (41%) or moderate (50%) intensity. A total <strong>of</strong> 2.1%<br />
adverse events (n = 7) in the pantoprazole <strong>and</strong> 1.2% (n =<br />
4) in the omeprazole MUPS group were <strong>of</strong> severe intensity.<br />
Most <strong>of</strong> adverse events were considered to be unrelated<br />
(55%) or unlikely related to the study medication<br />
(23%); only 2 were thought to be definitely related, headache<br />
in the pantoprazole <strong>and</strong> toxicoderma in the omeprazole<br />
MUPS group. The latter adverse event was <strong>of</strong> moderate<br />
intensity <strong>and</strong> led to premature discontinuation. In the<br />
entire study 4 serious adverse events were reported, 2 in<br />
the pantoprazole <strong>and</strong> 2 in the omeprazole MUPS group,<br />
but all were judged to be unrelated to the study medication<br />
by the investigator. Four patients from the pantoprazole<br />
group <strong>and</strong> 7 from the omeprazole MUPS group withdrew<br />
due to adverse events.<br />
<strong>Comparable</strong> <strong>Efficacy</strong> <strong>of</strong> <strong>Pantoprazole</strong> <strong>and</strong><br />
<strong>Omeprazole</strong> in Reflux Esophagitis<br />
Discussion<br />
The present study demonstrated pantoprazole 40 mg<br />
daily to be as effective as omeprazole MUPS 40 mg daily<br />
with respect to endoscopically proven healing <strong>of</strong> moderate<br />
to severe reflux esophagitis <strong>and</strong> relief <strong>of</strong> reflux symptom.<br />
So far, it is one <strong>of</strong> the largest multicenter studies on<br />
patients with moderate to severe GERD comparing equal<br />
doses <strong>of</strong> both drugs.<br />
Healing rates <strong>of</strong> 70.9 <strong>and</strong> 91.5% were observed after 4<br />
<strong>and</strong> 8 weeks, respectively, in the pantoprazole group (PP<br />
population). The corresponding healing rates in the omeprazole<br />
MUPS group were 72.6 <strong>and</strong> 93.0%. Both study<br />
drugs showed equivalent efficacy in healing the reflux<br />
esophagitis. There were no significant differences between<br />
the treatment groups with respect to GI symptom<br />
relief as assessed by the patient questionnaire. These findings<br />
are in good agreement with previous findings in<br />
patients with mild to severe GERD treated with 20 mg<br />
pantoprazole or 20 mg omeprazole MUPS [13]. The correlation<br />
between endoscopical healing <strong>and</strong> symptom relief<br />
was found to be rather low. The proportion <strong>of</strong> patients<br />
that were endoscopically healed but not symptom-free<br />
was 117.9% after 4 weeks <strong>and</strong> increased to 136.7% after<br />
8 weeks <strong>of</strong> treatment. This finding, that endoscopically<br />
healed patients still suffer from symptoms or vice versa<br />
(patients with symptoms do not necessarily have a positive<br />
endoscopic result) is well known <strong>and</strong> is currently<br />
under discussion. Thus, the Genval Workshop Report<br />
states that there is no positive predictive value <strong>of</strong> GERD<br />
symptoms (especially heartburn) for erosion [23].<br />
The factor analysis <strong>of</strong> the self-reported GI symptom<br />
questionnaire supports the previous findings that GERD<br />
is a disease with a heterogeneous symptom pattern, not<br />
only to be defined by the presence or absence <strong>of</strong> so-called<br />
predominant symptoms [24, 25]. Clinical studies indicate<br />
that multiple dimensions <strong>of</strong> symptoms are important in<br />
the assessment <strong>of</strong> GERD rather than the assessment <strong>of</strong><br />
predominant symptoms. However, only limited valid information<br />
exist on coexisting symptoms as a definition<br />
for GERD.<br />
It seems obvious that patient compliance has a strong<br />
influence on treatment effect. However, there are only few<br />
compliance studies found in the literature focusing on this<br />
parameter [26–28]. This is surprising, given that adherence<br />
to the recommended tablet intake (i.e. 100% intake)<br />
is a prerequisite for the healing process. Therefore, in this<br />
study, we additionally analyzed the subgroup <strong>of</strong> patients<br />
considered to be HC. Healing rates in the HC subgroup<br />
were 77.7% in the pantoprazole <strong>and</strong> 75.8% in the omepra-<br />
Digestion 2003;67:6–13 11
zole MUPS group after 4 weeks (PPHC). This increased to<br />
more than 94.0% in both treatment groups after a further<br />
4 weeks <strong>of</strong> treatment. Furthermore, the healing rates in<br />
the HC patient group were higher than those in the regular<br />
compliant patient group. We suggest that for the efficacy<br />
assessment <strong>of</strong> a given treatment, stronger emphasis<br />
should be put on the patient compliance. Compliance<br />
regarding tablet intake as determined in the protocol has<br />
an obvious effect on healing rates in moderate to severe<br />
reflux esophagitis.<br />
Infection with H. pylori is prevalent in patients with<br />
GERD, even though it does not appear to play an important<br />
role in the pathophysiology <strong>of</strong> the disease. However,<br />
the relevance <strong>of</strong> H. pylori for the management <strong>of</strong> GERD is<br />
being hotly debated. Some authors found that proton<br />
pump inhibitors (PPIs) were less effective in H. pylorinegative<br />
patients – a reason not to eradicate H. pylori in<br />
GERD patients. Other authors, by contrast, suggested<br />
that long-term PPI treatment <strong>of</strong> GERD may lead to atrophic<br />
gastritis <strong>and</strong> intestinal metaplasia in H. pylori-positive<br />
patients <strong>and</strong> increase the ri<strong>sk</strong> <strong>of</strong> developing gastric<br />
cancer – a reason to eradicate H. pylori [29, 30]. Numerous<br />
reviews also have discussed this topic [31–33]. In the<br />
present study H. pylori was present in 22.8% <strong>of</strong> PP<br />
patients at baseline. Infected patients had slightly higher<br />
healing rates than those with a negative test result. Hence,<br />
our data support previous findings that H. pylori infection<br />
seems to interfere with the acid-suppressive effects <strong>of</strong><br />
PPIs [34]. However, the difference in treatment effect<br />
between H. pylori-infected <strong>and</strong> -uninfected patients did<br />
not reach statistical significance, <strong>and</strong> after further 4 weeks<br />
<strong>of</strong> treatment this difference even disappeared. However,<br />
bearing in mind that high, 40-mg dosages <strong>of</strong> both PPIs<br />
were used in this study, it is well conceivable that no significant<br />
difference was found since the improved efficacy<br />
<strong>of</strong> PPIs in esophagitis healing in H. pylori-positive patients<br />
is seen most easily with lower doses <strong>of</strong> PPIs [35].<br />
The explanation for this finding is still lacking, <strong>and</strong> the<br />
potential benefit <strong>of</strong> retaining the H. pylori-infection is<br />
questionable considering the inflammatory activity <strong>of</strong> the<br />
bacterium in the mucosa <strong>and</strong> the acceleration <strong>of</strong> gastric<br />
atrophy caused by H. pylori infection. However, from the<br />
experience gained in this study, we suggest that eradication<br />
still appears advisable.<br />
Both study drugs were well tolerated, with only 1<br />
patient in each treatment group reporting adverse events<br />
that were considered to have a definite causal relationship<br />
to the study medication.<br />
Conclusion<br />
<strong>Pantoprazole</strong> <strong>and</strong> omeprazole MUPS were shown to<br />
be equivalent with respect to healing after 4 <strong>and</strong> 8 weeks<br />
<strong>of</strong> treatment in patients with reflux esophagitis grade II/<br />
III. There were also no significant differences between<br />
both study drugs regarding symptom relief. In summary,<br />
40 mg pantoprazole o.d. is as effective as 40 mg omeprazole<br />
MUPS o.d. in the treatment <strong>of</strong> moderate to severe<br />
GERD <strong>and</strong> associated GI symptoms.<br />
Acknowledgements<br />
This study was supported by a grant from ALTANA Pharma AG,<br />
Konstanz, Germany. We would like to thank Dr. Spranger <strong>and</strong> Dr.<br />
Weichsel, Ingolstadt, Germany, Dr. Echevarne, Barcelona, Spain,<br />
<strong>and</strong> Dr. Viollier, Basel, Switzerl<strong>and</strong>, for performing the laboratory<br />
investigations. The investigators are very grateful to IFE Institute for<br />
Research <strong>and</strong> Development, Witten, Germany, who was responsible<br />
for monitoring at the study sites, data collection, source data verification<br />
<strong>and</strong> biometrical analysis. Many thanks also to Dr. Birgit Köhne<br />
for preparing the manuscript. To all investigators collaborating in the<br />
study we express our gratitude (alphabetical order).<br />
Austria: B. Dragosics (Wien), P. Kratochvil (Graz), T. Stupnicki<br />
(Deutschl<strong>and</strong>sberg), H. Wurzer (Graz).<br />
Germany: A. Achim (Iserlohn), H. Böneke (Lienen), H. Bayer<br />
(Hamburg), A. Biedermann (Blankenhain), J. Bott (Elmshorn), W.<br />
Br<strong>and</strong>t (Potsdam-Babelsberg), G. Bretzke (Zwickau), W. Burmeister<br />
(Hamburg), H. Daake (Wiesbaden), A. Dettmer (München), A. Dietz<br />
(Ludwigsfelde), E. Dombrow<strong>sk</strong>i (Berlin), H. Eisold (Mössingen), W.<br />
Elsel (Zwickau), R.-R. Fink (Freising), G.-R. Franke (Dinkelsbühl),<br />
O. Friedrichs (Duisburg), C. Fritze (Jena), J. Großkopf (Wallerfing),<br />
B. Hägler (Neufahrn), J. Hein (Marburg), G. Heptner (Dresden),<br />
K.-H. Hey (Paderborn), J. H<strong>of</strong>fschröer (Bad Essen), T. Kammermeier<br />
(Bogen), S. Kaspari (Lüneburg), H.-U. Kellner (Kassel), R.<br />
Kern (Rödersheim-Gronau), C. Klein (Künzing), J. Krehbiel (Rödersheim-Gronau),<br />
H.-G. Krezdorn (München), V. Kroll (Markdorf),<br />
H. Kubisch (Chemnitz), K.-D. Kurzke (Sulingen), K. Lenz (Isny),<br />
M. Maaß (Markdorf), W. Marx (Elmshorn), J. Pankow (Flensburg),<br />
U. Pustlauk (Meinerzhagen), A. Schmidt (Offenbach), J. Schmitz<br />
(Fürth), G. Scholz (Offenbach), D. Sehl<strong>and</strong> (Rostock), U. Siebert<br />
(Haßfurt), R. Sievers (Bederkesa), T. Simon (München), K. Teubner<br />
(Stuttgart), T. Tibroni (Coesfeld), A. Ulmer (Ludwigsburg), R. Vogt<br />
(Mannheim), C. Völker (München), von Fritsch (Erlangen), R.<br />
Warncke (Elmshorn), U. Werkmeister (Isny), W. Zink (Nürnberg),<br />
K. Zöllner (Dippoldiswalde).<br />
Portugal: J. Fraga (Vila Nova de Gaia), L.A. Novais (Amadora).<br />
Switzerl<strong>and</strong>: P. Bänninger (Küsnacht), P. Duroux (Sion), F. Kapp<br />
(Basel), L. Kayasseh (Basel), M. Meyer (Luzern), G. Münst (Uster),<br />
K. Schulthess (Zürich), P. Stadler (Payerne), C. Valli (Visp), M. Voirol<br />
(Yverdon-les-Bains), P.-Y. Zaugg (Frauenfeld).<br />
The Netherl<strong>and</strong>s: A.J. Bosman-Laven (Hendrik Ido Ambacht),<br />
H.S. Emanuels (Zwijndrecht), F.I. Gulzar (Zwijndrecht), P.W.E.<br />
Haeck (Stad<strong>sk</strong>anaal), W.W. Meijer (Den Helder), W.J. Rijsdijk<br />
(Hendrik Ido Ambacht), P.A.H. Top (Zwijndrecht), R.J. van Houten<br />
(Hendrik Ido Ambacht).<br />
12 Digestion 2003;67:6–13 Körner/Schütze/van Leendert/Fumagalli/<br />
Costa Neves/Bohuschke/Gatz
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