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Clinical Outcome and Influencing Factors of a New Short-term Quadruple Therapy for Helicobacter pylori Eradication
A Randomized Controlled Trial (MACLOR Study)
Gerhard Treiber, MD;
Joachim Wittig, MD;
Susanne Ammon, MD;
Siegfried Walker, MD;
Leen-Jan van Doorn, PhD;
Ulrich Klotz, PhD
Arch Intern Med. 2002;162:153-160.
ABSTRACT
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Background Short-term therapies for eradicating Helicobacter
pylori in selected patients might offer advantages in terms of costs,
compliance, and adverse effects in contrast to standard 1-week triple therapy.
Methods To determine eradication success and influencing factors in a new short-term
quadruple therapy, a total of 243 patients positive for H pylori were randomly assigned to 1 of 3 regimens according to age,
smoking status, and diagnosis: a 5-day treatment with 3 antibiotics (amoxicillin,
1 g twice daily [bid]; clarithromycin, 250 mg bid; and metronidazole, 400
mg bid) and lansoprazole (30 mg bid [L5; reference treatment]) or ranitidine
hydrochloride (300 mg bid [R5]), or the same 3-day antibiotic-lansoprazole
combination (L3) with a 2-day pretreatment with lansoprazole.
Results A total of 234 patients completed the study. On an intention-to-treat
basis, overall eradication of H pylori was confirmed
in 86.4%: 89.2% in the L5 group vs 81.2% in the L3 group vs 88.8% in the R5
group; differences were not significant. Multiple logistic regression analysis
showed that younger age (<55 years; P = .03),
history of peptic ulcer disease (P = .04), smoking
(P = .03), metronidazole resistance (P = .003), low ranitidine trough serum concentrations (P = .005), cytotoxin-associated gene A–negative strains in peptic
ulcer disease (P = .04), and outer inflammatory protein
A–positive strains (P = .02) were associated
with eradication failure.
Conclusions This new quadruple H pylori eradication regimen
is efficacious, safe, well tolerated, and cost saving, and may be a treatment
option for patients older than 55 years with no history of peptic ulcer disease.
Furthermore, strains that are sensitive to all antibiotics, cytotoxin-associated
gene A–positive, and outer inflammatory protein A–negative could
be suitable for short-term quadruple therapy. Patients with an unfavorable
combination of characteristics should be treated for a minimum of 7 days.
INTRODUCTION
MORE THAN 10 years after the rediscovery of Helicobacter
pylori, H pylori eradication therapy is well
established for peptic ulcer disease (PUD) in terms of ulcer healing and prevention
of recurrence,1-2 but the impact
on nonulcer dyspepsia remains a matter of debate.3
However, there may be a small subgroup of patients with nonulcer dyspepsia
who receive a long-lasting benefit from H pylori
eradication.4 The relationship between H pylori and gastric cancer has become increasingly convincing.5-6
Numerous reviews and meta-analyses have tried to identify the value
of specific treatment combinations in eradication of H pylori, and several guidelines have been published.7-15
The so-called standard triple regimen, composed of 2 antibiotics and an acid-suppressive
drug, is recommended for 1 week as first-line therapy by the Maastricht Consensus
conferences13 or for up to 2 weeks by the American
College of Gastroenterology.15 Nevertheless,
these and other guidelines differ substantially concerning treatment duration
and drug dosage. This complex situation can be explained, at least in part,
by different health care resources, country-specific drug availability, and
package size. Most people would probably agree that the optimal treatment
recommendation for H pylori infection has not been
established. Further progress may be achieved with new drugs or drug combinations,
a vaccine, or a shorter treatment with a more convenient application schedule.
Several groups have focused on cost-effectiveness, mainly by decreasing the
duration of treatment; thus, patients may benefit by increased compliance
and fewer adverse effects. In addition, substantial savings in drug prescription
costs (of up to 30%-40%) as compared with standard triple therapy may be achievable
by either replacing a proton pump inhibitor (PPI) with an H2-receptor
antagonist or by treating for less than 7 days.
In 1998, our group16 described a successful
5-day regimen by combining all 3 antibiotics generally used for standard triple
therapy with a PPI. In the present study, we tried to expand on this short-term
concept by additionally identifying factors that influence clinical outcome
and subjective improvement of symptoms.
PATIENTS AND METHODS
STUDY DESIGN
This open-label controlled study involved 2 centers in southwest Germany
and was conducted from April 1, 1997, to March 31, 1999. The study protocol
was approved by the local ethics committee and regulating government authorities,
and all patients gave their written informed consent before study entry. All
patients were prospectively randomized centrally by a computer-generated predefined
list. We used stratified randomization (blocks of 6 patients within strata)
according to age ( 55 years or <55 years), smoking habits (smoker or
nonsmoker), and actual endoscopic diagnosis, classified as PUD (duodenal ulcer
or gastric ulcer) or non–peptic ulcer disease (NPUD) (characterized
by either erosive gastritis with macroscopic lesions <5 mm in diameter
or no visible lesions [nonulcer dyspepsia]), to assign patients to 1 of 3
treatment arms within 48 hours after endoscopic investigation. Patients then
received amoxicillin (1 g twice daily [bid]), metronidazole (400 mg bid),
and clarithromycin (250 mg bid) for 5 days together with either lansoprazole
(30 mg bid) (designated L5) or ranitidine hydrochloride (300 mg bid) (R5)
for 5 days, or the same antibiotics for only 3 days (L3; days 3-5) with a
2-day lansoprazole pretreatment (days 1-5). This design was used primarily
to answer the following questions: Are L3 and R5 inferior to the previously
evaluated reference arm L5? Are there factors that influence treatment success?
INCLUSION AND EXCLUSION CRITERIA
Patients were regarded eligible for study entry if they were between
18 and 85 years of age; if treatment was indicated because of either macroscopic
abnormalities on upper gastrointestinal tract endoscopy or persistent upper
gastrointestinal tract symptoms during the previous 3 months; and if H pylori status was positive, as assessed by rapid urease
test and serologic testing as well as facultatively by histologic testing
and/or culture. In a few cases, rapid urease testing (if not performed) was
replaced by a urea breath test (UBT). Exclusion criteria were the following:
severe illnesses with a life expectancy of less than 1 year, present viral
disease, known allergy against the intended medication, pregnancy and lactation,
severe renal and/or liver dysfunction (creatinine clearance of <30 mL/min
or liver cirrhosis, Child-Pugh classification stage B or C), cognitive impairment
or mental illness, and relevant disorders of the central or peripheral nervous
system. Patients were excluded from the study if they had been previously
(<4 weeks before study entry) treated with bismuth salts or antibiotics;
had had PPI pretreatment longer than 1 week; and/or had received more than
once-daily dosing of the equivalent of omeprazole, 20 mg/d.
ASSESSED DATA
At entry, age, body mass index and weight changes, smoking status (smoker,
nonsmoker, or abstinence for at least 6 months), alcohol intake (not relevant
if <20 g/d), concomitant use of aspirin or nonsteroidal anti-inflammatory
drugs, history of peptic ulcer disease, and actual endoscopic diagnosis were
recorded. The subjective measures (reported symptoms) nausea, vomiting, epigastric
pain, distention, heartburn, diarrhea, and loss of appetite were monitored
by means of visual analog scales (0-10 cm, with higher numbers indicating
more severe symptoms).
In addition to routine laboratory variables, we assessed serum gastrin
levels with an upper normal limit of 100 pg/mL (Gastrin-RIA; DPC Biermann,
Bad Nauheim, Germany) and pepsinogen I and II (PEPSI-I K and PEPSI-II K; DiaSorin,
Saluggia, Italy) by radioimmunoassay under fasting conditions. We assumed
the presence of gastric atrophy17 if the values
of pepsinogen I were less than 60 ng/mL or if the pepsinogen ratio (pepsinogen
I–pepsinogen II) was less than 3.5. Immunoblot (Helicoblot 2.0; Genelabs
Diagnostics Pte Ltd, Singapore) was used for outer inflammatory protein A
(oip-A) (35-kd band) as well as cytotoxin-associated gene A (cag-A) and vacuolating
cytotoxin A (vac-A) status (phenotyping) and compared in several patients
(n = 47) by a polymerase chain reaction–based assay (genotyping).18-19 When cultures were available (n =
56), we determined the resistance status for amoxicillin, clarithromycin,
and metronidazole by means of the Etest (AB Biodisk, Solna, Sweden) with cutoff
values of 4, 2, and 8 µg/mL, respectively. Creatinine clearance was
calculated from serum creatinine level, age, and body weight by means of the
equation of Cockcroft and Gault.20 Finally,
IgA and IgG serologic testing (Pyloriset EIA-A plus EIA-G; Orion Corporation
Orion Diagnostica, Espoo, Finland) was performed. If available (n = 120),
histologic findings of biopsy specimens from the antrum and corpus were classified
according to the upgraded Sydney system, where gastritis activity was 0 (none)
and 3 (maximum presence). The same system was applied for presence or absence
of metaplasia and atrophy.
For all patients, weight changes and reported symptoms were recorded
using visual analog scales at the end of treatment and after 1 and 3 months
(patients with NPUD were also seen at 6 months). In addition, follow-up evaluation
for the patient responses was performed concomitantly by questionnaire: change
in symptoms ("Do you now experience other symptoms than at the beginning of
treatment?"), constant symptoms ("Do you now experience the same symptoms
as at the beginning of treatment?"), improvement of symptoms ("Has an improvement
in symptoms occurred since the beginning of therapy?"), tolerability of therapy
("Was this treatment tolerable for you?"), reparticipation ("Would you participate
again in this therapy?"), and additional treatment ("Did you need additional
treatment from your general practitioner or self-medication since study entry?")
were assessed.
Adverse effects, such as metallic and other taste disturbances, diarrhea,
and rash or allergy, were assessed (any event) and patients were asked if
these effects had interfered with normal daily activities (major event). Adverse
effects were assumed to be therapy related if they first appeared during treatment
or if pretherapeutic symptoms (eg, diarrhea) worsened during therapy. Routine
laboratory measures were determined after treatment to detect any abnormalities
induced by treatment. Serum levels of the administered drugs were measured
in all patients during the last dosing interval under steady-state conditions
to test for compliance and to correlate the results with eradication failure.
Eradication success was determined by a UBT device (FanCi2; Fischer
ANalysen Instrumente GmbH, Leipzig, Germany) before and 30 minutes after ingestion
of 100 mg of urea labeled with carbon 13 (n = 223), assuming a delta over
baseline value of 2 or less. Only if both UBTs (performed 1 and 3 months after
treatment end) were negative, patients were classified as H pylori negative. Alternatively, at 3 months in 11 patients (4.7%),
1 negative UBT and a titer decline of more than 30% compared with baseline
was accepted in defining treatment success. This UBT device had previously
been validated against mass spectroscopy in-house, with 95% concordant results.
The rapid urease test and UBT had been compared in a previous study16 and obtained 98% concordant results. Thus, testing
was performed in accordance with actual official guidelines.21
DATA EVALUATION
Calculations were performed on the following variables by means of commercially
available statistical programs (Prism 2.01; GraphPad Software, Inc, San Diego,
Calif; and SPSS 9.0; SPSS Inc, Chicago, Ill) according to a prespecified order
of significance: treatment success according to regimen, factors influencing
treatment success, outcome of subjective symptoms, and adverse events. For
differences among patient groups, Fisher exact test was applied. For comparison
of metric data in multiple groups, 1-way analysis of variance (the so-called
post testing using the Bonferroni method) was used, and for analysis of influencing
factors, multiple logistic or linear regression analysis with and without
adjustment for putative confounding factors was used. The results are shown
as mean or median values with corresponding 95% confidence intervals (CIs)
or SD. P<.05 (2-sided) was regarded as significant.
As precalculated by a statistical program (StatMate; GraphPad Software, Inc),
the study was designed to detect a clinically relevant and significant (P<.05) difference of more than 10% between the reference
arm (L5, with a presumed mean success rate of 90%) and the 2 other treatment
arms by including 80 patients per treatment arm, assuming a power of 80%.
To be considered equivalent to the same prevalidated 5-day quadruple therapy,16 the 95% CI (per-protocol [PP] analysis) of all regimens
should be within the predefined range of 90%± 10% therapeutic success
rate.
RESULTS
ERADICATION AND ADVERSE EFFECTS
Two hundred forty-six patients fulfilled the entry criteria and were
regarded as eligible. Three patients withdrew their consent before randomization
and receiving the first dose; thus, 243 remained (intention-to-treat [ITT]
basis). Of these 243 randomized patients, 9 had to be excluded from final
analysis for the following reasons: 2 patients died of non–study-related
diseases (acute myocardial infarction [L3] and acute colonic ileus from previously
unrecognized malignancy [L3]), 2 stopped treatment because of drug-related
adverse effects (diarrhea [L5] and allergic reaction to amoxicillin [L5]),
1 patient had gastric malignancy diagnosed 2 weeks after study inclusion (L3),
1 patient was noncompliant without adverse events (L3), and 3 were unavailable
for follow-up [2 in L5 and 1 in R5].
The characteristics of the remaining 234 patients (PP basis) without
trial rule violation are shown in Table
1. The groups were comparable for all characteristics evaluated
at baseline. The outcome according to the regimens applied is summarized in Table 2. No significant differences were
observed between the 2 participating centers. The overall eradication rate
(ITT) averaged 86.4%. All treatments fulfilled the proposed Food and Drug
Administration criteria of efficacy for H pylori
eradication, ie, the lower limit of the 95% CI exceeded 70%. The reference
arm (L5) was equivalent to previous experience with 5-day quadruple therapy16 (93.7 vs 94.1% on a PP basis) and not superior over
the 2 other treatments. However, equivalence to L5 could be noted only for
the R5 but not for the L3 treatment arm: the upper limit of the 95% CI of
the difference between proportions for L3 and L5 is 18.8% and therefore above
the proposed criterion of 10% given by the Committee for Proprietary Medicinal
Products of the European Drug Agency or of 15% by the Food and Drug Administration.22 In addition, for L3, the 95% CI crosses below the
predefined lower margin of 80%.
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Table 1. Characteristics of Patients Entering the Prospective Randomized
Controlled Study*
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Table 2. Eradication Results for the 3 Regimens, Calculated on ITT
and PP Basis*
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Adverse effects (any event, including major events interfering with
daily activities) are listed in Table 3. All were reversible at the end of treatment except for mucosal
candidiasis in 2 patients, which had to be treated topically. By quantifying
any event according to the regimen used, the most common one was diarrhea,
appearing frequently in the R5 group (56.4% vs 36.9% with L5 [P = .056] and 36.3% with L3 [P = .08]). However,
this regimen caused fewer nonmetallic taste disturbances (1.3% vs 9.5% with
L5 [P = .06] and 11.3% with L3 [P = .02]) but more often induced a new loss of appetite (9.0% vs 1.2%
with L5; P = .03) and nonspecific, nonallergic erythemas
(9.0% vs 1.3% with L3; P = .06). Interestingly, 5
patients reported nonmetallic taste disturbances beyond the end of treatment.
No clinically relevant changes of routine laboratory measures were noticed.
Compliance, as assessed by monitoring of drug levels, exceeded 95%.
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Table 3. Incidence of Adverse Events Independent of the Applied Regimen
at the End of Therapy
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FACTORS AFFECTING ERADICATION SUCCESS
Multiple regression analysis identified several single factors that
had a significant impact on treatment outcome (Table 4): age, smoking status, history of peptic ulcer, and strain
properties (metronidazole resistance; presence or absence of oip-A). The effect
of smoking was no longer significant (P = .11) when
controlled for age. History of peptic ulcer was independent of other factors.
Taking 2 clinical variables (age and history of PUD) into account, the best
eradication rate was achieved in older patients (55 years) without a history
of PUD (Table 5), resulting in
an important 20% difference between the best- and worst-case scenario (P = .002).
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Table 4. Multiple Logistic Regression Analysis for Factors Influencing
Treatment Outcome Without Adjustment for Confounding Factors*
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Table 5. Eradication Results According to Clinical Factors (n = 234)
and Selected Strain Properties (n = 231)*
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Cultures were obtained in 56 patients for determination of resistance
background. Pretherapeutic resistances were 0% for amoxicillin, 7.3% for clarithromycin,
and 29.1% for metronidazole. During the study period, we obtained cultures
from 205 additional patients who could not be included in the study. The corresponding
resistance rates of this (control) population were 0% for amoxicillin, 9.3%
for clarithromycin, and 34.6% for metronidazole. Thus, in terms of resistance,
the studied patients can be regarded as representative of our 2 centers. Metronidazole
resistance had the greatest impact on H pylori eradication
failure (Table 6). However, if
the serum trough steady-state value of metronidazole was above the strain's
minimum inhibitory concentration for metronidazole, therapeutic outcome was
improved regardless of whether this strain had been classified "minimum inhibitory
concentration resistant." This finding did not hold true for clarithromycin
(Table 7).
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Table 6. Influence of Primary Resistance on Treatment Success
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Table 7. Association Between Drug Levels and Strain Susceptibility
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In 47 patients, we were able to genotype the strains, which was confirmed
in 96% of cases by the immunoblot expression for cag-A (119-kd band); for
vac-A, the signal(s) type s1 compared with 89-kd band, only 50% conformity
was observed. Overall, cag-A status did not correlate with the initial diagnosis
or the posttherapeutic H pylori status as indicated
by immunoblot. However, a subgroup of patients with peptic ulcer on endoscopy
and a cag-A–positive strain were more likely to respond to therapy than
patients with the cag-A–negative one (93.1% vs 76.5%; P = .04). The absence of oip-A was independent of clinical factors
and significantly (P = .02) associated with an improved
outcome of treatment (Table 4
and Table 5). No direct correlation
was seen between treatment outcome and presence of elevated gastrin level
or reduced pepsinogen ratio, which could have indicated mucosal atrophy.
Serum trough steady-state values of ranitidine were significantly (P = .005) and positively related to a negative posttherapeutic H pylori status, while there was only a slight positive
trend for lansoprazole and no difference for the antibiotics used (Table 8).
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Table 8. Minimal Steady-state Serum Concentrations (Css)
of the Applied Drugs According to Posttherapeutic Helicobacter
pylori Status
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A history of peptic ulcers was marginally related to a positive cag-A
status (P = .08). Age was significantly associated
with other factors: the presence of gastric atrophy (r
= 0.19, P<.003; atrophy itself was associated
with a positive cagA–status, P = .06) and parietal
cell mass, which is reflected by serum gastrin levels (r = 0.15, P = .04). Other factors positively
related to age were elevated titers of IgA (r = 0.28, P<.001) and IgG (r = 0.17, P = .005). Age was still significantly associated with
eradication success after adjusting for sex, history of peptic ulcer, cag-A
status, gastrin, and pepsinogen ratio (P = .05).
Finally, forward Wald logistic stepwise regression analysis at an entry P<.01 identified the absence of a history of peptic
ulcer disease (odds ratio, 0.38; 95% CI, 0.16-0.93) and of oip-A (odds ratio,
0.37; 95% CI, 0.15-0.89) as the factors best predicting H pylori eradication success (P = .007).
OUTCOME ACCORDING TO SYMPTOMS
During a 6-month follow-up, various symptoms were recorded, but only
the score on a visual analog scale for epigastric pain discriminated patients
according to their H pylori status (positive vs negative)
at month 3 (1.3 vs 0.7; P<.001) and month 6 (2.0
vs 0.7; P<.001) compared with prestudy levels
(3.5 vs 2.8; P = .20). Since a substantial number
of patients were asymptomatic at onset, we also calculated the proportion
of symptomatic patients at any monitored time point and analyzed the results
according to diagnosis (PUD and NPUD) and posttherapeutic H pylori status, which was different in H pylori–positive vs –negative patients with NPUD at month 3 (53.3%
vs 26.4%; P = .04) and at month 6 (58.3% vs 16.0%; P = .003), whereas patients with PUD did not differ. The
same observation in favor of H pylori eradication
held true for overall symptom improvement at 3 months (NPUD with 71.4% vs
93.3% [P = .03], PUD with 71.4% vs 98.6% [P = .02]) and at 6 months (75.0% vs 95.3%) (P
= .04). In symptomatic patients, we found a nonsignificant trend (because
of the small number of treatment failures) toward an almost 2-fold increase
of recurrence of identical symptoms associated with eradication failure involving
PUD and NPUD. At the end of treatment, 21.7% of H pylori–positive patients and 30.5% of H pylori–negative
patients complained about the same persisting symptoms, compared with 45.5%
vs 26.0% at month 3 and 58.3% vs 23.8% at month 6. Patients with and without
successful eradication showed no difference during follow-up in terms of abdominal
distention, nausea, loss of appetite, diarrhea, vomiting and heartburn, tolerability
of therapy, and consent for reparticipation. Only patients with successful
eradication showed a significant (P<.001) weight
gain (mean, 1.2 kg at month 6). In addition, the percentage of patients needing
further medication (antacids, prokinetics, H2-receptor antagonists
prescribed by their general practitioner or self-medicated) for symptom relief
was significantly higher at month 3 (33.3% vs 9.3%; P
= .002) and month 6 (33.3% vs 10.6%; P = .05) if H pylori infection persisted.
COMMENT
In 1998, our group introduced a 5-day quadruple therapy for H pylori eradication, consisting of 3 antibiotics (amoxicillin, clarithromycin,
and metronidazole) and a PPI. We compared it with 1-week standard triple therapy,
and equivalence was noted in terms of eradication (ITT: 90.1% vs 90.5%; PP:
94.1% vs 92.7%) and adverse effects.16 This
is in accordance with the latest data published for triple therapy (macrolide
plus either amoxicillin or metronidazole), with an ITT rate ranging from 81%
to 86%.10-11,23 We
have now reproduced these success rates, with an ITT rate ranging from 81.2%
to 89.2% (dependent on the regimen used), thus concluding that our present
and previously evaluated control arm (5-day PPI-based quadruple regimen) is
again comparable with standard triple therapy, although this therapy was actually
not included again. Although this study was not designed as an equivalence
trial, the replacement of a PPI by an H2-receptor antagonist in
a 5-day regimen seems to be possible, whereas shortening the treatment duration
to 3 days should be regarded with caution, even if the fraction difference
to the reference treatment may be below 10% (7.9%, ITT) and thus clinically
not important. These results were confirmed by a well-conducted and controlled
study by Neville et al,24 who demonstrated
that the same 5-day quadruple regimen was significantly more effective than
a 5-day triple regimen containing amoxicillin and clarithromycin (ITT: 88%
vs 59%; P<.001) but not than the 5-day combination
of metronidazole and clarithomycin (ITT: 88% vs 81%; P
= .38). Resistance to metronidazole had some impact on the efficacy of the
triple therapy with clarithromycin and metronidazole. Interestingly, age was
a predicting factor for treatment success in that English study. In an uncontrolled
trial, Okada et al25 reported an eradication
rate of 92% (ITT) with a similar but 1-week quadruple therapy. Their prevalence
of metronidazole resistance (16%) was much lower than in the English study
(52%)24 or in our present study (29%). Two
recently published studies26-27
had less power and did not report resistance data; they compared either a
5-day regimen of rabeprazole sodium, amoxicillin, and clarithromycin with
vs without metronidazole, which achieved 94.5% vs 80% cure (ITT, P<.05), or a 3-day regimen of omeprazole, amoxicillin, and clarithromycin
with metronidazole vs the same regimen without metronidazole but given for
10 days, which achieved 89.3% vs 81.8% cure (ITT, P
= .29). In summary, the mean success rates of all of these quadruple regimens
are consistently around 90% and appear to be influenced less by the local
pattern of metronidazole resistance. As highlighted in a recent review,23 these 4 studies and others provide strong evidence
that the amoxicillin-clarithromycin combination in triple therapy is clearly
inferior to the actual quadruple therapy in a short-term (<7 days) setting.
However, it must be emphasized that the type of culture, the methods
of resistance testing (Etest vs disk diffusion), and smoking status influence
the rates of metronidazole resistance.28-29
Another considerable factor is the serum drug levels achieved. As postulated
in a previous review9 and confirmed by our
direct measurements, the serum concentrations of metronidazole in contrast
to clarithromycin do not always exceed the strain's minimum inhibitory concentration
in patients with "sensitive" strains, indicating that higher doses might be
more effective and could overcome "clinical" metronidazole resistance. Since
metronidazole plays a key role in the success of all treatments for less than
7 days,23 this observation appears to be important.
However, as with all short-term multidrug regimens, loss of clinical efficacy
due to induced bacterial resistances after treatment failure is of major concern.
Two studies attenuated this fear by showing decreased secondary resistance
rates for clarithromycin if amoxicillin was used as comedication.30-31 This observation may further justify
the addition of amoxicillin to a metronidazole and macrolide-containing triple
therapy even in the absence of antibiotic resistance. With mostly sensitive
strains to metronidazole and clarithromycin, eradication rates do not significantly
benefit from the addition of amoxicillin16, 24;
however, the opposite could be true for primarily resistant strains to 1 of
these 2 antibiotics. New methods of detecting clarithromycin resistance32-33 may allow more individualized therapy
in the near future. Until then, it is important to be aware of the antibiotic
resistance pattern in the general population.
The quadruple therapy used was safe and generally as well tolerated
as triple therapy. Although the rate of any event may appear as high, we noted
only 2 drug-related dropouts, and the incidence of adverse effects interfering
with daily activities appeared as low as in other studies.16, 24-27
These observations were confirmed by the results of our questionnaire, demonstrating
that, even immediately after the end of treatment, 90% of all patients would
participate again in such a treatment. Finally, it is noteworthy that our
patients were exposed to drugs and related adverse events for 2 to 4 days
less than with standard 1-week triple therapy.
In the past, several factors were thought responsible for influencing
clinical outcome.28, 34-37
This study may be one of the largest to systematically investigate this issue.
For interpretation of our results, it must be emphasized that the 3 study
groups were well-balanced for a variety of predictive factors.
Age, as suggested by previous studies,26, 37
again appeared to have a major impact on success of eradication. Although
in H pylori–positive patients several pathophysiologic
changes (eg, atrophy, acid secretion) are affected by age,26, 38
none of these assessed variables directly influenced eradication success.
Apart from this, age directly and indirectly influences drug disposition.26, 39 Smoking must be regarded as a confounding
factor for age. Surprisingly, the absence of peptic ulcer history, independent
of present ulcer status, was closely associated with eradication success,
perhaps because of an association with a low likelihood of previous antibacterial
treatments (and induced resistance) for H pylori.
This factor was independent of all others except cag-A. In accordance with
other studies,26, 35 cag-A status
influenced eradication outcome in this study, solely in patients with PUD.
Of all other specific strain markers, only the presence of oip-A was associated
with eradication failure, which, to our knowledge, is the first such report
in the literature. The characteristics of oip-A have been described recently,26, 40 but it was noted earlier to be a
good marker for peptic ulceration by inducing interleukin 8 secretion.41-42
In the past, research focused on the influence of acid suppression on
successful eradication.36-37,43-45
We, therefore, compared a PPI with an H2-receptor antagonist in
a higher acid-suppressing dose. Although clinical results for both acid-suppressive
drugs did not differ, higher steady-state trough levels of ranitidine significantly
correlated with eradication success. This trend was also seen with lansoprazole.
Thus, it can be concluded that a certain extent of acid suppression is necessary
even in a multidrug regimen. Derived from these results, the substitution
of ranitidine for a PPI in patients with NPUD could lead to further cost savings
while eradication results are comparable with those of triple regimens.46-48
Evaluation of symptoms was not a primary objective in the present study.
However, for important clinical features (abdominal pain, overall symptom
improvement, persistence of identical symptoms, and need for additional medical
treatment), we observed that patients with NPUD with eradication success felt
better on a long-term basis than those with treatment failures, underlined
by an objective response (weight gain).
In summary, this short-term quadruple therapy (regardless of the drug
used for acid suppression) represents an efficacious, safe, well-tolerated,
and cost-saving treatment for H pylori eradication.
Especially the 5-day regimens may be a first-line treatment option for older
patients without a history of peptic ulcer. This population is easily defined
and might profit from fewer adverse events compared with 1-week standard triple
therapy because of a decreased treatment duration. Based on our results, patients
with unfavorable clinical characteristics, a metronidazole-resistant strain,
and/or a strain that does not express cag-A but does express oip-A may otherwise
benefit from a prolonged treatment duration23, 49
with or without a higher metronidazole dose.9, 50
Future trials should prospectively investigate this hypothesis.
AUTHOR INFORMATION
Accepted for publication April 18, 2001.
This study was supported in full by the Robert Bosch Foundation, Stuttgart,
Germany, and in part by a grant from Takeda Pharma, Aachen, Germany.
We thank Frieder Kees, MD, Department of Pharmacology, University of
Regensburg, Regensburg, Germany, for his help in drug analysis and Marita
Schwabe, Biologische Analysen System Company, Lich, Germany, for her support
concerning immunoblot analysis. The technical assistance of Erika Schneider
and secretarial help of Heidi Köhler are highly appreciated.
Corresponding author and reprints: Gerhard Treiber, MD, Department
of Gastroenterology/Hepatology, University Hospital of Magdeburg, Leipziger
Str 44, D-39120 Magdeburg, Germany (e-mail: gerhard.treiber{at}medizin.uni-magdeburg.de).
From the Department of Gastroenterology, Robert Bosch Hospital, Stuttgart,
Germany (Dr Treiber); Department of Gastroenterology, Hospital of Bietigheim,
Bietigheim, Germany (Drs Wittig and Walker); Dr Margarete Fischer-Bosch Institute
of Clinical Pharmacology, Stuttgart (Drs Ammon and Klotz); and Delft Diagnostic
Centre R.deGraaf Group (SSDZ), Delft, the Netherlands (Dr van Doorn). Dr Treiber
is now with the Department of Gastroenterology/Hepatology, University Hospital
of Magdeburg, Magdeburg, Germany.
REFERENCES
| |
1. Treiber G, Lambert JR. The impact of Helicobacter pylori eradication
on peptic ulcer healing. Am J Gastroenterol. 1998;93:1080-1084.
FULL TEXT
|
ISI
| PUBMED
2. Penston G. Clinical aspects of Helicobacter pylori eradication
therapy in peptic ulcer disease. Aliment Pharmacol Ther. 1996;10:469-486.
FULL TEXT
|
ISI
| PUBMED
3. Talley NJ, Axon A, Bytzer P, Holtmann G, Lam SK, Van Zanten S. Management of uninvestigated and functional dyspepsia: a working party
report for the World Congresses of Gastroenterology 1998. Aliment Pharmacol Ther. 1999;13:1135-1148.
FULL TEXT
|
ISI
| PUBMED
4. Moayyedi P, Soo S, Deeks J, et al. Systematic review and economic evaluation of Helicobacter
pylori eradication treatment for non-ulcer dyspepsia. BMJ. 2000;321:659-664.
FREE FULL TEXT
5. Huang JQ, Sridhar S, Chen Y, Hunt RH. Meta-analysis of the relationship between Helicobacter
pylori seropositivity and gastric cancer. Gastroenterology. 1998;114:1169-1179.
FULL TEXT
|
ISI
| PUBMED
6. Watanabe T, Tada M, Nagai H, Sasaki S, Nakao M. Helicobacter pylori infection induces gastric
cancer in mongolian gerbils. Gastroenterology. 1998;115:642-648.
FULL TEXT
|
ISI
| PUBMED
7. Penston JG, McColl KEL. Eradication of Helicobacter pylori: an objective
assessment of current therapies. Br J Clin Pharmacol. 1997;43:223-243.
FULL TEXT
|
ISI
| PUBMED
8. Treiber G. The influence of drug dosage on Helicobacter pylori eradication: a cost-effectiveness analysis. Am J Gastroenterol. 1996;91:246-257.
ISI
| PUBMED
9. Huang J-Q, Hunt RH. The importance of clarithromycin dose in the management of Helicobacter pylori infection: a meta-analysis of triple therapies
with a proton pump inhibitor, clarithromycin and amoxicillin or metronidazole. Aliment Pharmacol Ther. 1999;13:719-729.
FULL TEXT
|
ISI
| PUBMED
10. Pipkin GA, Williamson R, Wood JR. One-week clarithromycin triple therapy regimens for eradication of Helicobacter pylori. Aliment Pharmacol Ther. 1998;12:823-837.
FULL TEXT
|
ISI
| PUBMED
11. Houben M, VanDeBeek D, Hensen E, Craen A, Rauws EA, Tytgat GN. A systematic review of Helicobacter pylori
eradication therapy: the impact of antimicrobial resistance on eradication
rates. Aliment Pharmacol Ther. 1999;13:1047-1055.
FULL TEXT
|
ISI
| PUBMED
12. Laheij R, VanRossum L, Jansen J, Straatman H, Verbeek AL. Evaluation of treatment regimens to cure Helicobacter
pylori infection: a meta-analysis. Aliment Pharmacol Ther. 1999;13:857-864.
FULL TEXT
|
ISI
| PUBMED
13. Malfertheiner P, Megraud F, O'Morain C, et al for the European Helicobacter Pylori Study
Group (EHPSG). Current European concepts in the management of Helicobacter
pylori infection: the Maastricht Consensus Report. Gut. 1997;41:8-13.
FREE FULL TEXT
14. National Institutes of Health. Consensus conference: Helicobacter pylori
in peptic ulcer disease. JAMA. 1994;272:65-69.
FULL TEXT
|
ISI
| PUBMED
15. Howden CW, Hunt RH. Guidelines for the management of Helicobacter pylori infection. Am J Gastroenterol. 1998;93:2330-2338.
ISI
| PUBMED
16. Treiber G, Ammon S, Schneider E, Klotz U. Amoxicillin/metronidazole/omeprazole/clarithromycin: a new, short quadruple
therapy for Helicobacter pylori eradication. Helicobacter. 1998;3:54-58.
FULL TEXT
|
ISI
| PUBMED
17. Oksanen A, Sipponen P, Karttunen R, et al. Atrophic gastritis and Helicobacter pylori
infection in outpatients referred for gastroscopy. Gut. 2000;46:460-463.
FREE FULL TEXT
18. van Doorn LJ, Figueiredo C, Sanna R, et al. Expanding allelic diversity of Helicobacter pylori vacA. J Clin Microbiol. 1998;36:2597-2603.
FREE FULL TEXT
|
