Download Combination Drug Therapy for Gastroesophageal

Drug Information Rounds
Combination Drug Therapy for Gastroesophageal
Reflux Disease
L Brian Cross and Lori N Justice
OBJECTIVE:
To evaluate the role of combination therapy with proton-pump inhibitors (PPIs) and histamine2 receptor antagonists in
gastroesophageal reflux disease (GERD).
DATA SOURCES: Clinical literature identified through MEDLINE (January 1966–August 2001). Key search terms included
gastroesophageal reflux, benzimidazoles; omeprazole; lansoprazole; pantoprazole; rabeprazole; receptor antagonists, histamine2;
therapy, combination drug; therapy, combined modality; and combinations, drug.
DATA SYNTHESIS: Approximately 80–90% of patients show healing of reflux esophagitis after 8 weeks of once-daily PPI therapy.
Patients taking PPI therapy twice daily still have nocturnal acid breakthrough (periods of gastric pH <4 lasting for ≥60 min during the
night) as much as 70% of the time. The clinical application of this finding has not been shown. One trial has shown that omeprazole
in the morning plus ranitidine at bedtime is not as effective as omeprazole twice daily given before the morning and evening meals
at controlling nocturnal acid breakthrough. Further, 1 small trial in healthy subjects without GERD showed that the addition of a 1time dose of ranitidine at bedtime to a twice-daily regimen of omeprazole may decrease the occurrence of nocturnal acid
breakthrough. However, the clinical significance of this finding is not clear.
CONCLUSIONS: No studies in patients with GERD demonstrate that the addition of histamine2 receptor antagonists to twice-daily PPI
therapy provides any further benefit above that derived from PPIs alone. The parameter used to measure the efficacy of
combination regimens for GERD thus far — nocturnal acid breakthrough — has not been proven to correlate with improvement of
GERD symptoms in any controlled or prospective clinical trials. Further investigation is needed to determine optimal therapy in
patients refractory to standard doses of PPIs.
KEY WORDS: combination therapy, gastroesophageal reflux disease, histamine2
receptor antagonists, proton-pump inhibitors.
Ann Pharmacother 2002;36:912-6.
REQUEST
What is the role of combination therapy with proton-pump inhibitors (PPIs) and histamine2 receptor antagonists (H2RAs)
in gastroesophageal reflux disease (GERD)?
RESPONSE
BACKGROUND
The use of pharmacologic agents to decrease the production of, or neutralize, gastric acid in the treatment of
GERD has continued to increase as more effective agents
are being made available. With the 1986 approval of cimetidine, the first available H2RA, clinicians had access to an
agent that was a significant improvement over previously
available therapies. The approval of omeprazole, the proto-
Author information provided at the end of the text.
912
■
The Annals of Pharmacotherapy
■
typical benzimidazole in 1989, brought further understanding of the function of the parietal cell and the final common pathway of gastric acid production through the H+/K+
adenosine triphosphatase (ATPase) pump. Many trials1-5
have studied the use of various combination therapies for
the treatment of GERD; however, none of these trials studied the use of combination therapy with PPIs and H2RAs.
This article reviews the available literature about this combination of PPIs and H2RAs in the treatment of GERD.
Understanding parietal cell physiology during the production of gastric acid and how the pharmacology of different agents affects that physiology helps to define the
role of combination therapy with PPIs and H2RAs. It is
known that the parietal cell membrane undergoes a significant morphologic change when stimulated to secrete acid.6
Three important changes occur in the activated cell: (1) intracellular tubovesicular membranes significantly decrease
in number, (2) apical canalicular membranes significantly
2002 May, Volume 36
Downloaded from aop.sagepub.com at PENNSYLVANIA STATE UNIV on May 10, 2016
www.theannals.com
increase in number, and (3) long apical microvilli become
apparent.7 Some evidence suggests that the H+/K+ ATPase
conductances are transported from the tubulovesicles to
the apical secretory canaliculus before acid secretion.8 Activation of H+/K+ ATPase is the final step in the secretion
of acid; blocking its action with a PPI should therefore inhibit acid secretion from all sources.
PPIs are weak base prodrugs that become concentrated
in the secretory canaliculi of the parietal cells, where they
are protonated to their active forms. This activated form
then binds the luminal α subunit of the H+/K+ ATPase by
irreversible covalent sulfhydryl bonds. PPIs can only effectively inhibit parietal cells in the stimulated state described
above. Therefore, the degree of acid secretion activation at
the time of PPI administration will dictate the effectiveness
of the medication.9 Increased effectivness has been reported when PPIs were given with a meal compared with a
fasting state.10 Decreased efficacy would be expected in
fasting patients because significant numbers of parietal
cells would be in the unstimulated phase and therefore unable to trap and activate the PPI.
H2RAs are reversible, competitive antagonists of the actions of histamine on H2 receptors, thereby decreasing the
production of acid from the parietal cell. It has been suggested7 that cimetidine, as well as the anticholinergic agent
atropine, blocks the transformational change of the parietal
cell mentioned above. Whether this is a class effect with all
H2RAs is not known. In addition, one report11 has shown a
significant decrease in the effect of omeprazole in dogs
when acid secretion was inhibited by H2RAs. This complex relationship between parietal cell physiology and the
pharmacology of these 2 drug classes is important to consider when reviewing the available literature on the use of
combination therapy with PPIs and H2RAs.
LITERATURE REVIEW
Two reviews12,13 address the treatment of GERD patients
who were refractory to normal doses of PPIs and who received combination therapy with PPIs and H2RAs. Hatlebakk et al.13 discuss many issues that should be considered
in a patient who seems to be refractory to PPI therapy.
Some of these include variability in bioavailability of the
PPI, inappropriate dosage timing (PPI therapy is significantly more effective when given prior to or with a meal
because more proton pumps will be in the active phase of
secreting acid and therefore able to be inhibited), reduced
efficacy of PPIs in Helicobacter pylori–negative patients
and in rapid metabolizers of omeprazole, decreased PPI effects in acid hypersecretors, and omeprazole resistance
(possible abnormality with the proton pump). Patients who
seem refractory to acid suppression therapy should also be
evaluated for such conditions as presence of peptic strictures, Barrett’s esophagus mistaken for unhealed esophagitis,
gastric stasis, lower esophageal sphincter dysfunction, ineffective esophageal peristalsis, and nonacid gastroesophageal
reflux. For the purposes of this article, nondrug issues are
not discussed.
www.theannals.com
Peghini et al.14 studied patients refractory to PPI therapy
and normal volunteers. They used intragastric pH monitoring during both upright and supine positions to assess pH
control of 3 different groups taking PPIs therapy twice daily before meals. The first group consisted of 17 patients
with persistent GERD symptoms who had been taking
twice-daily omeprazole for ≥1 month. The second group
included 16 healthy male volunteers given omeprazole twice
daily, with pH monitoring performed on day 7 of therapy.
Group 3 included 12 healthy male volunteers given lansoprazole twice daily, with pH monitoring performed on day
7 of therapy. The investigators showed that as high as 70%
of all subjects (GERD patients and volunteers) taking twicedaily PPI therapy had nocturnal acid breakthrough, defined
as pH <4 for >60 minutes during the overnight period.
Nocturnal acid breakthrough occurred with equal frequency in all 3 groups studied, therefore questioning the clinical
significance of this finding. Of further concern is that assessments were not made to determine the association of
nocturnal acid breakthrough with esophageal acid exposure; thus, no evidence is given as to the clinical relevance
of nocturnal acid breakthrough. It has been reported15 that
as many as 50% of patients with Barrett’s esophagus or
scleroderma with GERD do have increased overnight
esophageal acid exposure during nocturnal acid breakthrough and may therefore represent the subset of patients
who would possibly benefit from the improvement in nocturnal acid breakthrough.
The severity of mucosal injury in reflux esophagitis
highly correlates with the percentage of time within a 24hour period that either the esophagus is exposed to refluxate with a pH <4 or the intragastric contents are at a pH
<4.16,17 However, all experimental trials to date assessing
combined therapy with PPIs and H2RAs for the treatment
of GERD have measured nocturnal acid breakthrough, assuming that improvement in GERD symptom outcomes
would follow improvement in pH control.
In another trial, Peghini et al.18 compared 4 regimens after
7 days of therapy in 12 healthy, asymptomatic volunteers.
The regimens included omeprazole 20 mg twice daily before meals for 7 days, followed by the addition at bedtime
on day 8 of (1) placebo, (2) omeprazole 20 mg, (3) ranitidine 150 mg, or (4) ranitidine 300 mg. Each of these were
given in random sequence, with the exception that omeprazole was given as the last added bedtime therapy in all patients. All 4 regimens were completed over the following
4 –21 days (median 7). Overnight gastric pH monitoring
(from 1700 until 0630 the next morning) was performed in
the 12 subjects on day 8 of therapy with each of the various regimens. Median intragastric pH values were <4 for
all regimens included in the trial. However, when comparing percent of time at pH <4, differences were apparent.
Intragastric pH <4 occurred in 48% of the subjects receiving placebo at bedtime, 31% of the subjects receiving
omeprazole, 5% of the subjects receiving ranitidine 150
mg, and 6% of the subjects receiving ranitidine 300 mg.
Each ranitidine dose was reported to be statistically better
The Annals of Pharmacotherapy
Downloaded from aop.sagepub.com at PENNSYLVANIA STATE UNIV on May 10, 2016
■
2002 May, Volume 36
■
913
LB Cross and LN Justice
in pH control versus both the additional third dose of
omeprazole (p < 0.01) or placebo (p < 0.0001). The authors speculated that fasting breakthrough nocturnal acid
secretion in patients receiving omeprazole twice daily is
most likely due to histamine sources. One of the limitations
of this study was that it included only a small number of
healthy volunteers. As such, no clinical implications to patients with GERD can be drawn from the conclusions of its
data. Improvement in pH was compared after only onetime doses of the varied regimens studied, and therefore
the applications to clinical practice are unclear.
Robinson et al.19 compared 4 regimens in the treatment
of 16 heartburn patients in a randomized crossover trial. The
regimens included: (1) omeprazole 20 mg in the morning
and at bedtime, (2) omeprazole 20 mg in the morning and
ranitidine 75 mg at bedtime, (3) omeprazole 20 mg in the
morning and placebo at bedtime, and (4) placebo in the
morning and at bedtime. The 16 patients received each of
the above regimens for 6 days, with a 1-week washout period separating each regimen change. Twenty-four-hour
pH monitoring was performed on day 6 of each regimen.
No significant difference between the omeprazole twice-daily regimen and the omeprazole in the morning and ranitidine
at bedtime regimen was detected with respect to gastric pH
profiles for each hour of the day and night. Nocturnal acid
breakthrough occurred in 68.75% of patients taking the
morning omeprazole/bedtime ranitidine regimen, 87.5% of
patients taking both the omeprazole twice-daily regimen
and the morning omeprazole/bedtime placebo regimen,
and 100% of the patients on the placebo twice-daily regimen. There were no statistical differences found between
these regimens. This study has been criticized for administering the second dose of omeprazole at bedtime instead of
before the evening meal, since PPIs have been shown to be
more effective when given with or before meals. One
study20 has since been completed that contradicts the results reported in this trial.
A randomized, double-blind, crossover study20 of 20
healthy volunteers investigated omeprazole 20 mg twice
daily before meals plus placebo at bedtime compared with
omeprazole 20 mg in the morning, placebo before dinner,
and ranitidine 150 mg at bedtime. Each treatment arm was
completed in 7 days, with a 1-week washout period between study periods. On day 8, gastric pH was measured
for 24 hours, and the percentage of time pH was <4 for total, upright, and recumbent positions were compared between the 2 regimens. The median percentage of time that
pH was <4 was less with the omeprazole twice-daily regimen (18.9%) than with the morning omeprazole/bedtime
ranitidine regimen (29.7%; p = 0.003). Clinical differences
between these 2 regimens were not studied. As in other trials assessing the combination of PPI and H2RA therapy,
the assumption is that an improvement in nocturnal acid
breakthrough in healthy volunteers will correlate to improvement of GERD in patients with active disease. An
additional concern is that the duration of therapy in this
study and other previously mentioned trials of combination
regimens was only 1 week.
914
■
The Annals of Pharmacotherapy
■
It has been suggested21 that tolerance to H2RA therapy
develops over long-term use, a phenomenon that might not
be seen in these trials. This subject was addressed by a study
presented at the American College of Gastroenterology
meeting in October 2000. In this study, Fackler et al. assessed the effect on nocturnal acid breakthrough of the addition of a bedtime dose of ranitidine 300 mg to omeprazole
20 mg twice daily before meals in both healthy volunteers
and patients with GERD. Twenty subjects (11 healthy volunteers, 9 pts. with GERD) were given omeprazole 20 mg
twice daily for 2 weeks. Ranitidine 300 mg was then added
to the PPI regimen at bedtime and measures of nocturnal
acid breakthrough were performed at the end of 1 week of
the combination regimen. The combination of omeprazole
20 mg twice daily before meals and ranitidine 300 mg at
bedtime was continued, and measures of nocturnal acid
breakthrough were performed again after 3 more weeks of
therapy. Forty-five percent of subjects had suppressed nocturnal acid breakthrough after 1 week of combination therapy; however, this had decreased to 25% by the end of 4
weeks with combination therapy. The authors suggested
that bedtime ranitidine did not eliminate nocturnal acid
breakthrough, and the effect of ranitidine on nocturnal gastric acid reduction was minimal and lessened with prolonged therapy. As with other trials in this review, small
subject numbers limit the clinical application of the trial.
DISCUSSION
Since the advent of PPIs, the treatment and healing rates
of reflux disease have improved significantly compared
with those of former therapies.12 Healing rates for reflux
esophagitis using standard PPI doses (omeprazole 20 mg
once daily or lansoprazole 30 mg once daily) have been reported to be 80–90% after 8 weeks. A small portion of patients is refractory to standard once-daily PPI therapy; this
group may be at increased risk for more serious complications of reflux disease, such as Barrett’s esophagus. For this
reason, discovering why the patient is refractory to therapy
is paramount. According to the results by Khoury et al.20
adding an H2RA to once-daily PPI therapy would not be
appropriate. The overwhelming majority of patients should
respond to twice-daily PPI therapy given before the morning and evening meals. The clinician should first eliminate
patient-specific and medication-specific causes of treatment
failure. Current American College of Gastroenterology
practice guidelines22 for the diagnosis and treatment of
GERD recommend reconsidering the diagnosis, current
therapy, or both for patients who present with GERD refractory to twice-daily PPI therapy. In the small minority of
true treatment failures of twice-daily PPI therapy, the next
step in medical management is not completely clear.
One option would be to simply further increase the dose
of the PPI. In a limited number of patients, Leite et al.23
found that by increasing the dose of omeprazole to 80 mg/d,
improvement of omeprazole resistance was seen. This would
only be useful if pH monitoring indicates a continued low
pH despite standard doses of PPI therapy. Due to the sig-
2002 May, Volume 36
Downloaded from aop.sagepub.com at PENNSYLVANIA STATE UNIV on May 10, 2016
www.theannals.com
Drug Information Rounds
nificant interpatient variability in response to PPI therapy,
a second option would be to change to a different PPI.24
Many patients who seem refractory to twice-daily PPI
therapy might be considered for fundoplication. This approach is probably incorrect. The most appropriate surgery
candidate is the patient who is a complete responder to PPI
therapy but prefers surgery. Patients who are PPI resistant
as proven by pH monitoring and patients who are suggestive of nonacid reflux may also be appropriate surgery candidates.13 However, due to recent results of a long-term
outcome trial25 comparing medical management and surgery
for the treatment of GERD that showed an unexpected increase in mortality at 10-year follow-up in the surgically
managed patients, the appropriate time to refer patients for
surgical management of GERD is in question now more
than ever. Finally, a trial of twice-daily PPI with the addition of an H2RA could be considered. However, to date, no
trials have compared the efficacy of regimens beyond
twice-daily PPI therapy in GERD patients.
SUMMARY
No studies in patients with GERD demonstrate that the
addition of H2RAs to twice-daily PPI therapy provides any
further benefit above that derived from PPIs alone. The parameter used to measure the efficacy of combination regimens for GERD thus far — nocturnal acid breakthrough
— has also not been proven to correlate to improvement of
GERD symptoms in any controlled or prospective clinical
trials. Further investigation is needed to determine optimal
therapy in patients refractory to standard doses of PPIs.
L Brian Cross PharmD CDE, Assistant Professor, Department of
Pharmacy Practice & Pharmacoeconomics, College of Pharmacy,
University of Tennessee, Memphis, TN
Lori N Justice PharmD, Assistant Professor, Department of Pharmacy Practice & Pharmacoeconomics; Interim Director, Drug Information Center, College of Pharmacy, University of Tennessee
Reprints: L Brian Cross PharmD CDE, College of Pharmacy, University of Tennessee, 847 Monroe Ave., Ste. 205 C, Memphis, TN
38163-2109, FAX 901/448-1221, E-mail [email protected]
We thank the following colleagues for their review of this article: Patricia B Amadio
MD, J Richard Brown PharmD, Kenneth DeVault MD, and J Douglas Wurtzbacher
PharmD.
References
1. McKenna CJ, Mills JG, Goodwin C. Combination of ranitidine and cisapride in the treatment of reflux oesophagitis. Eur J Gastroenterol Hepatol 1995;7:817-22.
2. Vigneri S, Termini R, Leandro G. A comparison of five maintenance
therapies for reflux esophagitis. N Engl J Med 1995;333:1106-10.
3. Richter JE, Sabesin SM, Kogut DG. Omeprazole versus ranitidine or
ranitidine/metoclopramide in poorly responsive symptomatic gastroesophageal reflux disease. Am J Gastroenterol 1996;91:1766-72.
4. Lieberman DA. Medical therapy for chronic reflux esophagitis: long
term follow-up. Arch Intern Med 1987;147:717-20.
5. Galmiche JP, Fraitag B, Filoche B. Combined therapy with cisapride and
cimetidine in severe reflux oesophagitis: a double blind placebo-controlled trial. Gut 1988;29:675-81.
6. Helander HF. Parietal cell structure during inhibition of acid secretion.
Scand J Gastroenterol 1984;19(suppl 101):21-6.
7. Redel CA, Zwiener RJ. Anatomy and anomalies of the stomach and duodenum. In: Feldman M, ed. Sleisenger & Fordtran’s gastrointestinal and
liver disease. 6th ed. Orlando, FL: WB Saunders, 1998:587-99.
www.theannals.com
8. Hersey SJ, Sachs G. Gastric acid secretion. Physiol Rev 1995;75:155-9.
9. Soll AH. Peptic ulcer and its complications. In: Feldman M, ed. Sleisenger & Fordtran’s gastrointestinal and liver disease. 6th ed. Orlando, FL:
WB Saunders, 1998:621-63.
10. Hatlebakk JG, Katz PO, Castell DO. Proton pump inhibitors: better before breakfast than without breakfast (abstract). Am J Gastroenterol
1998;93:1636.
11. De Graef J, Woussen-Colle M. Influence of the stimulation state of the
parietal cells on the inhibitory effect of omeprazole on gastric acid secretion in dogs. Gastroenterology 1986;91:333-7.
12. DeVault KR. Overview of medical therapy for gastroesophageal reflux
disease. Gastroenterol Clin North Am 1999;28:831-46.
13. Hatlebakk JG, Katz PO, Castell DO. Medical therapy: management of
the refractory patient. Gastroenterol Clin North Am 1999;28:847-60.
14. Peghini PL, Katz PO, Bacy NA, Castell DO. Nocturnal recovery of gastric secretion on twice daily dosing of proton pump inhibitors. Am J Gastroenterol 1998;93:763-7.
15. Katz PO, Tutuian R. Histamine receptor antagonists, proton pump inhibitors and their combination in the treatment of gastro-oesophageal reflux disease. Best Pract Res Clin Gastroenterol 2001;15:371-84.
16. Dent J. Roles of gastric acid and pH in pathogenesis of gastro-oesophageal
reflux disease. Gastroenterol 1994;29(suppl 201):55-61.
17. Bell NJV, Burget D, Howden CW, Wilkinson J, Hunt RH. Appropriate
acid suppression for management of gastro-oesophageal reflux disease.
Digestion 1992;51(suppl 1):59-67.
18. Peghini PL, Katz PO, Castell DO. Ranitidine controls nocturnal gastric
acid breakthrough on omeprazole: a controlled study in normal subjects.
Gastroenterology 1998;115:1335-9.
19. Robinson M, Rodriguez-Stanley S, Miner PB. Zantac 75 = Prilosec 20
mg to block nighttime acid (abstract)! Am J Gastroenterol 1998;93:1623.
20. Khoury RM, Katz PO, Hammond R, Castell DO. Bedtime ranitidine
does not eliminate the need for a second daily dose of omeprazole to
suppress nocturnal gastric pH. Aliment Pharmacol Ther 1999;13:675-8.
21. Fackler WK, Vaezi MF, Ours TM, Richter JE. Nocturnal acid breakthrough and H2RAs — another viewpoint (abstract). Am J Gastroenterol
2000;95:2419.
22. DeVault K, Castell DO. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol 1999;94:
1434-42.
23. Leite LP, Johnston BT, Just RJ. Persistent acid secretion during omeprazole therapy: a study of gastric acid profiles in patients demonstrating
failure of omeprazole therapy. Am J Gastroenterol 1996;91:1527-31.
24. Hatlebakk JG, Camacho-Lobato L, Katz PO. Omeprazole 20 mg b.i.d.
vs. lansprazole 30 mg b.i.d. in control of intragastric acidity (abstract).
Am J Gastroenterol 1998;93:1636.
25. Spechler SJ. Long-term outcome of medical and surgical therapies for
gastroesophageal reflux disease: follow-up of a randomized controlled
trial. JAMA 2001;285:2331-8.
EXTRACTO
OBJETIVO: Evaluar el rol de la terapia combinada de los inhibidores de la
bomba de protones con los antagonistas de los receptores de histamina 2
en el tratamiento de reflujo gastroesofágico.
FUENTES DE INFORMACIÓN: Se identificó la literatura clínica utilizando
MEDLINE (enero 1966–agosto 2001). Los términos utilizados en la
búsqueda incluyeron reflujo gastroesofágico, benzimidazoles; terapia,
combinación de drogas; terapia, modalidad combinada; y
combinaciones de drogas.
SÍNTESIS: Aproximadamente el 80–90% de los pacientes se curan de la
esofagitis por reflujo después de 8 semanas de tratamiento con
inhibidores de la bomba de protones administrados 1 vez al día. Los
pacientes que toman los inhibidores de la bomba de protones 2 veces al
día pueden sentir episodios de acidez nocturna (períodos de pH gástrico
<4 que dura ≥60 min durante la noche) hasta en un 70% de las veces.
No se ha demostrado la aplicación clínica de este hallazgo. Un estudio
demostró que el omeprazol en las mañanas más ranitidina al acostarse
no es tan eficaz para controlar la acidez nocturna como el omeprazol 2
veces al día administrado antes del desayuno y de la cena. Más aún, un
estudio menor con personas saludables sin reflujo gastroesofágico
demostró que añadir la ranitidina 1 vez al día a la hora de acostarse al
The Annals of Pharmacotherapy
Downloaded from aop.sagepub.com at PENNSYLVANIA STATE UNIV on May 10, 2016
■
2002 May, Volume 36
■
915
LB Cross and LN Justice
régimen de omeprazol 2 veces al día puede disminuir la ocurrencia de la
acidez nocturna. Sin embargo, la significancia clínica de este hallazgo
no se ha esclarecido.
CONCLUSIONES: Ningún estudio en pacientes con reflujo gastroesofágico
ha demostrado que la adición de un antagonista de los receptores de la
histamina 2 a la terapia de un inhibidor de la bomba de protones 2 veces
al día provee mayor beneficio que el uso de los inhibidores de la bomba
de protones por si solos. El parámetro utilizado hasta el momento, la
acidez nocturna, para medir la eficacia de los regímenes para el reflujo
gastroesofágico (GERD, por sus siglas en inglés) no ha podido
establecer una correlación con la mejoría de los síntomas de esta
condición en ningún estudio controlado ni prospectivo.
Rafaela Mena
RÉSUMÉ
Evaluer le rôle d’une association d’inhibiteurs de la pompe à
protons (IPP) et d’inhibiteurs des récepteurs H2 de l’histamine (anti-H2)
dans le reflux gastro-œsophagien.
REVUE DE LITTÉRATURE: Littérature clinique repérée par une recherche
sur MEDLINE (janvier 1966–août 2001). Les mots-clefs employés
comportaient reflux gastro-œsophagien, benzimidazoles, oméprazole,
OBJECTIF:
lansoprazole, pantoprazole, rabéprazole, anti-H2, et association.
RÉSUMÉ: Environ 80 à 90% des patients présentent une guérison de
l’œsophagite par reflux après 8 semaines de traitement par IPP une fois
par jour. Le faible nombre de patients réfractaires à ce schéma devrait
répondre à un traitement par IPP donné avant les repas du matin et du
soir. Cependant, ces sujets présentent encore des périodes d’acidité
nocturne (pH <4 pendant au moins 60 min) dans 70% des cas: les
conséquences cliniques de cette constatation n’ont pas été démontrées.
Un essai de faible taille chez des sujets sains a montré que l’association
oméprazole le matin plus ranitidine au coucher n’est pas aussi efficace
que l’oméprazole donné avant les repas du matin et du soir pour
diminuer les périodes d’acidité nocturne. Un essai de faible taille chez
des sujets sains a montré que l’addition d’une dose de ranitidine au
coucher à un schéma comportant de l’oméprazole 2 fois par jour est
susceptible de diminuer l’occurrence des périodes d’acidité nocturne.
Néanmoins, la signification clinique de ces constatations n’est pas claire.
CONCLUSIONS: Aucune étude chez des patients atteints de reflux gastroœsophagien n’a montré que l’addition d’anti-H2 à un schéma
comportant des IPP 2 fois par jour procure un bénéfice par rapport aux
IPP seuls.
Bruno Edouard
Full text access to the Annals of Pharmacotherapy is available to subscribers only.
Personal, Student, and Resident Subscriptions
To access full text articles through The Annals Web site (www.theannals.com), simply enter your
subscriber number which appears on the mailing label, in both the user name and password boxes.
The subscriber number appears in the top row of the label. It starts with the letters TP and includes the
first group of numbers. For example, the highlighted portion of this label is the subscriber number.
TP
TP 34712
34712 0111 1108
John Q Clinician, PharmD.
123 Main St.
Cincinnati, OH 45678
You would enter TP34712 (without a space between the letters and numbers) as the user name
and password.
Institutional Subscriptions
Subscriptions have automatic full text access based on the subscriber’s IP address. If you have not
submitted your IP address, please contact customer service at [email protected] and provide your IP address and subscriber number.
916
■
The Annals of Pharmacotherapy
■
2002 May, Volume 36
Downloaded from aop.sagepub.com at PENNSYLVANIA STATE UNIV on May 10, 2016
www.theannals.com