SEARCH

SEARCH BY CITATION

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Background  Studies to date have not directly compared the pharmacodynamic efficacies of different proton pump inhibitors in controlling intragastric acidity in patients treated with non-steroidal anti-inflammatory drugs.

Aim  To compare acid suppression with once-daily esomeprazole 40 mg, lansoprazole 30 mg and pantoprazole 40 mg in patients receiving non-selective or cyclo-oxygenase-2–selective non-steroidal anti-inflammatory drug therapy.

Methods  In this multicentre, open-label, comparative, three-way crossover study, adult patients (n = 90) receiving non-steroidal anti-inflammatory drugs were randomized to one of six treatment sequences. At the study site, patients were administered esomeprazole 40 mg, lansoprazole 30 mg and pantoprazole 40 mg for 5 days each, with a washout period of ≥10 days between each treatment. Twenty-four–hour pH testing was performed on day 5 of each dosing period.

Results  The mean percentage of time during the 24-h pH monitoring period that gastric pH was >4.0 was significantly greater with esomeprazole (74.2%) compared with lansoprazole (66.5%; P < 0.001) and pantoprazole (60.8%; P < 0.001), and significantly greater with esomeprazole (P < 0.05) than with the comparators regardless of whether using non-selective vs. cyclo-oxygenase-2–selective non-steroidal anti-inflammatory drugs.

Conclusions  At the doses studied, esomeprazole treatment provides significantly greater gastric acid suppression than lansoprazole or pantoprazole in patients receiving non-selective or cyclo-oxygenase-2–selective non-steroidal anti-inflammatory drugs.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Through the inhibition of gastric mucosal cyclo-oxygenase-1 (COX-1) and reduced synthesis of protective prostaglandins, non-selective non-steroidal anti-inflammatory drug (NSAID) use increases the risk of developing gastroduodenal ulcer complications two- to fivefold.1, 2 Importantly, gastric acid also appears to play a central role in the development of NSAID-associated gastroduodenal ulcers and ulcer complications. Results of previous studies suggest that NSAIDs increase gastric acid secretion compared with placebo,3 and this effect may be related to the fact that prostaglandins exert an inhibitory effect on gastric acid-producing parietal cells.4 Also, it appears that NSAID-induced gastric mucosal damage may be greater when pH is <4.0.5 The clinical correlate of the pivotal role of gastric acid in the development of gastroduodenal mucosal injury is that proton pump inhibitor (PPI) co-therapy has been shown to heal, maintain healing and reduce the risk of developing NSAID-related ulcers6–11 and to decrease NSAID-related upper gastrointestinal (GI) symptoms.8, 9, 12, 13 Practice guidelines often recommend co-prescribing an acid inhibitor, such as a PPI, with NSAIDs in patients at risk of developing GI complications.14–16 However, no studies have compared the pharmacodynamic actions of different PPIs in controlling intragastric acidity in patients using NSAIDs.

The primary objective of this study was to compare the efficacy of oral once-daily esomeprazole 40 mg, lansoprazole 30 mg, and pantoprazole 40 mg for controlling intragastric acidity (per cent time with pH > 4.0) in patients taking non-selective or COX-2–selective NSAIDs. Secondary objectives included assessments of nocturnal intragastric acid control, intragastric acid control using thresholds other than pH 4.0, and mean hourly integrated gastric acidity (IGA) over 24 h.

Materials and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Study design

Institutional Review Boards approved the protocol for this multicentre, randomized, open-label, comparative three-way crossover study (D9612L00063), and the study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. All patients provided written informed consent before initiation of any study procedure.

Patients were randomly assigned to one of six possible treatment sequences. Each patient received esomeprazole 40 mg, lansoprazole 30 mg and pantoprazole 40 mg for 5 days each, with a washout period of ≥10 days between each treatment. All previous PPI and H2RA use was discontinued at least 10 and 7 days, respectively, before the first dose of study medication. Study personnel administered all five doses of each treatment daily, 30 min before breakfast, while the patient was under observation as an out-patient at the study site. At each daily visit, patients were asked about their NSAID usage to make sure that they were taking the minimum required. On day 5 of each 5-day dosing period (i.e. steady state), a 24-h pH study was performed at the investigation site. Patients were provided with antacid medication (Gelusil; Parke-Davis, Morris Plains, NJ, USA) for relief of acute symptoms and were instructed to take no more than six tablets per day or 30 tablets over any 10-day period and not to take this antacid after midnight before or during the 24-h pH study on day 5.

Patients

Adults aged 18–70 years with a medical diagnosis of a condition that required daily prescription-strength non-selective or COX-2–selective NSAID treatment for ≥5 days per week for ≥1 month before enrollment were eligible for this study. NSAID treatment was to remain at a minimum predefined required daily dose for the duration of the study (including during the PPI and H2RA washout periods). The patients must have had a body weight within 40% of ideal, as assessed by the investigator using insurance charts provided to them. Women of child-bearing potential were required to be non-pregnant and non-lactating and to use an acceptable form of contraception throughout the study. Data on past PPI and nicotine use were not collected; however, patients were told to maintain a consistent level of nicotine, alcohol and caffeine use throughout the study. Patients were required to be Helicobacter pylori-negative by serology or, if seropositive, negative by urea breath test, and to have no clinically significant GI pathology (e.g. erosive oesophagitis, gastric or duodenal ulcers, neoplasm, Zollinger–Ellison syndrome, Barrett's oesophagus or dysplasia, oesophageal motility disorder, inflammatory bowel disease, pancreatitis or malabsorption).

Patients were also excluded for any of the following: clinically significant GI bleeding within 3 days of randomization or on endoscopy conducted at baseline; previous gastric or oesophageal surgery; severe cardiovascular, pulmonary, liver, or renal disease; active malignant disease (except minor superficial skin disease); unstable diabetes mellitus; unstable seizure disorder; cerebral vascular disease; or any condition that may require surgery during the study; use of anticoagulants, aspirin at doses >165 mg daily, prostaglandin analogues, antineoplastic agents, corticosteroids, promotility drugs, anticholinergic medications, sucralfate, phenytoin, or medication dependent on the presence of gastric acid for optimal absorption (i.e. ketoconazole, iron salts, digoxin and ampicillin); routine laboratory values outside of normal ranges; a history of drug or alcohol dependence within the previous 12 months; or known intolerance to or lack of response to PPIs or sensitivity to PPI ingredients or Gelusil.

pH measurements

On day 5 of each treatment period, patients underwent a catheter-based 24-h intragastric pH study. All sites used dual-probe microelectrodes attached to GERDcheck data loggers (Sandhill Scientific, Highlands Ranch, CO, USA). The distal electrode was placed 10 cm below the lower oesophageal sphincter (LES), using the LES locator and/or by formal oesophageal manometry. The distance of the electrode from the nostrils was noted during the first pH recording test and used thereafter for accurate electrode placement during subsequent monitoring sessions. The electrode was calibrated before and after each 24-h recording, using standard buffers of pH 7.0 and 4.0. Site staff administered study medication after placement of the pH probe, and patients were instructed to take their usual NSAID dose with breakfast. Patients received low-fat, low-calorie meals during the pH monitoring period to minimize the dietary effects on the pH monitoring results. Guidelines and menus were provided to the study sites for these meals. Mealtimes and the time patients went to lie down at night and get up in the morning (nocturnal period) were recorded. Study electrodes were removed on the morning of day 6. A central reader (P.K.S.) determined the validity of pH recordings, based on ≥20 h of valid pH data within the reference range of 0–9, no technical failures of the pH recording and <1 continuous hour with pH data outside the reference range. Although this was an open-label study, both the site personnel performing the pH study and the central pH reader were blinded to each patient's study treatment.

During the 24-h monitoring period, intragastric pH values were recorded every 5 s. For a given patient during a single monitoring session, the per cent time with pH greater than predetermined pH thresholds (i.e. 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5 or 6.0) was calculated as the per cent of the total data points for which the pH was greater than that pH threshold. The number of hours at or above pH thresholds was calculated by multiplying the per cent time at or above that threshold by 24 h.

Analyses

The primary efficacy variable was per cent time with pH > 4.0 during the 24-h monitoring period. Secondary efficacy variables were per cent time with pH ≥2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5 and 6.0 during the nocturnal period, per cent time pH was ≥2.5, 3.0, 3.5, 4.5, 5.0, 5.5 and 6.0 during the 24-h monitoring period and the mean hourly IGA during the 24-h monitoring period.

Primary and secondary efficacy analyses used data from all patients who received all PPI doses in each of the three treatment periods, had valid pH data and had no major protocol violations or deviations (per-protocol population). Patients who used a COX-2–selective NSAID plus aspirin (≤165 mg/d) were classified as non-selective NSAID users for all analyses.

The mean hourly IGA was calculated using a linear trapezoidal method.17 pH values < 0.8 were deemed non-physiological and were set to 0.8 in the analysis.18 IGA was summarized and analysed in the same manner as the primary efficacy variable for each hour during the 24-h monitoring period on day 5 beginning at the time of probe insertion.

The safety analyses included all patients who took at least one dose of study medication. Safety and tolerability data were summarized descriptively.

Primary and secondary efficacy variables were analysed using a mixed model with fixed effects for treatment sequence, treatment period and treatment. Differences between treatments were tested using a significance level of 0.05.

Sample-size calculations assumed that the within-patient s.d. of the per cent time with pH > 4.0 was 10%, based on a previous study.19 It was estimated that a total of 66 completed patients would be needed to provide 95% overall power to detect a difference of 7% over 24 h between the treatment groups in the number of hours per 24 h that pH was >4.0 with a significance level of 0.05.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

This study was conducted at seven USA sites between June and November 2004. Of the 90 patients randomized, 77 (86%) completed the protocol and were included in the analyses. Reasons for withdrawal were unwillingness to continue in the study (n = 6), development of study-specific discontinuation criteria (i.e. equipment failure, final pH test ineligible, pH probe failure, and not enough data from pH insertion testing) (n = 4), lost to follow-up (n = 2) and a missed visit because of weather (n = 1).

Demographic and baseline characteristics are presented in Table 1. Approximately half of the patients in this study were taking non-selective NSAIDs. There were no notable demographic differences between patients in the non-selective and COX-2–selective NSAID groups, except that the mean age of patients who were taking COX-2–selective NSAIDs tended to be higher than that of patients who were taking non-selective NSAIDs (47 vs. 43 years). Among patients ≥50 years old, the primary reason for NSAID use was arthritis (osteoarthritis, rheumatoid arthritis or undefined arthritis). Among patients aged <50 years, reasons for NSAID use were more varied (nearly 50% for arthritis and 50% for various types of pain/injury). NSAID use is shown in Table 2.

Table 1.  Demographic and baseline characteristics of patients included in per-protocol analyses (n = 77)
  1. BMI, body mass index; COX, cyclo-oxygenase; NSAID, non-steroidal anti-inflammatory drug; s.d., standard deviation.

  2. * Included six patients taking COX-2–selective NSAIDs plus aspirin.

Women, n (%)52 (68)
Mean age, years (range)44.8 (18–70)
White/black/other, n (%)62/13/2 (81/17/3)
Mean (s.d.) BMI, kg/m228.8 (4.9)
Type of NSAID use, n (%) 
 Non-selective*39 (51)
 COX-2–selective only38 (49)
History of acid reflux, n (%)43 (56)
Table 2.  NSAID use by patients included in analyses (n = 77)
NSAIDNo. of patientsTotal daily dose range (mg)
  1. COX, cyclo-oxygenase; NSAID, non-steroidal anti-inflammatory drug.

  2. * One patient also used etodolac, and one patient also used 81 mg aspirin.

  3. † The total daily dose of aspirin was 81 mg.

  4. ‡ Sites were informed of the withdrawal of rofecoxib during the study. Switching patients from rofecoxib to another NSAID was at the discretion of the investigator. At the time the withdrawal was announced, seven patients (six who took rofecoxib and one who took rofecoxib + aspirin) had already completed the study; two continued on rofecoxib for 13 and 21 days, respectively; one patient remained on rofecoxib + aspirin for 10 days; and four patients were switched to other NSAIDs (two to valdecoxib, two to celecoxib).

Non-selective
 Ibuprofen*201800–3200
 Naproxen10750–1200
 Etodolac + aspirin†2800
 Meloxicam17.5
 Valdecoxib + aspirin†110
 Celecoxib + aspirin†3200–400
 Rofecoxib‡ + aspirin†212.5–25
COX-2–selective
 Valdecoxib1010–40
 Celecoxib16200–400
 Rofecoxib‡1212.5–50

pH analyses

As shown in Figure 1, suppression of gastric acid was significantly greater with esomeprazole than with lansoprazole and pantoprazole as determined by the per cent time with intragastric pH > 4.0 on day 5 of treatment. The least-squares (LS) mean (S.E.M.) per cent time with pH > 4.0 for esomeprazole was 74.2% (2.4%) compared with 66.5% (2.4%) for lansoprazole (P = 0.0003), and 60.8% (2.4%) for pantoprazole (P < 0.0001). Gastric pH was >4.0 for 17.8 h with esomeprazole, 15.9 h with lansoprazole and 14.6 h with pantoprazole (Figure 2). Suppression of gastric acid with esomeprazole vs. lansoprazole and pantoprazole was also significantly greater at the other pH thresholds (2.5–6.0) measured, as assessed by the mean hours with pH above the threshold (Figure 2). The highest acid suppression was achieved with esomeprazole in 51 (66%) patients, with lansoprazole in 19 (25%) patients and with pantoprazole in seven (9%) patients.

image

Figure 1. Least-squares (LS) mean (S.E.M.) percentage of 24-h monitoring period intragastric pH was >4.0 after administration of esomeprazole, lansoprazole and pantoprazole (n = 77).

Download figure to PowerPoint

image

Figure 2. Calculated mean number of hours per 24 h on day 5 that intragastric pH was >2.5–6.0 in 0.5 increments by treatment group. * P < 0.01 vs. lansoprazole; † P < 0.0001 vs. pantoprazole; ‡ P < 0.001 vs. lansoprazole;  § P ≤ 0.0001 vs. lansoprazole (n = 77).

Download figure to PowerPoint

As a secondary endpoint, LS mean per cent nocturnal time with pH > 4.0 was 56%, 53% and 52% for esomeprazole, lansoprazole and pantoprazole, respectively, with no significant differences between treatments. LS mean per cent nocturnal time with pH above other thresholds (2.5–6.0) was also not significantly different between treatments.

There were no apparent differences between results with non-selective NSAIDs or COX-2–selective inhibitors. Regardless of the type of NSAID (non-selective or COX-2–selective) patients were taking, treatment with esomeprazole provided significantly greater control of intragastric acid than lansoprazole or pantoprazole treatment. In the non-selective NSAID group (n = 39), the LS mean per cent time with intragastric pH > 4.0 was 75.4% for esomeprazole compared with 66.0% for lansoprazole (P = 0.0017) and 60.8% for pantoprazole (P < 0.0001). In the COX-2–selective NSAID group (n = 38), the LS mean per cent time with intragastric pH > 4.0 was 72.9% for esomeprazole compared with 66.7% (P = 0.0364) for lansoprazole and 61.1% for pantoprazole (P < 0.0002).

Integrated gastric acidity measures the cumulative gastric acidity hourly from the time of probe insertion; therefore, lower values represent less acidity, or more effective cumulative acid suppression, for each hour. The mean cumulative IGA was significantly lower with esomeprazole than with pantoprazole for 18 of 24 h (between hours 4 and 21 after probe insertion) or lansoprazole for 4 of 24 h (between hours 14 and 17 after probe insertion) (Figure 3). Although no other significant differences were observed, IGA was numerically and consistently lower with esomeprazole than with both comparators from hour 5 on day 5 through the end of the pH study on day 6.

image

Figure 3. Mean cumulative integrated gastric acidity on day 5 by hour after probe insertion (n = 77).

Download figure to PowerPoint

All PPI treatments were well tolerated. The most common adverse events were nausea (n = 4), abdominal pain (n = 3) and dyspepsia (n = 3). Three patients had adverse events considered by the investigator to be related to treatment: one patient had abdominal distension while receiving esomeprazole; one patient each had headache and abdominal pain while receiving lansoprazole; and one patient had diarrhoea and nausea while receiving pantoprazole. There were no serious adverse events or discontinuations because of adverse events.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Gastric acidity plays an important role in the development of NSAID-related gastroduodenal ulcers and ulcer complications. As previously noted, intragastric acidity may increase in patients who take non-selective NSAIDs compared with control subjects.3 Control of gastric acidity using acid-suppressive therapy has been proposed as an effective means of healing ulcers6–11 and controlling and preventing NSAID-associated upper GI injury and ulcer complications.8, 9, 12–16 Although both H2RAs and PPIs can be used as acid-suppressive agents in the treatment of other disease states, PPIs are preferable to standard doses of H2RAs for preventing NSAID-associated endoscopic injury.9, 20 Results of recent studies have shown that esomeprazole treatment significantly decreased the development of ulcers associated with the use of COX-2–selective and non-selective NSAIDs.21 Moreover, maintenance co-therapy with lansoprazole has been effective in the prevention of recurrent upper GI complications in aspirin users.22

To date, there have been no direct comparisons of currently available PPIs to determine which PPI is most effective in counteracting and preventing NSAID-related GI complications. As a first step to address this issue, we designed the current study to assess the potential differences between the once-daily PPI treatments of esomeprazole 40 mg, lansoprazole 30 mg and pantoprazole 40 mg for controlling intragastric pH in adults receiving non-selective or COX-2–selective NSAID therapy.

The results of our study show that esomeprazole 40 mg provided significantly greater control of intragastric acid at steady state (day 5) than oral doses of lansoprazole or pantoprazole, based on the percentage of the 24-h period with intragastric pH > 4.0. Furthermore, significantly greater gastric acid suppression occurred during treatment with esomeprazole vs. lansoprazole or pantoprazole in the subgroups of patients taking non-selective or COX-2–selective NSAIDs. The results for other pH thresholds (2.5–6.0) were consistent with those for pH > 4.0 for the entire 24-h monitoring period.

The significantly lower IGA observed for esomeprazole vs. pantoprazole between hours 4 and 21 and lansoprazole between hours 14 and 17 after probe insertion and the disparity between that and the evaluation of time above various pH thresholds may be explained by considering that low pH values influence the IGA more than pH values close to 4.0.17

Overall, the results of this study are consistent with previous comparative pH studies that have shown a relatively greater control of intragastric pH with esomeprazole than with lansoprazole or pantoprazole at standard doses.19, 23 Although we have shown a difference in pH control with esomeprazole, the limitation is that a clinical correlation has not been established. Specifically, it is unknown whether this relatively greater acid control translates into clinical benefit. To address this question, additional studies that include endoscopic and clinical endpoints need to be conducted.

A strength of our study was the inclusion of patients with a broad age range, but generalization to the older population, who are at the greatest risk for NSAID-associated GI complications,24, 25 may be limited by the lack of focus of this study on this population. As noted in Table 1, the mean age of patients was relatively young (mean, 44.8 years). Patients older than 70 years were not included in this study because of upper GI safety concerns regarding the withholding of acid suppressive agents during the washout periods.

In conclusion, once-daily use of oral esomeprazole 40 mg provided significantly greater control of intragastric acidity at steady state than once-daily oral doses of lansoprazole 30 mg or pantoprazole 40 mg in patients taking daily non-selective or COX-2–selective NSAIDs.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Dr Jay Goldstein discloses that he has served as a consultant to and has received honoraria, travel expenses, educational grants, and/or research grants from AstraZeneca, Pfizer, TAP Pharmaceutical Products Inc, and Novartis. This study was supported by AstraZeneca LP (Wilmington, DE, USA). J.G. and P.K.S. were also supported in part by the Federal Clinical Research Center at the University of Illinois at Chicago, which is funded by NIH Grant No. Mo1-RR-13987. Lisa Klumpp, Tracy Wetter and Judy Fallon of Thomson Scientific Connexions (Newtown, PA, USA) provided medical writing services on behalf of AstraZeneca LP. The authors thank Shawn Jones (AstraZeneca, LP) for study management; Donna Curtis (AstraZeneca, LP) for editorial assistance; and the study participants, study-site staff and the following investigators: Vijayalakshmi S. Pratha, MD (San Diego, CA, USA); Vikram S. Jayanty, MD (Houston, TX, USA); Steven L. Dukor, MD, FACG (Orange, CA, USA); Dennis S. Riff, MD, FACG (Anaheim, CA, USA); and Mark S. Eisner, MD (Zephyrhills, FL, USA).

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  • 1
    Laine L. The role of proton pump inhibitors in NSAID-associated gastropathy and upper gastrointestinal symptoms. Rev Gastroenterol Disord 2003; 3 (Suppl. 4): S309.
  • 2
    Hernandez-Diaz S, Rodriguez LAG. Association between nonsteroidal anti-inflammatory drugs and upper gastrointestinal tract bleeding/perforation: an overview of epidemiologic studies published in the 1990s. Arch Intern Med 2000; 160: 20939.
  • 3
    Savarino V, Mela GS, Zentilin P, et al. Effect of one-month treatment with nonsteroidal antiinflammatory drugs (NSAIDs) on gastric pH of rheumatoid arthritis patients. Dig Dis Sci 1998; 43: 45963.
  • 4
    Ligumsky M, Goto Y, Yamada T. Prostaglandins mediate inhibition of gastric acid secretion by somatostatin in the rat. Science 1983; 219: 3013.
  • 5
    Elliott SL, Ferris RJ, Giraud AS, et al. Indomethacin damage to rat gastric mucosa is markedly dependent on luminal pH. Clin Exp Pharmacol Physiol 1996; 23: 4324.
  • 6
    Agrawal NM, Campbell DR, Safdi MA, Lukasik NL, Huang B, Haber MM. Superiority of lansoprazole vs. ranitidine in healing nonsteroidal anti-inflammatory drug-associated gastric ulcers: results of a double-blind, randomized, multicenter study. NSAID-Associated Gastric Ulcer Study Group. Arch Intern Med 2000; 160: 145561.
  • 7
    Ekstrom P, Carling L, Wetterhus S, et al. Prevention of peptic and dyspeptic ulcer symptoms with omeprazole in patients receiving continuous non-steroidal anti-inflammatory drug therapy. A Nordic multicentre study. Scand J Gastroenterol 1996; 31: 7538.
  • 8
    Yeomans ND, Tulassay Z, Juhasz L, et al. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal anti-inflammatory drugs. Acid-Suppression Trial: Ranitidine versus Omeprazole for NSAID-Associated Ulcer Treatment (ASTRONAUT) Study Group. N Engl J Med 1998; 338: 71926.
  • 9
    Hawkey CJ, Karrasch JA, Szczepañski L, et al. Omeprazole compared with misoprostol for ulcers associated with nonsteroidal anti-inflammatory drugs. Omeprazole versus Misoprostol for NSAID-Induced Ulcer Management (OMNIUM) Study Group. N Engl J Med 1998; 338: 72734.
  • 10
    Lai KC, Lam SK, Chu KM, et al. Lansoprazole reduces ulcer relapse after eradication of Helicobacter pylori in non-steroidal anti-inflammatory drug users – a randomised trial. Aliment Pharmacol Ther 2003; 18: 82936.
  • 11
    Goldstein JL, Johanson J, Suchower L, Brown K. Esomeprazole vs ranitidine for the healing of NSAID-induced ulcers. Am J Gastroenterol 2005; 100: 26507.
    Direct Link:
  • 12
    Stupnicki T, Dietrich K, Gonzalez-Carro P, et al. Efficacy and tolerability of pantoprazole compared with misoprostol for the prevention of NSAID-related gastrointestinal lesions and symptoms in rheumatic patients. Digestion 2003; 68: 198208.
  • 13
    Hawkey C, Talley NJ, Yeomans ND, et al. Improvements with esomeprazole in patients with upper gastrointestinal symptoms taking non-steroidal anti-inflammatory drugs, including selective COX-2 inhibitors. Am J Gastroenterol 2005; 100: 102836.
    Direct Link:
  • 14
    American College of Rheumatology Subcommittee on Osteoarthritis Guidelines. Recommendations for the medical management of osteoarthritis of the hip and knee. Arthritis Rheum 2000; 43: 190515.
  • 15
    American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis. Arthritis Rheum 2002; 46: 32846.
  • 16
    Kimmey MB, Lanas A. Review article: appropriate use of proton pump inhibitors with traditional nonsteroidal anti-inflammatory drugs and COX-2 selective inhibitors. Aliment Pharmacol Ther 2004; 19(Suppl. 1) 605.
  • 17
    Gardner JD, Rodriguez-Stanley S, Robinson M. Integrated acidity and the pathophysiology of gastroesophageal reflux disease. Am J Gastroenterol 2001; 96: 136370.
    Direct Link:
  • 18
    Hoogerwerf WA, Pasricha PJ. Agents used for control of gastric acidity and treatment of peptic ulcers and gastroesophageal reflux disease. In: Hardman, JG, Limbird, LE, Gilman, AG, eds. Goodman & Gilman's the Pharmacological Basis of Therapeutics, 10th edn. New York: McGraw-Hill, 2001: 100520.
  • 19
    Miner P, Katz PO, Chen Y, Sostek M. Gastric acid control with esomeprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole: a five-way crossover study. Am J Gastroenterology 2003; 98: 261620.
    Direct Link:
  • 20
    Taha AS, Hudson N, Hawkey CJ, et al. Famotidine for the prevention of gastric and duodenal ulcers caused by nonsteroidal antiinflammatory drugs. N Engl J Med 1996; 334: 14359.
  • 21
    Scheiman JM, Yeomans N, Talley N, et al. Prevention of ulcers by esomeprazole in at-risk patients using non-selective NSAIDs and COX-2 inhibitors. Am J Gastroenterol 2006. Available online at http://www.blackwell-synergy.com/loi/ajg; publication date 22 February 2006; doi: 10.1111/j.1572-0241.2006.00499.x
    Direct Link:
  • 22
    Lai KC, Lam SK, Chu KM, et al. Lansoprazole for the prevention of recurrences of ulcer complications from long-term low-dose aspirin use. N Engl J Med 2002; 346: 20338.
  • 23
    Röhss K, Lind T, Wilder-Smith C. Esomeprazole 40 mg provides more effective intragastric acid control than lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg and rabeprazole 20 mg in patients with gastro-oesophageal reflux symptoms. Eur J Clin Pharmacol 2004; 60: 5319.
  • 24
    Griffin MR, Piper JM, Daugherty JR, Snowden M, Ray WA. Nonsteroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in elderly patients. Ann Intern Med 1991; 114: 25763.
  • 25
    Laine L, Bombardier C, Hawkey CJ, et al. Stratifying the risk of NSAID-related upper gastrointestinal clinical events: results of a double-blind outcomes study in patients with rheumatoid arthritis. Gastroenterology 2002; 123: 100612.