Management of gastroduodenal ulcers and gastrointestinal symptoms associated with nonsteroidal anti-inflammatory drug therapy: A summary of four comparative trials with omeprazole, ranitidine, misoprostol, and placebo

Management of Castroduodenal Ulcers and Gastrointestinal Symptoms Associated with Nonsteroidal Anti-Inflammatory Drug Therapy: A Summary of Four Comparative Trials with Omeprarole, Ranitidine, Misoprostol, and Placebo MSc,’ Peter Wahlqvist, MSc,’ lngalill Wilson, MSc,’ G6ran L%ytr6m, Anders Walan, MD, PhD,‘,’ Angela Wiklund, PhD,‘z3 and jmrgen Naesdal, MD, PhDlT4 ‘AstraZeneca R&D Miilndui, Mtilrtdul, Sweden, *Department of internal Medicine, University of Linkiiping, Sweden, ‘Department of Public He&h and Primary Health Care, University of Bergen, Norway, 4Department of Biomedicine and Surgery, University of Linktiping, Sweden

ABSTRACT

Bockground:

Nonsteroidal anti-inflammatory drugs (NSAlDs) are effective in of systemic diseases such as rheumatoid arthritis but are associated with a range of adverse gastrointestinal (Cl) side effects, including dyspepsia, peptic ulcer, and ulcer complications. Several studies have compared the relative efficacy and tolerability of omeprazole, ranitidine, and misoprostol in the management of NSAlDassociated GI adverse events. Objectfve: The purpose of this paper is to summarize and evaluate the results of 4 clinical studies that compared the efficacy and tolerability of omeprazole, misoprostol, and ranitidine in the acute and maintenance treatment of NSAID-associated gastroduodenal ulcers and CI symptoms. Methods: The 4 trials, which included 1822 patients being treated continuously with NSAIDs, studied omeprazole (20 and 40 mg once daily) as acute treatment for healing gastroduodenal ulcers and erosions and as prophylaxis (20 mg once daily) over 3 to 6 months. Comparators were misoprostol 200 pg 4 times daily or ranitidine 150 mg twice daily in the acute phases and misoprostol 200 pg twice daily, ranitidine 150 mg twice daily, or placebo in the prophylactic phases, Resrrltr: Gastric and duodenal ulcer healing rates were higher with omeprazole than with either misoprostol (P = 0.004 for gastric ulcers; P < 0.001 for duodenal ulcers) or ranitidine (P < 0.001 for gastric ulcers; P = 0.032 for duodenal ulcers). A significantly larger percentage of patients taking misoprostol had the number of gastric or duodenal erosions reduced from >lO to ~5 com-

the treatment

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September 25, 200 I.

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pared with patients taking omeprazole (P < 0.001), whereas a significantly larger percentage of patients taking omeprazole achieved the same reduction in number of erosions compared with patients taking ranitidine (P = 0.008). More patients taking omeprazole remained in remission than patients taking misoprostol (P = 0.001), ranitidine (P = 0.004), or placebo (P < 0.001). More patients taking misoprostol (16.9%) or ranitidine (14.1%) discontinued treatment because of adverse events, lack of efficacy, or other reasons compared with patients taking omeprazole (9.9% and 10.2% in 2 studies). Conclusions: Omeprazole was more effective in healing and prophylaxis of NSAID-associated gastroduodenal ulceration and symptoms than misoprostol and ranitidine in chronic NSAID users, and was better tolerated than misoprostol. Key words: gastroduodenal ulcer, dyspepsia, misoprostol, nonsteroidal antiinflammatory drugs, omeprazole, ranitidine. (Curr Ther Res Clin Exp. 2001;62: 835-850)

INTRODUCTION Nonsteroidal anti-inflammatory drug (NSAID) therapy is associated with a range of gastrointestinal (GO adverse events; these events account for 20% and 25% of all reported drug-related adverse events in the United Kingdom and the United States, respectively. 1'2 NSAID-associated adverse events range from dyspeptic symptoms, experienced by 15% to 40% of NSAID users, 3 to peptic ulceration (occurring in 10% to 30% of users) and ulcer complications 4-6 that lead to hospitalization and are associated with high mortality. It has been estimated that >100,000 hospital admissions per year and 16,500 deaths per year in the United States are due to NSAID-associated GI complications. 7 Despite their inherent problems, however, NSAIDs are consumed daily by >30 million people worldwide, and this number is increasing. NSAIDs account for -20 million prescriptions per year in the United Kingdom and 70 million prescriptions per year in the United States. 8 The benefits of NSAIDs must be emphasized, however. Without continuous NSA|D therapy, the symptoms of basic systemic diseases such as rheumatoid arthritis would worsen markedly. This would likely result in impairment of quality of life and the ability to work. The H2-receptor antagonists are used to heal and prevent NSAID-associated ulcers, but their efficacy is limited, particularly when NSA1D therapy is prolonged. 9-12 The prophylactic effect of H2-receptor antagonists may be improved, however, by using high doses. ]2 The prostaglandin analog misoprostol also has a prophylactic effect, z3 but its use has been limited by its own GI side effects (eg, diarrhea, abdominal cramps) ~4 and its abortifacient properties. ~5'~6 Proton pump inhibitors such as omeprazole provide more reliable 24-hour

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suppression of acid secretion than H2-receptor antagonists or prostaglandin analogs 17'18 and may provide a better treatment option for management of NSAID-associated GI side effects. An international program of clinical studies has investigated the therapeutic efficacy and tolerability of omeprazole versus misoprostol ~9 and ranitidine 2° in the acute and maintenance treatment of NSAID-associated GI symptoms, peptic erosions, and ulcers in patients receiving continuous NSAID therapy. The efficacy of omeprazole as primary prophylaxis against gastroduodenal lesions and dyspeptic symptoms has also been studied. 2L22 The majority of patients in these studies had either osteoarthritis (45%) or rheumatoid arthritis (39%), and all required continuous NSAID treatment. The purpose of this paper is to summarize the results of this research program to facilitate selection of the best treatment strategy for patients who require continuous, long-term NSAID therapy.

PATIENTS AND METHODS Four clinical studies, known as OMN1UM19 (Omeprazole versus Misoprostol for NSAID-lnduced Ulcer Management), ASTRONAUT 2° (Acid Suppression Trial: Ranitidine v e r s u s O m e p r a z o l e for NSAID-Associated Ulcer T r e a t m e n t ) , OPPULENT21 (Omeprazole versus Placebo as Prophylaxis of ULcers and Erosions from NSAID Treatment), and S C U R 22 (Scandinavian Collaborative Ulcer Recurrence), were conducted in 21 countries in North America and Europe, as well as Australia, New Zealand, and South Africa. The 4 studies enrolled a total of 1822 patients aged 20 to 85 years who required continuous NSAID therapy. Informed consent was obtained in all the studies. OMNIUM and ASTRONAUT were designed to include an acute treatment phase as well as a maintenance phase, whereas OPPULENT and SCUR were designed as prophylactic studies only. All 4 studies used a double-blind, double-dummy design (Table I). All patients underwent an endoscopic examination each time they visited their local clinic (with the exception of the initial visit in SCUR), and symptoms were also assessed. An ulcer was defined as a break in the mucosa of at least 3 mm in diameter and 1 mm in depth. Patients completed symptom diary cards during the first 4 weeks of the acute phases in OMNIUM and ASTRONAUT, recording the presence or absence of epigastric or abdominal pain and heartburn. Helicobacter pylori status was assessed in antral biopsies using a rapid urease test (CLO ® test, Delta West, Bentley, Australia). Inclusion Criteria To be eligible for the acute treatment phase in OMNIUM and ASTRONAUT, patients had to have at least 1 ulcer and/or >10 erosions in the stomach or duodenum. Patients could continue in the maintenance phase if they had no ulcers, <5 erosions, and no more than mild dyspeptic symptoms after initial treatment.

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In the OPPULENT study at entry, patients could have had mild dyspeptic symptoms, but no ulcer and no more than 10 erosions in the stomach or duodenum. The SCUR study enrolled NSAID-naive patients with a history of dyspepsia or uncomplicated peptic ulcer disease who, at entry, had no more than mild dyspeptic symptoms.

Exclusion Criteria The main exclusion criteria in all studies were clinically important GI bleeding, a history of gastric surgery, pyloric stenosis, and use of oral steroids in excess of an equivalent of 10 mg/d prednisolone. Patients with erosive reflux esophagitis were excluded in all studies except ASTRONAUT, in which these patients were treated but excluded from symptom analyses.

Study End Points Treatment success in the acute phases in the OMNIUM study and ASTRONAUT was defined as no ulcers in the stomach or duodenum, <5 erosions in the stomach and duodenum, and no more than mild dyspeptic symptoms. Patients who met these criteria were rerandomized to prophylactic therapy. Failure of prophylactic treatment was defined in all 4 studies as the occurrence of a gastric or duodenal ulcer, >10 erosions in the stomach or duodenum, or moderate to severe symptoms of dyspepsia requiring active treatment. Adverse events resulting in discontinuation of treatment were included as a criterion for treatment failure in the OMNIUM study and ASTRONAUT. Statistical analyses are described e l s e w h e r e ) 9-22

RESULTS Patient Demographic Characteristics The treatment groups in all 4 studies were well balanced with respect to baseline characteristics. The demographic and clinical characteristics of patients in the treatment groups are presented in detail elsewhere. 19-22

Acute Treatment Effects After 8 weeks in the OMNIUM study, treatment success was achieved in 76% of patients taking omeprazole 20 mg once daily compared with 71% of patients taking misoprostol 200 pg 4 times daily (P = 0.37). In ASTRONAUT, the treatment success rate was 80% for patients taking omeprazole 20 mg once daily compared with 63% for those taking ranitidine 150 mg twice daily (P < 0.001). Because the higher dose of omeprazole (40 mg/d) was not significantly different from the 20-mg dose in terms of efficacy or tolerability, it is not discussed further here; however, details of this comparison are presented elsewhere. 19,20

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When ulcer healing and erosion healing were examined separately, gastric and duodenal ulcer healing rates were significantly higher with omeprazole than with either misoprostol or ranitidine, at both 4 and 8 weeks (Table II). The differences in healing were significant whether ulcers were -~3 mm or -~5 mm in diameter at baseline. The difference in healing rates between omeprazole and ranitidine was particularly pronounced for gastric ulcers ~-5 mm (83% vs 59%; P-- 0.001). In ASTRONAUT, which compared omeprazole and ranitidine, treatment with omeprazole reduced the number of erosions to <5 in more patients than did treatment with ranitidine, whereas in the OMNIUM study, comparing omeprazole and misoprostol, more patients had the number of erosions reduced to <5 with misoprostol than with omeprazole (87% vs 77% at 8 weeks; P < 0.001) (Table II). A greater proportion of patients with moderate to severe dyspeptic symptoms at entry obtained relief after 4 weeks of omeprazole than after 4 weeks of misoprostol or ranitidine (Figure 1). Diary card data showed that more patients taking omeprazole were relieved of heartburn during the first 4 weeks of treatment (Figure 2) and spent more time free of heartburn compared with patients taking misoprostol or ranitidine. Heartburn was recorded on 16% of days during treatment with omeprazole and 29% of days during treatment with misoprostol (P < 0.001) in OMNIUM. Similarly, in ASTRONAUT, patients taking omeprazole experienced heartburn on 16% of treatment days compared with 24% of days among those taking ranitidine (P = 0.005). Diary card data showed that patients had less abdominal pain in the first 4 weeks during omeprazole treatment than during treatment with misoprostol; there was no difference between omeprazole and ranitidine in this respect.

Tolerability o f Acute T r e a t m e n t Diarrhea was the most frequently reported adverse event during acute treatment, affecting about twice as many patients taking misoprostol as patients taking omeprazole (11.4% vs 4.5%); a similar incidence ratio was observed between patients taking ranitidine and those taking omeprazole (4.0% vs 1.7%). More patients taking misoprostol (16.9%) or ranitidine (14.1%) discontinued treatment due to adverse events, lack of efficacy, or other reasons than patients taking omeprazole (9.9% in OMNIUM and 10.2% in ASTRONAUT).

Prophylactic Treatment Effects In all 4 studies, a greater proportion of patients remained in remission in the groups treated with omeprazole compared with those treated with misoprostol 200 pg twice daily, ranitidine 150 mg twice daily, or placebo (Figure 3). Reasons for treatment failure in each study arm are shown in Figure 4. In the OMNIUM study, cumulative occurrence of peptic ulcer over 6 months was the reason for relapse in 14.6% of patients taking omeprazole, 19.6% of those taking misoprostol, and 42.6% of those taking placebo. Ulcer relapse occurred less frequently in

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ASTRONAUT (5.7% with omeprazole and 19.5% with ranitidine). The ulcer relapse rate was 3.6% with omeprazole and 16.5% with placebo over 6 months in the OPPULENT study, and 4.7% with omeprazole and 16.7% with placebo over 3 months in the SCUR study. More patients experienced relapse of dyspeptic symptoms in the placebo groups than during omeprazole treatment in both studies.

Tolerability of Prophylactic Treatment The rate of adverse events leading to discontinuation of therapy was higher among patients receiving misoprostol (16.8%) than among those receiving omeprazole or placebo in the OMNIUM study (12.1% and 10.3%, respectively), whereas the rates were similar for patients treated with omeprazole and ranitidine in ASTRONAUT (14.5% and 13.3%, respectively). The most common adverse events were GI and musculoskeletal events. In both the OPPULENT and SCUR studies, omeprazole and placebo were equally well tolerated.

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Figure 3. Proportion of patients remaining in remission during prophylactic treatment in each study. Omeprazole 20 m g once daily was compared w i t h misoprostol 200 pg twice daily and placebo in O M N I U M , w i t h ranitidine 150 m g twice daily in ASTRONAUT, and w i t h placebo in OPPULENT and SCUR. O M N I U M = Omeprazole versus Misoprostol for NSAIDInduced Ulcer M a n a g e m e n t ; ASTRONAUT -- Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-Associated Ulcer Treatment; OPPULENT = Omeprazole versus Placebo as Prophylaxis of ULcers and Erosions from NSAID Treatment; SCUR -- Scandinavian Collaborative Ulcer Recurrence.

DISCUSSION

The results of the clinical studies reviewed herein indicate that omeprazole has greater clinical efficacy and tolerability compared with misoprostol and ranitidine in the management of NSAID-associated gastroduodenal ulceration and GI symptoms. Omeprazole was more effective than misoprostol, ranitidine, and placebo in keeping patients in remission, defined as absence of gastroduodenal ulcers, multiple erosions, and dyspeptic symptoms, and it was better tolerated than misoprostol. Thus, direct and potent acid inhibition with a proton pump

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inhibitor was more effective than either H2-receptor blockade or the addition of an exogenous prostaglandin in these studies. The results are based on a solid foundation of randomized clinical trials in >1800 chronic NSAID users, the large majority of whom had osteoarthritis or rheumatoid arthritis. The advantages of omeprazole over misoprostol and ranitidine were evident with respect to both healing and prevention of gastric and duodenal ulcers during continuous NSAID treatment. These findings can be explained largely by differences in the ability of the 3 drugs to inhibit gastric acid secretion. Omeprazole 20 mg once daily maintains intragastric pH above 3 for most of a 24-hour period, whereas the H2-receptor antagonists at standard doses achieve an intragastric pH of ---3 for 6 to 7 hours less per day than omeprazole23'24; misoprostol in standard doses does not differ significantly from placebo in this respect. ]8 However, misoprostol has been used largely because of its cytoprotective action on the gastric mucosa, which also involves effects on mucosal blood flow. 13'25 Omeprazole has also been shown to protect against acute gastric damage caused by aspirin in a dose-dependent manner, 26 which further supports the t heor y that acid plays an important part in the development of such lesions. 27 Misoprostol had a more p r o n o u n c e d effect than omeprazole on healing and prevention of erosions alone. However, the relationship between erosions

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and the subsequent development of ulceration and complications has been questioned. 28 Patients treated with omeprazole achieved more rapid control of dyspeptic symptoms than did patients treated with ranitidine or misoprostol. Furthermore, omeprazole provided significantly better relief of reflux symptoms, abdominal pain, and indigestion symptoms than did misoprostol. Misoprostol induced diarrhea, 29 which is consistent with the adverse event reports in the maintenance phase; the incidence of dyspeptic symptoms in the misoprostol group was 3 times higher than in the omeprazole group and was the main cause of relapse. Given the impact of symptoms on patients' quality of life, and the need for further consultations and treatment, this may have both clinical and economic relevance. The occurrence of ulcers in 42.6% and 16.5% of the placebo-treated patients after 6 months in the OMNIUM and OPPULENT studies, respectively, and in 16.7% of placebo-treated patients at 3 months in the SCUR study underlines the fact that there is significant ulcer development during NSAID therapy in the absence of effective prophylactic treatment both in those who have had recent ulcers (OMNIUM) and in those who have not (OPPULENT and SCUR). In fact, it has been suggested that an epidemic of NSAID-associated ulcers and ulcer complications is occurring. 3° In addition, there is a considerable economic burden associated with NSAID-related gastroduodenal damage. In the United States, the adjusted mean annual cost for all types of medical care for GI diseases is approximately double in regular NSAID users and even higher in highdose NSAID users, compared with non-NSAID users. 31 These costs might increase further if NSAIDs become more widely used for the prevention of colon cancer and Alzheimer's disease and if the use of low-dose aspirin for cardiovascular protection continues to increase. Cost-effectiveness analyses based on the results from the OMNIUM study and ASTRONAUT have been performed in Sweden 31 and Canada 32 and indicate that omeprazole is cost-effective for the acute treatment of ulcers. Health economic evaluations of prophylactic treatment are more complicated, since multiple variables driving costs and effectiveness need to be considered. However, previous studies indicate that the risk of GI side effects is the main factor that determines the cost-effectiveness of the different prophylactic treatment strategies. 33'34 Furthermore, although costs for treating GI side effects of NSAIDs are substantial, studies have shown that costs related to arthritis patients' inability to work and their need for home and community care represent a far greater proportion of the total costs of arthritis. 35-39 When the present clinical study program was designed, cyclooxygenase-2 (COX-2)-selective NSAIDs were not available. Although these drugs represent a step forward in NSAID therapy in that they reduce the risk of ulcer complications, they are still associated with upper GI symptoms, and their lack of an aspirin-like or conventional NSAID-like effect on thromboxane production and platelet aggregation might be a problem in patients at risk for cardiovascular

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complications. 4°-42 In the VIGOR study, the incidence of myocardial infarction was significantly higher among rofecoxib users than among users of naproxen (0.4% vs 0.1%; 95% CI, 0.1%-0.4%), which could be explained by the cardioprotective effect of naproxen. 4~ The findings in the VIGOR study will probably lead to coprescription of low-dose aspirin for users of COX-2-selective NSAIDs who are at risk for cardiovascular disease. In a comparison of users of celecoxib and concomitant low-dose aspirin with users of conventional NSAIDs, the annualized incidence rates of ulcer complications were similar in the 2 groups (2.01% and 2.12%, respectively). 42 These findings, which are likely to represent class effects, are of clinical relevance to the substantial p r o p o r t i o n of COX-2selective NSAID users who require c o n c o m i t a n t t r e a t m e n t with low-dose aspirin. Additional randomized, controlled trials and postmarketing experience are required to determine whether the COX-2-selective NSAIDs will significantly diminish the need for concomitant treatment with drugs like omeprazole in patients at risk of developing dyspeptic symptoms, ulcers, and ulcer complications.

CONCLUSIONS Treatment with omeprazole, as acute or maintenance therapy, allows patients with or at risk of NSAID-associated gastroduodenal ulcers and GI symptoms to continue their NSAID treatment with the purpose of controlling inflammation and pain. Omeprazole was significantly more effective than misoprostol and ranitidine in the acute treatment of ulcers and GI symptoms during continuous NSAID treatment and significantly more effective than misoprostol, ranitidine, and placebo in preventing ulcers and GI symptoms during continuous NSAID treatment for up to 6 months.

ACKNOWLEDGMENT This clinical research program was funded by AstraZeneca R&D M61ndal, MBlndal, Sweden.

REFERENCES 1. Wolfe F, Kleinheksel SM, Spitz PW, et al. A multicenter study of hospitalization in rheumatoid arthritis. Frequency, medical-surgical admissions, and charges. Arthritis Rheum. 1986;29:614-619. 2. Hazleman BL. Incidence of gastropathy in destructive arthropathies. Scand J Rheumatol Suppl. 1989;78:1--4. 3. Hirschowitz BI. Nonsteroidal antiinflammatory drugs and the gastrointestinal tract. Gastroenterologist. 1994;2:207-223. 4. Griffin MR. Epidemiology of nonsteroidal anti-inflammatory drug-associated gastrointestinal injury. A m J Med. 1998;104(Suppl 3A):23S--29S.

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Address correspondence to: J o r g e n Naesdal, MD, PhD Clinical Science A s t r a Z e n e c a R&D MBlndal S-431 83 M61ndal Sweden E-mail: j o r g e n . n a e s d a l @ a s t r a z e n e c a . c o m

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