Maintenance therapy of gastroesophageal reflux disease | SpringerLink

Clin J Gastroenterol (2010) 3:61–68 DOI 10.1007/s12328-010-0139-z

CLINICAL REVIEW

Maintenance therapy of gastroesophageal reflux disease Akihito Nagahara • Mariko Hojo • Daisuke Asaoka Sumio Watanabe

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Received: 8 January 2010 / Accepted: 8 January 2010 / Published online: 19 February 2010 Ó Springer 2010

Abstract The aims of treatment of gastroesophageal reflux disease (GERD) are to cure mucosal breaks, control symptoms, and prevent complications (e.g. stricture, Barrett’s esophagus, and esophageal adenocarcinoma). Proton pump inhibitors (PPIs) are known to be the best drugs to cure esophagitis; however, a highrecurrence rate of about 80% was described after the completion of initial therapy. Regretfully, not so many physicians perform maintenance therapy in clinical practice. Histamine H2 receptor antagonists have an insufficient effect in maintenance therapy compared with PPIs; therefore, they could be prescribed for mild reflux esophagitis. Several clinical trials have been conducted to investigate the efficacy of continuous PPI administration maintenance therapy for GERD. Among these trials, recent large-scale studies showed that esomeprazole was equal to or superior to other kinds of PPIs. On the other hand, on-demand PPI studies have been conducted, mainly in patients with nonerosive reflux disease or uninvestigated GERD;however, this strategy was less effective than continuous therapy in many studies. Because on-demand therapy is less expensive, it is worth confirming this strategy in further studies. Studies of maintenance therapy with investigations conducted for as long a period as 5 years have described that PPI maintenance therapy could be considered as effective, safe, and well tolerated. Keywords GERD Reflux esophagitis Maintenance therapy On-demand therapy

A. Nagahara (&) M. Hojo D. Asaoka S. Watanabe Department of Gastroenterology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan e-mail: [email protected]

Clinical characteristics of GERD in Japan Gastroesophageal reflux disease (GERD) is defined as a condition which develops when reflux of the stomach contents causes troublesome symptoms and/or complications. This definition includes reflux esophagitis, which is defined endoscopically by visible breaks of the distal esophageal mucosa, and nonerosive reflux disease (NERD), which is defined by the presence of troublesome refluxassociated symptoms and the absence of mucosal breaks on endoscopy [1]. Various factors, such as the decreasing prevalence of Helicobacter pylori infection [2], the increase in both basal and stimulated gastric acid secretion over the past 20 years in the elderly/nonelderly populations irrespective of H. pylori infection [3], and the westernization of eating habits [4] possibly contribute to the occurrence of GERD in Japan. In addition to the mechanical effects of obesity, such as an increase in intraabdominal pressure from large amounts of adipose tissue, substances that adipose tissues secrete, such as tumor necrosis factor-alpha, interleukin-6, leptin, and insulin-like growth factor-1, have been proposed to be pathogenic links to GERD and its complications [5]. Among the elderly population, the incidence of GERD is more common, especially in women [6]. In Japanese postmenopausal women, kyphosis induced by multiple vertebral fractures is often seen, and the presence and severity of vertebral fractures are associated with the presence of hiatal hernia [7]. We also reported that the presence of vertebral fractures was significantly associated with the presence of either reflux esophagitis or hiatal hernia [8]. Because the presence of hiatal hernia could contribute to excessive esophageal acid exposure [9], this might be the reason for the high incidence of reflux esophagitis among the elderly generation.

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Clin J Gastroenterol (2010) 3:61–68

Accordingly, circumstances of increasing GERD are seen in Japan. Indeed, Fujiwara and Arakawa [10] reported that the prevalence of GERD began to increase rapidly from the end of the 1990s. A systematic review reported that the prevalence of GERD was as high as 10%–20%, whereas the incidence was as low as 4.5–19.6 per 1000 person-years, suggesting that GERD is likely to persist for many years; on average, 18–44 years [11]. Accordingly, GERD could be considered as a chronic disease, and therefore maintenance therapy as well as the initial therapy would be important for the management of GERD.

severe reflux esophagitis, 30% of them would consider such therapy for all cases of reflux esophagitis, and 6% of them would not consider maintenance therapy irrespective of severity. Among the participating primary care physicians, 58%, 24%, and 18%, respectively, would consider maintenance therapy for each of the above groups [18]. This report revealed the actual conditions in which not so many physicians perform maintenance therapy in clinical practice; in other words, it is hard to say that physicians have been aware of the significance of maintenance therapy.

What is the difference between NERD and GERD?

Maintenance therapy with histamine H2 receptor antagonists (H2RAs)

Initially, it had been thought that NERD was just a mild form of GERD and that a subset of these patients may progress over time to develop erosive esophagitis [12]. However, the clinical characteristics of NERD are different from those of reflux esophagitis i.e., the onset occurs at a younger age, with female predominance and lower weight, and the patients are less likely to have a hiatal hernia [13]. A study from Japan reported similar findings, i.e., female predominance, low body mass index (BMI), not smoking, absence of hiatal hernia, and severity of gastric atrophy were positively associated with NERD [14]. Although the characteristics of functional impairment such as impaired lower esophageal sphincter (LES) pressure, motility abnormalities, and percentage time of acid regurgitation are milder than in reflux esophagitis [12], heartburn severity and intensity are similar to the high incidence in NERD [15] [16]. Patients with NERD have begun to be common in Japan; the proportions of NERD and reflux esophagitis were 58.6% and 41.4%, respectively [10]. Therefore, the clinical significance of NERD is important.

Are physicians aware of the clinical significance of maintenance therapy ? The aims of GERD treatment are to cure mucosal breaks, control symptoms, and prevent complications, e.g., stricture, Barrett’s esophagus, and esophageal adenocarcinoma. Proton pump inhibitors (PPIs) are known to be the best drugs to cure esophagitis; however, after completion of therapy, the remission rates were described as only 10% and 25% in patients to whom placebo was administered for 6 months [11, 17]. As this shows, esophagitis could be considered as liable to show recurrence. According to a questionnaire survey in which physicians in seven Asia-Pacific regions participated, 64% of gastroenterologists would consider maintenance therapy for

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Some studies have employed H2RAs for maintenance therapy of GERD. After complete healing of esophagitis, 172 patients were randomly prescribed either 20 or 40 mg twice-daily famotidine dosing regimens. Relapse rates at 6 months were 22% (P \ 0.001 vs. placebo) for famotidine 20 mg BID, 11% (P \ 0.001 vs. placebo) for famotidine 40 mg BID, and 62% for placebo. Compared with placebo, patients in the famotidine groups were significantly less likely to note global symptomatic deterioration, as measured by the distribution of global assessment responses [19]. A study from Japan compared the efficacy of different H2RAs; either 150 mg nizatidine or 20 mg famotidine twice a day, for maintenance therapy of erosive esophagitis for 6 months. Nizatidine had a superior effect on remission (nizatidine 57% vs. famotidine 28%) and the nonrecurrence rates of esophagitis were only 11% and 25% in patients with severe esophagitis [20]. In fact, a review has described as insufficient results showing that with H2RA and prokinetics (cisapride) roughly 60% of the patients could be maintained in remission [21]; as this shows, the power of these drugs is considered weak for maintenance therapy. Therefore, these drugs could be suitable for the treatment of mild reflux esophagitis. There are some studies which compare H2RAs and PPIs in NERD or mild reflux esophagitis. In daily practice physicians treat their patients with GERD on the basis of symptom relief. So The Dutch Reflux Study Group focused on symptom relief in the maintenance therapy of GERD, assuming standard daily practice. Patients with mild esophagitis after initial therapy were randomized to maintenance treatment with omeprazole 10 mg daily or ranitidine 150 mg twice daily and investigated for symptomatic relapse every 3 months. The estimated proportions of patients in remission after 12 months of maintenance treatment with omeprazole 10 mg daily (n = 134) and ranitidine 150 mg twice daily (n = 129) were 68% and 39%, respectively (p \ 0.0001),


suggesting that low-dose omeprazole is more effective than standard-dose ranitidine in keeping patients in remission for a period of 12 months [22]. A multicenter study by The European Study Group involving NERD and mild erosive esophagitis assessed intermittent treatment over 12 months. Recurrences of moderate or severe heartburn during follow up were treated with omeprazole 10 or 20 mg daily or ranitidine 150 mg twice daily. About half of the patients did not require treatment for at least 6 months, and this was similar in all three treatment groups. They concluded that intermittent treatment is simple and applicable in general practice, where most patients are seen [23]. In the general practice setting, some patients who visit a clinic suffering from reflux symptoms may undergo endoscopy; however, many of them would be treated empirically on a symptomatic basis. The latter group is referred to as having uninvestigated GERD. In a study focusing on the treatment of uninvestigated heartburn in primary care for a long period, pantoprazole (20 mg/day) produced significantly higher rates of complete control of symptoms than ranitidine (300 mg/day) at 4 weeks (40% vs. 19%; P \ 0.001), 8 weeks (55% vs. 33%; P \ 0.001), 6 months (71% vs. 56%; P = 0.007), and 12 months (77% vs. 59%; P = 0.001). The study authors concluded that low-dose pantoprazole was an effective alternative to standard-dose ranitidine [24].

Maintenance therapy with continuous PPI administration As indicated above, the efficacy of PPIs in the maintenance therapy of GERD is greater than that of H2RAs. Several clinical trials have been conducted to examine the efficacy of PPIs in GERD maintenance therapy, comparing different PPI doses and different PPIs, as shown in Table 1. A dose-finding study of omeprazole maintenance therapy was conducted in a placebo controlled trial, and omeprazole showed a curative effect in a dose-dependent manner [25]. Another study employing esomeprazole concluded that esomeprazole (40 and 20 mg) was effective and well tolerated in the maintenance of healing of erosive esophagitis [26]. However, a study comparing 20 mg versus 40 mg pantoprazole found an equal effect on remission [27]. Studies focused on comparisons of efficacy between different PPIs, rabeprazole and omeprazole, showed similar results after 52 weeks [28]. Recent large-scale studies employing more than a thousand patients revealed that 20 mg esomeprazole was superior to other kinds of PPIs [29–31], but one study concluded that pantoprazole 20 mg and esomeprazole 20 mg were equally effective [32]. Because any kind of PPI would have a sufficient effect on the initial therapy of GERD, large-scale studies might

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clarify these small differences, or might show that the longterm effect of PPIs in maintenance therapy might differ by the kind of PPI. A study assessed predictive factors for treatment success in the maintenance phase (lansoprazole 15 or 30 mg daily) of healed esophagitis. The dose of lansoprazole, symptom severity, grade of reflux esophagitis, H. pylori infection status, LES resting tone, percentage of 24 h with an esophageal pH of less than 4.0, and median 24 h intragastric pH before the start of treatment were investigated as predictive values, and the results of this study described that the dose of lansoprazole (P = 0.01) and symptom severity (P \ 0.05) both significantly predicted time to relapse; however, differences in the other factors were not significant [33]. As mentioned above, complications such as stricture sometimes occur in GERD; in this situation, dilatation therapy of the stenosis is performed. In a study with a relatively short-term maintenance period, 30 patients with severe esophagitis with complicating stricture who completed dilatation therapy and achieved healing of esophagitis and dysphagia relief were randomly assigned to 4 weeks of maintenance treatment with double-dose PPIs. In the omeprazole (20 mg b.d.) group, 90% remained in remission ; in the lansoprazole (30 mg b.d.) group, the rate was 20%, and in the pantoprazole (40 mg b.d.) group, the rate was 30% [34]. Though the duration of maintenance therapy was only 4 weeks and the sample size was small, this study indicated that PPIs have an effect in maintenance therapy for GERD patients with complications.

Polymorphism of PPI metabolism in maintenance therapy PPIs are mainly metabolized by cytochrome P450 2C19 (CYP2C19), and the genotypes of CYP2C19 are classified into three groups, homozygous extensive metabolizer (homo-EM), heterozygous extensive metabolizer (heteroEM), and poor metabolizer (PM). Plasma PPI levels and intragastric pH with PPI treatment are highest in the order of PM, hetero-EM, and homo-EM [33, 35–38]. These CYP2C19 genotype-dependent differences in the pharmacokinetics and pharmacodynamics of PPIs influence the cure rates for GERD [39]. We ask the question: does polymorphism of CYP2C19 difference influence the remission of erosive reflux esophagitis during maintenance therapy as well as initial therapy? The frequencies of these polymorphic alleles show marked interethnic variation [40]. Among Japanese, the proportions of homo-EM, hetero-EM and PM are 35%, 49%, and 16%, respectively [41]. There are some studies of these factors in maintenance therapy of GERD in Japanese. Kawamura et al. [42] reported that 82 Japanese patients

123

123

1303

Goh [32]

Randomized, double-blind


Randomized


Randomized, double-blind, placebo-control





Study design

Healed reflux esophagitis grades A–D

Healed erosive esophagitis grades A–D

Healed erosive esophagitis

Healed reflux esophagitis Los Angeles (LA) grades A–D

Helicobacter pylorinegative healed esophagitis

Healed erosive GERD

Healed GORD II or III

Nonerosive esophagitis

Healed esophagitis grade 1–4

Subject

GERD gastroesophageal reflux disease, GORD gastro-oesophageal reflux disease, CI confidence interval

1026

Devault [31]

375

Vakil [26]

2766

243

Thjodleifsson [28]

Labenz [30]

433

Plein [27]

1391

495

Venables [35]

Lauritsen [29]

168

N (maintenance)

Laursen [29]

Author

Table 1 Maintenance therapy with continuous proton pump inhibitor (PPI) administration

Pantoprazole 20 mg once daily esomeprazole 20 mg once daily

Esomeprazole 20 mg once daily lansoprazole 15 mg once daily

Esomeprazole or pantoprazole (both 20 mg once daily)

Esomeprazole 20 mg once daily lansoprazole 15 mg once daily

Esomeprazole 40, 20, 10 mg, or placebo once daily

Rabeprazole 10, 20 mg or omeprazole 20 mg once daily

Pantoprazole 20, 40 mg once daily

Omeprazole 10 mg every morning or placebo

Omeprazole 20, 10 mg daily or placebo

Maintenance treatment

Endoscopic/symptomatic remission rate, esomeprazole 84.8% and lansoprazole 75.9% (P = 0.0007) Endoscopic and symptomatic remission, pantoprazole 84% and esomeprazole 85%, equally effective

6 months

Endoscopic and symptomatic remission, esomeprazole 87.0% and pantoprazole 74.9% (P \ 0.0001)

Remission, esomeprazole 83% (95% CI, 80%–86%) and lansoprazole 74% (95% CI, 70%–78%) P \ 0.0001

Maintenance of healing, esomeprazole 40 mg (87.9%), 20 mg (78.7%), or 10 mg (54.2%), compared with placebo (29.1%) (P \ 0.001)

Relapse rate, rabeprazole 10 mg 5%, 20 mg 4% and omeprazole 5%, equivalent

Endoscopic remission, pantoprazole 20 mg (75%), 40 mg (78%), 20 mg is adequate, minimal drug exposure and lower costs after12 months

Cumulative symptom relapse rate, omeprazole (27%), placebo (52%) P = 0.0001

Remission, omeprazole 20 mg (59%), 10 mg (35%) and placebo (0%), P \ 0.002

Outcome

6 months

6 months

6 months

6 months

52 weeks

12 months

6 months

6 months

Duration

64 Clin J Gastroenterol (2010) 3:61–68


with initial healing of reflux esophagitis were treated with lansoprazole 15 mg daily for 6 months and the proportions of patients in remission were 61.5%, 78.0%, and 100% among homo-EM, hetero-EM, and PM, respectively. A study which investigated symptom recurrence by maintenance therapy of PPIs, either rabeprazole (10 mg/day), omeprazole (20 mg/day), or lansoprazole (15 mg/day) for 6 months in 99 patients reported that the recurrence rates of GERD symptoms were 38.5%, 10.9%, and 5.6% in homoEM, hetero-EM, and PM, respectively [43]. Another study investigating symptomatic recurrence during low-dose lansoprazole maintenance therapy revealed that the hazard ratios of symptomatic recurrence of GERD in hetero-EM and PM compared with homo-EM were 0.40 (95% confidence interval [CI], 0.19–0.87, P = 0.021) and 0.19 (95% CI, 0.05–0.69, P = 0.011) [44]. In contrast, Ohkusa et al. [45] reported that, in a total of 119 Japanese patients with recurrent reflux esophagitis receiving daily omeprazole 10 mg or 20 mg for 6–12 months, serum gastrin increased during the first 3 months of dosing but stabilized thereafter, and no significant differences were seen either in the rate of reflux esophagitis healing or symptom improvement among genotype groups. Accordingly, whether CYP2C19 polymorphism might affect the clinical outcome in maintenance therapy for GERD is controversial.

Maintenance therapy with on-demand PPIs As noted above, maintenance therapy with PPIs is meaningful for GERD patients; however, in clinical practice, during long-term maintenance therapy, the therapeutic strategy is sometimes switched to step-down to H2RA or on-demand therapy because of medical expenses (including limitations of medical insurance) and/or patients’ compliance. Therefore, it is important to verify the efficacy of on-demand therapy in the maintenance treatment of GERD. There are some studies regarding on-demand therapy of GERD, as shown in Table 2 [46–53]. Many of these studies were conducted in patients with NERD or uninvestigated GERD and assessed symptom relief or patient satisfaction, because control of reflux symptoms should be the main goal of therapy in patients with NERD or mild and uninvestigated GERD [54]. In looking at the results of these studies, which compared on-demand and continuous arms, it can be seen that continuous treatment provided better outcomes [46–49]. In a study that assessed quality of life (QOL) during the maintenance therapy using the Short-Form 36 and QOL in reflux and dyspepsia (QOLRAD), QOL improvement was maintained during the 6-month follow up, with a slight difference in terms of QOL in reflux and dyspepsia scores and patients’ satisfaction in favor of the continuous

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treatment strategy [46]. A pilot study concerning the expense of medication in on-demand, continuous, and intermitted therapy revealed that on-demand therapy was 30% cheaper, whereas intermittent therapy was 55% cheaper than the most expensive daily treatment; however, the general satisfaction with each treatment option was high and nonsignificantly different between the groups [46]. Because on-demand therapy is less expensive, it is worth confirming this strategy for the maintenance therapy of GERD in further studies.

Long-term follow-up studies In regard to the duration of studies regarding maintenance therapy, many of them were 6 months to 1 year, but some studies’ investigations continued for several years. In a study of 78 patients with endoscopically proven esophagitis, the patients were followed for 5 years with lansoprazole 30 mg and gastric mucosal condition was evaluated. The total endoscopic relapse rate was 14.1%; this was regarded as efficacious, and no histological changes had occurred in H. pylori-negative patients, and the development of glandular atrophy and intestinal metaplasia was not accelerated in H. pylori-positive patients [55]. A prospective randomized study in which 5 years’ treatment of erosive GERD with rabeprazole (10 or 20 mg daily) or omeprazole (20 mg daily) was performed revealed similar efficacy in all groups, and gastric biopsy showed no evidence of any harmful effects [56]. Another study employing rabeprazole 10 and 20 mg with placebo investigated the 5-year maintenance of healing in patients previously diagnosed with erosive/ulcerative GERD and healed in an acute efficacy trial. Relapse rates in each group were: rabeprazole 20 mg, 11%; 10 mg, 23%; placebo, 63%; P \ 0.001 for rabeprazole versus placebo; P = 0.005 for rabeprazole 20 vs. 10 mg. And the rabeprazole groups were also shown to be significantly superior to placebo in preventing symptom recurrence and improving patient QOL [57]. Accordingly, long-term PPI maintenance therapy could be considered as effective, safe, and well tolerated. Miyamato et al. reported step-down therapy in symptomatic GERD patients in the primary care setting for 5 years in Japan. After the PPI-based step-down initial therapy (PPI to H2RA to prokinetics), the optimal medication for each patient was continued for 5 years. As results, reflux symptoms were reduced by the PPI-based step-down therapy, and the prevalence of H. pylori infection was significantly lower and the serum pepsinogen I/II ratio was significantly higher in the PPI treatment group [58]. It is well known that H. pylori causes atrophic gastritis, resulting in a lower pepsinogen I/II ratio and lower

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123 Randomized, single blind

Randomized

Randomized

622

Norman Hansen [53] 2156

5265

60

268

216

Tsai [52]

Pace [54]

Cibor [47]

Morgan [48]

Tepes [49]

Omeprazole 20 mg on-demand, omeprazole 10 mg daily

Omeprazole 20 mg daily

ERD (LA grade C, D)

Rabeprazole 20 mg continuous or on-demand

Lansoprazole 30 mg ‘‘ondemand’’, lansoprazole 15 mg daily, lansoprazole 30 mg in 4week courses during a relapse

Esomeprazole 20 mg/day or esomeprazole on demand

Esomeprazole 20 mg daily continuously or on-demand or ranitidine 150 mg twice-daily continuously

Esomeprazole 20 mg on-demand lansoprazole 15 mg continuous

On-demand treatment with rabeprazole 10 mg versus placebo

Lansoprazole(30 mg) on-demand, omeprazole (20 mg) on-demand

Maintenance treatment

NERD, ERD (LA grade A, B)

GERD (heartburnpredominant)

NERD

Symptoms suggestive of GERD

Symptoms of GERD

Endoscopy-negative gastroesophageal reflux disease

Nonerosive reflux disease

Reflux esophagitis, absence of symptoms

Subject

NERD nonerosive reflux disease, ERD erosive reflux disease, QOLRAD quality of life in reflux and dyspepsia

Randomized

Randomized

Randomized


418

Bytzer [51]


300

N (maintenance) Study design

Johnsson [50]

Author

Table 2 Maintenance therapy with on-demand PPI administration

12

6

12

6

6

6

6

6

Cumulative relapse rate, 34.9% (95% CI, 24.6–45.2%) in omeprazole on-demand, 15.3% (7.6–22.9%) in 10 mg daily, 40% (18.5–61.5%) in 20 mg daily

Mean percentage of heartburn-free days was 90.3% in the continuous arm and 64.8% in the on-demand arm (P \ 0.0001)

Intermittent therapy (4-week courses) showed a significantly lower efficacy in comparison to other groups (P \ 0.05)

QOLRAD scores were better in the continuous arm, patients’ response rate of very satisfied was slightly higher in the continuous arm (64.5%) than in the on-demand arm (59.7%).

Completely/very satisfied with esomeprazole continuous (82.2%) and esomeprazole on-demand (75.4%) compared with ranitidine continuous (33.5%) treatment (P \ 0.0001)

Significantly more patients were willing to continue taking esomeprazole ondemand than lansoprazole continuous therapy after 6 months (93% vs. 88%; P = 0.02).

Discontinuation rates because of inadequate heartburn control were 20% for placebo vs. 6% for rabeprazole (P \ 0.00001)

The patients had significantly fewer reflux symptoms the more medication they consumed. There was no difference in the number of capsules consumed between the two drugs

Duration (months) Outcome

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acid output [59, 60]; because H. pylori-negative patients have higher acid secretion, the strongest acid-suppressor PPI is chosen for their maintenance therapy.

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