Medical Therapy of Gastroesophageal Reflux Disease

Medical therapy of gastroesophageal reﬂux disease Emmanuel Corona, Jan G. Hatlebakkb and Jean-Paul Galmichea

Purpose of review Introduction Proton pump inhibitors remain the mainstay of medical Gastroesophageal reflux disease (GERD) is a very therapy in gastroesophageal reflux disease. Despite their common disorder that negatively influences quality of life. increasing use, up to 40% of patients are not fully satisfied According to an international working group [1], GERD with their antireflux therapy. Recent data on efficacy and is a ‘condition that develops when the reflux of stomach safety are reviewed and causes of failure are discussed. contents causes troublesome symptoms and/or compli- Recent findings cations’. Recent literature (i.e. published since January Several randomized studies and a metaanalysis have shown 2006) covering the different aspects of antireflux drug marginal differences in efficacy between various proton therapy is discussed. The review includes both acid pump inhibitor regimens. In subgroups, however, such as suppression and novel pharmacological approaches. severe esophagitis, esomeprazole may be superior. Poor Endoscopic antireflux procedures and specific aspects of compliance is one of the main causes of failure. Nonacid treatment for Barrett’s esophagus are discussed in the reflux is likely to play an important role, especially in patients review by Krishnadath [2]. with regurgitation or cough persisting on therapy. Genetic polymorphisms involved in proton pump inhibitor Therapeutic endpoints metabolism, Helicobacter pylori infection or nocturnal acid GERD is considered a benign disease in most affected breakthrough during therapy are probably less important individuals. Since symptoms occurring at least once a week than initially suspected. Recent pharmacological adversely affect quality of life and because nonerosive developments include new proton pump inhibitor isomers, reflux disease (NERD) is the most prevalent form of potassium competitive acid blockers and inhibitors of GERD, emphasis has been given during the last decade transient lower esophageal sphincter relaxations. to the relief of symptoms as the primary endpoint of Summary therapy for the majority of patients. GERD, however, There are still important unmet needs in the treatment of can also incur severe lesions and complications. Few data gastroesophageal reflux disease. Optimizing acid control is are available concerning GERD-related mortality. unlikely to improve the condition of the majority of patients Interestingly, a population-based retrospective study with incomplete proton pump inhibitor response. Inhibition determined the mortality from GERD in Finland between of transient lower esophageal sphincter relaxations remains 1987 and 2000 [3]. During that period of time, annual the major pharmacological target for future drug mortality from GERD significantly increased from development. 0.18/100 000 to 0.46/100 000. Concomitantly, a significant increase was noted in the use of proton pump inhibitors Keywords (PPIs) and H2 blockers and in the annual rate of antireflux acid and nonacid reflux, proton pump inhibitors, transient surgery. Of the 213 patients who died as a result of GERD- lower esophageal sphincter relaxations related causes, 180 had received medical treatment, including four patients whose death was related to either Curr Opin Gastroenterol 23:434–439. ß 2007 Lippincott Williams & Wilkins. diagnostic or therapeutic endoscopy. Other causes of death in the medical group were hemorrhage from esophagitis aDepartment of Gastroenterology and Hepatology, University Hospital, Nantes, France and bInstitute of Medicine, Haukeland University Hospital, (n ¼ 82), aspiration pneumonia (n ¼ 41), ulcer perforation University of Bergen, Norway (n ¼ 25), esophageal rupture (n ¼ 15), and stricture Correspondence to Dr E. Coron, CHU Nantes, Institut des Maladies de (n ¼ 13). Antireflux surgery contributed to 33 deaths l’Appareil Digestif, Service He´pato-Gastroente´rologie, Nantes, F-44000, France Tel: +33 2 40 08 31 51; fax: +33 2 40 08 31 54; (24 early complications; nine late failures). No data were e-mail: [email protected] given on the frequency of adenocarcinoma of the

Current Opinion in Gastroenterology 2007, 23:434–439 esophagus, also related to GERD.

Abbreviations The risk of GERD-associated cancer of the airways is also ERD erosive reflux disease GERD gastroesophageal reflux disease an area of interest. Recently, Vaezi et al. [4] performed a NERD nonerosive reflux disease case–control study evaluating the risks of smoking, P-CAB potassium-competitive acid blocker PPI proton pump inhibitor alcohol and GERD in the development of laryngeal TLESR transient relaxation of the lower esophageal sphincter cancer. They matched 96 de-novo cancers with 192 controls with respect to age, gender and ethnicity. ß 2007 Lippincott Williams & Wilkins 0267-1379 They found that smoking [odds ratio (OR) 6.08;

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confidence interval (CI) 2.82–13.10] and GERD of these patients, chronic cough and laryngeal symptoms (OR 2.11, CI 1.16–3.85) were independent factors for had resolved at 2 years. Patients with persistent respira- laryngeal cancer on multivariate analysis. Prospective tory symptoms had significantly higher Reflux Disease studies are needed to confirm these findings since this Questionnaire (RDQ) reflux score. In contrast, duration was a retrospective study with important shortcomings. and category of disease (ERD, NERD, Barrett) were not associated with the resolution of cough or laryngeal Clinicians should not forget the potentially severe com- symptoms, nor was PPI therapy. plications of GERD despite their low incidence. Healing (and maintenance of healing) of moderate/severe lesions In 35 patients with recently diagnosed laryngo-pharyngeal represents an important goal of therapy. reflux symptoms, Wo et al. [11] conducted a 12-week randomized controlled trial of pantoprazole (40 mg once Proton pump inhibitor therapy and acid a day) versus placebo. Forty percent of patients in the suppression pantoprazole group reported adequate relief compared Proton pump inhibitor (PPI) therapy represents the main- with 42% of those in the placebo group (nonsignificant). stay of therapy across the whole GERD spectrum. In Furthermore, there was no significant correlation between general, extraesophageal syndromes are less responsive improvement in laryngeal mucosal abnormalities nor than esophageal syndromes to acid suppression. change in hypo-pharyngeal reflux (pH-metry) and symptom improvement. Esophageal syndromes Several large randomized trials have compared various These results are consistent with those observed by Baldi PPI regimens administered for different therapeutic et al. [12]. Thirty-six patients with a diagnosis of reflux indications (healing and maintenance). All studies documented by endoscopy or abnormal esophageal pH- showed marginal and probably irrelevant differences metry and a positive response to a 4-week PPI trial were between these regimens [5,6–8]. A metaanalysis of randomly assigned to receive either 30 mg lansoprazole 10 randomized clinical trials (including 15 316 patients) once a day or 30 mg lansoprazole twice a day for 12 weeks. [5] was performed in order to compare esomeprazole to Twenty-one patients (60.0%) reported complete relief of other PPIs. Overall, at 8 weeks, there was a significant their cough with no difference between the two increase of 5% in the probability of healing esophagitis in treatment groups. More than 80% of the patients who favor of esomeprazole. Esomeprazole also conferred a had complete relief of their cough at the end of the significant increase of 8% for symptom relief at 4 weeks. treatment had shown a positive response to the PPI test. This advantage may be of little clinical significance for the majority of reflux patients but it is likely to be Reflux is the most frequent cause of chest pain of relevant in cases of severe esophagitis. noncardiac origin. Patients referred by a cardiologist after a comprehensive and negative cardiac work up were The effects of PPI therapy on histological consequences enrolled in a randomized controlled 1-week crossover trial of GERD are poorly documented. Vieth et al. [9] assessed of rabeprazole 20 mg twice a day versus placebo [13]. Of the effects of esomeprazole treatment in the proGERD the 35 patients enrolled, 16 (46%) were diagnosed as cohort. Patients had either erosive (ERD; n ¼ 720) or GERD positive and 19 (54%) as GERD negative on the nonerosive disease (NERD; n ¼ 35) and biopsy samples basis of pH monitoring and endoscopy. GERD-positive were obtained from the Z-line and 2 cm above. After PPI patients improved significantly more during rabeprazole treatment, the thickness of the basal layer and length of than placebo periods. In contrast, there was no significant papillae were significantly reduced in NERD and ERD difference in the GERD-negative group. These results patients, but especially in those with Los Angeles grades confirmed a previous trial published by the same group a C and D esophagitis. Hence, proliferative changes decade ago [14]. present in the squamous epithelium can be reversed by acid suppression, even in cases of severe esophagitis. New proton pump inhibitor isomers and potassium competitive acid blockers Extraesophageal syndromes Esomeprazole was the first PPI developed as an isomer to Whether PPIs are effective or not in extraesophageal show a better pharmacological profile than its racemate manifestations of GERD remains an important area of compound, omeprazole. Recently an S-enantiomer of controversy and uncertainty. Recently, Jaspersen et al. pantoprazole was developed and a comparative trial was [10] reported the clinical course of extraesophageal conducted by Pai et al. [15]. These authors compared the reflux symptoms in the 6215 patients of the ProGERD efficacy and tolerability of S-pantoprazole (20 mg once study, treated with different PPIs. Among 4404 patients daily) with racemic pantoprazole (40 mg once daily) in with a 2-year follow up, 570 had chronic cough and 369 patients. S-pantoprazole was more effective than its 454 laryngeal symptoms at baseline. In 63% and 74% racemate in terms of symptom relief, but equally effective

with respect to healing of esophagitis and gastric erosions. significant decrease in calcium absorption compared with Both drugs were safe and well tolerated. placebo. Moreover, a large case–control study [20] reported an increased risk for hip fracture in long-term Potassium-competitive acid blockers (P-CABs) represent PPI users compared with controls. Such results suggest a new class of drugs acting through a reversible binding that careful monitoring of individuals at risk of osteoporosis mechanism different from classical (irreversible) PPIs. In should be recommended. pharmacological studies, they have shown a fast onset of action with a maximum effect obtained after the first Proton pump inhibitor failure dose, whereas classical PPIs need several days to reach Although there is no universal definition of PPI failure, their steady-state effect. Moreover, P-CABs are active in according to recent surveys, only 58% of GERD patients the absence of stimulated acid secretion and their effect are fully satisfied with their antireflux medications (for a is rapidly reversible. In an experimental model of isolated review, see [21]). This disappointing finding was recently gastric glands, Kirchhoff et al. [16] showed that AZD0865 confirmed by a survey conducted by Jones et al. [22]in was able to inhibit acid secretion at a 100-fold lower the UK, Canada, Germany and France. Randomly concentration than omeprazole. Unfortunately, in a selected general practitioners participated in this survey subsequent clinical study reported only as an abstract, and their GERD patients were interviewed using a this effect did not translate into better clinical efficacy in standard questionnaire (927 patients analysed; mean GERD treatment and the development of that specific duration of symptoms approximately 1.5 years). Only compound was stopped. Other P-CABs, however, are 36% of patients receiving prescription therapy were currently being developed by pharmaceutical companies currently asymptomatic and 20.5% of them were still and early phase trials are in progress. taking at least one over-the-counter medication.

Proton pump inhibitor safety and tolerance Several factors have been reported to be associated with Despite the prevailing view that PPIs are extremely safe PPI failure [21]. Among them, compliance is probably the and well tolerated drugs in the short or medium term, most common cause [23]. The PPI usage pattern was their impact on the gastric mucosa in the very long term retrospectively analysed in a large cohort of 16 311 new remains poorly documented. Recent information comes PPI users [24]. Interestingly, an increasing number of from a study conducted in 215 GERD patients treated prescriptions and a PPI dosing of more than once daily medically or surgically and followed up for 7 years with were associated with a lower degree of compliance. More- gastric biopsies [17]. Most patients were Helicobacter over, up to 25% of patients without a proper indication for pylori negative at baseline or had an effective eradication PPI maintenance therapy (e.g. nonreflux dyspepsia and therapy. In these patients, no change occurred during H. pylori-associated indications) still used PPIs after surveillance, except hyperplasia in the endocrine cell 6 months, suggesting that overuse of PPIs is frequent population (P ¼ 0.03). Moreover, in patients who were in the general population. In contrast, a substantial still positive for H. pylori after 7 years, omeprazole proportion of patients with Barrett’s esophagus or severe induced mucosal inflammation and atrophy. These data esophagitis used their treatment only intermittently. support the opinion that H. pylori eradication is indicated in patients treated with continuous long-term PPI The role of nonacid reflux in the pathogenesis of persisting therapy. symptoms occurring under PPI therapy is now better understood thanks to the development of pH–impedance Risks of renal complications have been reported by monitoring, which allows the detection of nearly all reflux Geevasinga et al. [18] who identified 18 cases of biopsy- episodes. When PPI refractory patients are monitored proven PPI-associated acute interstitial nephritis causing while taking their medication, two recent studies showed acute renal failure. In the same retrospective study, the that regurgitation and cough are the symptoms most authors also reported additional cases of biopsy proven frequently associated with nonacid reflux [25,26]. interstitial nephritis (n ¼ 31), suspected interstitial nephri- Moreover these studies strongly suggested that few tis (n ¼ 10), unclassified acute renal failure (n ¼ 20) and patients are resistant to PPIs because of insufficient control renal failure (n ¼ 26) from a national registry database. All of acid secretion (Fig. 1). It is also worth noting that during five commercially available PPIs were responsible for the last year no further important data have been reported these complications, suggesting a pharmacological class concerning the therapeutic relevance of the so-called effect. nocturnal acid breakthrough.

Malabsorption may result from hypochlorhydria. Recently, To optimize acid control, increasing the dosing frequency the effects of 1 week of omeprazole treatment on fractional or switching to another PPI are two potentially available calcium absorption was assessed in 18 women aged strategies that were compared by Fass et al. [27]. 65 years or over [19]. The results showed a dramatic and According to these authors, switching from lansoprazole

Figure 1 Symptom–reflux association in patients on proton negative individuals. Therefore, these results support pump inhibitor therapy the opinion that H. pylori infection is not a major issue with regard to response to GERD therapy. This does not imply that H. pylori eradication is not important for Group II prevention of gastric cancer. patients on therapy n = 71 In patients with incomplete response to PPI and nonacid reflux (alone or associated with acid reflux), other Symptoms No symptoms therapeutic approaches are needed. Inhibition of transient n = 60 n = 11 relaxations of the lower esophageal sphincter (TLESRs) is currently the most promising. Indeed, TLESRs represent Negative SAP Positive SAP the common pathophysiological mechanism for both 38 (63.3%) 22 (36.7%) acid and nonacid reflux episodes [31]. Accordingly, encouraging results were reported in pilot studies [32] Acid only Acid and nonacid Nonacid only with baclofen (a prototype g-aminobutyric acid B agonist) 3 (5.0%) 9 (15.0%) 10 (16.7%) given in combination with omeprazole. These data, however, have not received confirmation from randomized Total acid Total nonacid prospective trials. Moreover, the development of 12 (20.0%) 19 (31.7%) compounds better tolerated than baclofen is necessary for their introduction into clinical practice (see below). Note that only 5% of patients with persistent symptoms have ‘acid only’ reflux associated with their symptoms. SAP, symptom association Drugs active on motility or visceral perception probability. Reproduced with permission from Zerbib et al. [25 ]. Even if acid suppression with PPIs is the most effective and practical drug therapy for GERD, this approach does not address the pathogenetic factors of the disease. 30 mg once daily to esomeprazole 40 mg once daily was as Other pharmacological targets are important to consider, effective as increasing the dosage and dosing frequency especially those involved in the control of esophageal to lansoprazole 30 mg twice daily. motility and sensitivity (for a review, see [33]).

The metabolism of PPIs is influenced by genetic Among new drugs, tegaserod is a partial 5-HT4-receptor polymorphisms. Indeed, the 2C19 isoform of cytochrome agonist acting throughout the gastrointestinal tract and P450 (CYP2C19) is the principal enzyme involved in these which may also act as a promotility agent or sensitivity metabolic pathways. Since PPI metabolites are inactive, modulator. Tegaserod was compared with placebo in poor metabolizers may have faster (and potentially 42 patients with mechanical hypersensitivity who under- stronger) acid inhibition. This theoretical assumption is went sensory tests with an esophageal barostat and acid supported by the recent report from Sugimoto et al. [28]. infusion [34]. Patients received tegaserod 6 mg twice daily Indeed, the median time to reach a gastric pH above or placebo for 14 days, and crossed over to the alternate 5.5 after intravenous infusion of omeprazole 20 mg twice treatment after 7–10 days of washout. Tegaserod signifi- daily was significantly shorter in poor and heterozygous cantly decreased the frequency of heartburn/acid reflux, metabolizers compared with the group of homozygous regurgitation, and distress from regurgitation. The global metabolizers (0.9 and 2.8 versus 1.3 h respectively; preference for tegaserod was 63.4% compared with 12.2% P < 0.05). The clinical implications of these findings, for placebo. Moreover, tegaserod significantly increased however, remain doubtful. Indeed, a previous study [29] the pressure threshold for distension-induced pain, and the conducted in 205 ERD patients failed to identify any mean and maximum wall tension at pain. Tegaserod, correlation between CYP2C19 genotype and endoscopic however, did not alter pain induced by acid infusion. healing rates. One cannot exclude, however, that geno- Therefore, these results do not rule out the possibility typing may help PPI titration in severe or complicated of an indirect mechanical effect rather than a true disease. modulation of visceral sensation. Moreover, as far as therapy of GERD is concerned, tegaserod lacks effect The role of H. pylori infection in PPI refractoriness remains on TLESRs, as recently shown by Tutuian et al. [35]. an area of research. De Boer et al. [30] analysed the results These authors conducted a double-blind randomized of a 1-week rabeprazole treatment according to baseline three-period crossover placebo-controlled trial in H. pylori status in a large prospective cohort study. 20 healthy volunteers. In this study, no significant differ- Complete symptom relief (heartburn and regurgitation) ence was noted in the numbers of acid and nonacid reflux was achieved in more than 70% of patients with no episodes, nor in distal esophageal contraction amplitude or difference in response between H. pylori positive and bolus transit time.

As previously underlined, most reflux episodes occur unmet needs persist, especially with respect to more during TLESRs, which do represent a major target for pathophysiologically oriented treatments. Inhibition of drug development in GERD therapy. Inhibition of TLESRs is the most promising approach in terms of TLESRs (sometimes called antirelaxation therapy) could novel drug development provided that drug tolerance be potentially useful as an add-on therapy (e.g. in combi- can be improved compared with the prototype substance nation with PPIs, when these fail) or as a single-agent baclofen. Finally, the recently recognized role of obesity approach. This latter strategy may be attractive in children in GERD pathogenesis certainly indicates that some for which many pediatricians are reluctant to prescribe dietary recommendations should be reconsidered. long-term potent acid suppression. Interestingly, a recent randomized, double-blinded, placebo-controlled trial [36] References and recommended reading evaluated the effect of 0.5 mg/kg baclofen on the rates of Papers of particular interest, published within the annual period of review, have been highlighted as: TLESRs, reflux episodes, and gastric emptying in of special interest 30 children. Baclofen significantly reduced the incidence of outstanding interest of TLESRs and the number of acid reflux episodes; it also Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 483). significantly accelerated gastric emptying. In contrast, it had no effect on the swallowing rate, pattern of esophageal 1 Vakil N,vanZantenSV, Kahrilas P, etal., GlobalConsensus Group. TheMontreal definition and classification of gastroesophageal reflux disease: a global peristalsis, or lower esophageal sphincter pressure. The evidence-based consensus. Am J Gastroenterol 2006; 101:1900–1920. major issue with baclofen, however, remains its poor A landmark paper concerning a new global definition of GERD. tolerance and the frequent occurrence of side effects that 2 Krishnadath KK. Novel findings in the pathogenesis of esophageal columnar metaplasia or Barrett’s esophagus. Current Opinion in Gastroenerology 2007. considerably limit its usefulness in clinical practice. Novel 3 Rantanen TK, Sihvo EI, Rasanen JV, Salo JA. Gastroesophageal reflux disease compounds acting more selectively on TLESRs are cur- as a cause of death is increasing: analysis of fatal cases after medical and rently under development, but clinical evaluation is surgical treatment. Am J Gastroenterol 2006; 102:246–253. A population-based retrospective study reporting increasing mortality from GERD. eagerly awaited. 4 Vaezi MF, Qadeer MA, Lopez R, Colabianchi N. Laryngeal cancer and gastroesophageal reflux disease: a case–control study. 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