Description of the condition
Gastro-oesophageal reflux disease (GORD) develops when the reflux of gastric contents into the oesophagus results in troublesome symptoms or complications (Rosemurgy 2011; Vakil 2006). The refluxate contains varying amounts of acid, pepsin, bile salts and trypsin. The injury caused by these agents outside the stomach may manifest as a wide range of symptoms at oesophageal and at extra-oesophageal sites. The classical symptoms of GORD are heartburn, regurgitation and chest pain. Patients with GORD who have endoscopic evidence of erosions or ulcerations in the lower end of the oesophagus are considered to have erosive oesophagitis. GORD is one of the most common medical conditions with an estimated prevalence of 10% to 20% in the western world (Dent 2005; Peery 2012). It is the most frequent gastrointestinal outpatient diagnosis in the USA and the most common indication for upper endoscopy (Peery 2012). It is associated with reduced quality of life, reduced work productivity, and places a huge financial burden on society (Dent 2005).
Description of the intervention
Proton pump inhibitors (PPIs) are effective in suppressing gastric acid production and are the cornerstone of GORD therapy (Hrelja 2011). PPIs are effective in healing oesophagitis, improving symptoms and preventing recurrent oesophageal strictures. They are generally well-tolerated with a convenient once a day dosing schedule. In patients with erosive oesophagitis, it is a common practice to double the dose of PPI with the objective of improving the healing and producing faster relief of symptoms (Meineche-Schmidt 2004). This practice is, however, based on limited evidence. Randomized controlled trials (RCTs) which have been conducted to compare the efficacy of high dose PPI with the standard dose have shown varying efficacy. The overall efficacy of such an approach needs to be systematically assessed. Moreover, the side effects of high dose PPI are likely to be higher than with standard dose PPI.
How the intervention might work
The pharmacokinetic and pharmacodynamic profiles of currently available PPIs are suboptimal, leading to lack of sustained acid suppression that results in inadequate symptom relief as well as incomplete mucosal healing. The traditional PPIs (omeprazole, lansoprazole, pantoprazole and rabeprazole) block the action of proton pumps resulting in reduction in acid secretion but have a short half life of 1 to 1.5 hours. However, proton pumps are continuously regenerated thereby restoring the capacity to secrete acid once the serum levels of the drug starts dropping. Doubling the dose of PPI provides more sustained serum levels possibly resulting in better acid suppression and translation into better healing and symptom relief.
Why it is important to do this review
Currently only the standard doses of PPIs are licensed for use in the short term treatment of reflux oesophagitis, based on the available evidence. Current guidelines by the American Gastroenterology Association recommend using a standard dose of PPI for the short term management of GORD (Kahrilas 2008). However, they opined that the data supporting the use of PPIs in doses higher than the standard dose are weak and thus have not explicitly recommended their use. The efficacy of such an approach needs to be systematically assessed given the increasing body of evidence generated in recent large multicentre trials. A Cochrane review, published in 2007, partially addressed this issue (Moayyedi 2007). However, since its publication there have been newer RCTs that have addressed the issue of the efficacy of high dose versus standard dose PPI in oesophagitis. Also, newer PPIs, mainly in the form of enantiomers of the traditional PPIs, have been added to the armamentarium of drugs available for treatment. Enantiomers of traditional PPIs have been developed with the intention to provide better stereoselective pharmacokinetic properties resulting in higher bioavailability, a more homogenous response to therapy, and better efficacy with equal safety (Abel 2010; Zhou 2008). Esomeprazole, an enantiomer of omeprazole; dexlansoprazole, an enantiomer of lansoprazole; dexrabeprazole, an enantiomer of rabeprazole; and S-pantoprazole, an enantiomer of pantoprazole have been introduced into the market. Recent RCTs have evaluated the performance of these agents in comparison to their primary molecules. There have been previous systematic reviews and narrative reviews which have focused on either esomeprazole versus other agents, dexlansoprazole versus other agents, or the role of high dose PPI in a severe erosive oesophagitis subset and have made comparisons between various drug classes (Edwards 2001; Edwards 2006; Gralnek 2006; Klok 2003; Kushner 2011). Thus a systematic, comprehensive update is necessary in order to inform decision makers about the best available evidence for management of this condition.
Moreover, the FDA has recently issued warnings on the use of PPIs as recent studies have found that their long term use is associated with serious side effects in the form of increased risk of fractures, low magnesium levels, pneumonia and C difficile infection (Eom 2011; Moayyedi 2012). Also, high dose therapy has to be cost-effective in order to justify the expenditure incurred by government or the patient. Thus a pragmatic balance is necessary in assessing the risks versus benefits in prescribing high dose PPI therapy in the short term management of reflux oesophagitis.