Concise guide to management of reflux disease in primary care

Transcription

1 Drug review GORD Concise guide to management of reflux disease in primary care Kumar Kanti Basu BSc, FRCP Reflux is a common disorder often aggravated by lifestyle and other medications. Our Drug review discusses the symptoms, pathophysiology, investigations and drug therapy of GORD, followed by a review of the prescription data and sources of further information. Dyspepsia is common, accounting for 5 per cent of primary-care workload. 1 Patients can be subgrouped into reflux, peptic and functional dyspepsia groups, which have different management strategies. In primary care, symptoms and medication response are the best way of making a diagnosis. It is helpful to think of reflux presenting with above the diaphragm symptoms as opposed to the other conditions with predominantly below the diaphragm complaints. Of note secondary reflux can occur due to delayed gastric emptying, in which case a mixture of symptoms may be present. Extra oesophageal reflux syndromes are described and may present without typical oesophageal symptoms (see Table 1). 2 This article concentrates on the management of gastro-oesophageal reflux disease (GORD). Symptoms Classical reflux symptoms include heartburn, regurgitation and dysphagia. Less common symptoms include belching, nausea, atypical chest pain and odynophagia. Odynophagia should alert the clinician to the possibility of infective or pill oesophagitis. These are not reflux-related conditions and respond to specific treatments or removal of offending drugs, which include bisphosphonates, tetracyclines, potassium supplements, NSAIDs, antibiotics and immunosuppressants (causing infection usually candidosis). It is important to ask about the frequency, duration and severity of symptoms, with emphasis on quality of life and functional impairment including sleep disturbance, meal avoidance and exercise limitation. Exerciseinduced chest pain needs angina excluding. Nocturnal heartburn can predict more difficult symptom control. CPD questions available for this article. See page 28 Prescriber August

2 Oesophageal disease nonerosive reflux disease oesophagitis oesophageal stricture Barrett s oesophagus oesophageal adenocarcinoma *proposed associations Table 1. Spectrum of reflux syndromes Extraoesophageal disease dental enamel erosion laryngitis and reflux cough (LPR) reflux asthma idiopathic lung fibrosis* recurrent otitis media* sinusitis* Response to medication is important and many patients will have already tried over-the-counter agents including low-dose proton-pump inhibitors (PPIs). A trial with a full-dose PPI for four weeks is a cost-effective test for reflux. 3 No response to a PPI should make you think about alternative diagnoses. Review of diet and drugs is important to exclude risk factors that potentiate reflux, including coffee, alcohol, chocolate, fat, fizzy drinks, beta-blockers, nitrates, calcium channel blockers, anticholinergics, acetyl cholinesterase inhibitors and progesterone. Lifestyle changes to avoid medication dependence should be encouraged, though for severe reflux the evidence for lifestyle intervention remains unclear. Interventions include: weight control smoking cessation alcohol reduction regular meals and slow eating not lying down within three hours of eating or drinking avoidance of fizzy drinks and foods that cause symptoms raising the head of the bed by 20cm (not extra pillows) avoidance of tight clothing. PPI therapy should not be used to allow continuation of an unhealthy lifestyle. Pathophysiology Reflux is often thought of as being a purely acidrelated disease due to the fact that acid-reducing drugs are effective, but other agents including bile and pepsin can also cause symptoms and oesophagitis (see Figure 1); reflux may still occur on PPIs but is less acidic. This may account for some treatment failures. Reflux commonly results from failure of the lower oesophageal sphincter (LOS) due to saliva oesophagus lower oesophageal sphincter (LOS) hiatus hernia diaphragm stomach pylorus gastric refluxate containing acid, pepsin, bile and food Mechanism of reflux lack of neutralising saliva decreased oesophageal motility with reduced clearance increased transient LOS relaxations (tlosrs) low-pressure LOS lack of diaphragm crural support sump for reflux increased intra-abdominal pressure excess gastric contents excess acid impaired gastric emptying impaired pyloric function duodenum Bile reflux Figure 1. Pathophysiology of GORD 20 Prescriber August

3 Timing of endoscopy Same-day admission 2-week-wait referral Routine or open access Table 2. Endoscopy guidance Drug Antacids Alginates H 2 -antagonists PPIs Prokinetics Low-dose tricyclics Table 3. Drug therapy for GORD Indication significant upper GI bleeding alarm symptoms: dysphagia persistent vomiting dyspepsia and unexplained weight loss unexplained iron-deficiency anaemia epigastric mass unexplained persisting recent dyspepsia above 55 years abnormal barium study persistent/severe reflux symptoms despite medical optimisation previous stricture or severe-grade oesophagitis known Barrett s with new persistent reflux increased transient LOS relaxations (tlosrs). Other abnormalities can include a low-pressure LOS and reduced oesophageal clearance (especially in scleroderma). Hiatus hernia, delayed gastric empty - ing and increased intra-abdominal pressure (obesity and COPD) are also factors. Acid hypersecretion as Indication mild reflux mild and moderate reflux adjunct to PPIs for breakthrough aid PPI weaning laryngopharyngeal reflux mild-moderate reflux PPI intolerance adjunct in nocturnal reflux first-line therapy for moderate/severe disease diagnostic test healing of oesophagitis laryngopharyngeal reflux maintenance for: prevention of oesophageal strictures Barrett s oesophagus reflux secondary to delayed gastric emptying functional heartburn noncardiac chest pain a cause of reflux occurs in hypercalcaemia, Zollinger-Ellison syndrome (rare) and most commonly due to rebound hyperacidity following the use of PPIs. Only 40 per cent of patients with reflux develop oesophagitis, which can lead to complications including strictures and Barrett s oesophagus. It is estimated that less than 10 per cent 4 of people with oesophagitis develop Barrett s after five years, a premalignant condition with a risk of 0.12 to 0.5 per cent per annum 5 for oesophageal adenocarcinoma. Rebound hyperacidity The concept of rebound hyperacidity is an important factor contributing to PPI dependence, which is preventable. In one trial, 40 per cent of healthy volunteers developed heartburn after stopping an eight-week PPI course. This is due to the development of raised gastrin levels resulting in excess acid production when the PPI block is removed. 6 This is a self-limiting phenomenon but can take several weeks to resolve. Weaning PPIs by reducing the dose over four to six weeks and using alginates may prevent rebound relapse in a substantial proportion of patients. 7 Other investigations Endoscopy This test is invasive, costly and unnecessary in patients with controllable symptoms. It is useful to determine the presence of oesophagitis in severe or persistent symptoms and to exclude other pathology in diagnostic doubt. It must be considered urgently for all those with alarm symptoms. There is no current established role for Barrett s screening. For endoscopy referral guidance see Table 2. PPIs should be stopped two weeks before diagnostic endoscopy. Oesophageal studies These represent the gold standard for reflux diagnosis in difficult cases with suboptimal response to PPI therapy as they allow direct correlation of reflux events with symptoms. New developments include the wireless Bravo oesophageal capsule allowing capture of ph data for up to 96 hours, and oesophageal impedance probes that measure electrical impedance in the oesophagus allowing for the capture of all reflux events including weak or nonacid reflux. In an impedance study in patients with heartburn despite taking twice-daily PPIs, around 40 per cent of patients had nonacid reflux that benefited from escalation of reflux therapy including antireflux surgery, and around 50 per cent had no reflux-related symptoms at all, representing functional heartburn Prescriber August

4 Drug therapy for reflux Mild symptoms may be treated with over-the-counter antacids, alginates or H 2 -antagonists (see Table 3). Moderate and severe symptoms should be treated with full-dose PPI therapy for four to eight weeks and maintained with the lowest effective dose or on an asrequired basis. PPIs are the most effective agents for symptom control, healing of oesophagitis and stricture prevention. Knowledge of how they work helps understand how to use them more effectively. They irreversibly block the final enzyme pathway of acid production, which is why they are the most effective acid suppressants. They are absorbed within 30 minutes and have short serum halflives of around one hour. They only block active open proton pumps (stimulated by a meal); the stomach can regenerate new pumps within 24 hours. Blocking more pumps leads to better acid suppression, so taking a PPI 30 minutes before a meal and twice-daily dosing improve efficacy. Failure to control symptoms indicates that therapy is suboptimal. self-medication failure and primary-care consultation GORD symptoms heartburn regurgitation dysphagia* detailed history other diagnoses alarm symptoms 2-week-wait pathway secondary care symptom assessment lifestyle modification symptoms intermittent and controlled by antacid, alginates, H 2 -antagonists, low-dose PPI persistent symptoms affecting quality of life trial PPI at full dose 4 8 weeks routine referral to secondary care/openaccess endoscopy symptoms resolved breakthrough symptoms diagnostic doubt no PPI effect chronic symptoms reassurance and discharge use lowest effective maintenance dose or as required optimise medical therapy: twice-daily dosing 30 minutes premeals add alginate post meals and nocte consider: add nocte H 2 -antagonist add prokinetic symptoms persist *urgent referral Figure 2. Recommended management of GORD adapted from the NICE guideline 9 Prescriber August

5 Adverse event Increased enteric infections including Clostridium difficile Increase in community-acquired pneumonia Iron-deficiency/B 12 deficiency Hypomagnesaemia Increased fracture risk/osteoporosis Rebound hyperacidity and dependence Gastric adenocarcinoma risk Gastric carcinoid risk Decreased protective clopidogrel effect Table 4. Adverse events with long-term PPI therapy Optimised PPI therapy Check the PPI is being used appropriately in terms of adherence and timing. Dose escalation should be with twice-daily dosing, ie omeprazole 20mg twice daily, not 40mg once daily. This is especially important for nocturnal symptoms when a single morning dose or last dose at night may not be effective. This may also reduce sideeffects. If there is no response at all to twice-daily therapy, then revisit the diagnosis and consider referral. Only a few patients benefit from further dose increase, eg omeprazole 40mg twice daily from 20mg twice daily, or a change from an older to newer PPI such as esomeprazole or rabeprazole (Pariet). Adjuvant therapy Adding an alginate after meals with a late-night dose is helpful if there are breakthrough symptoms on PPIs. Alginates do not interfere with PPI absorption. They have a barrier function forming a raft in the stomach and may also trap pepsin and bile within the raft. Addition of H 2 -antagonists such as ranitidine 300mg at night may be helpful in nocturnal breakthrough and used on a two-week-on and two-week-off basis to avoid development of tolerance. Prokinetics may be helpful in patients with symptoms of delayed gastric emptying such as nausea, bloating and satiety but generally have weak effects. Long-term use may result in side-effects such as tardive Evidence base relative increased risk of 2; dose and other patient factors contribute weak association contributing factor, exclude other causes occurs in some patients epidemiological evidence suggestive of small increased risk but confounding factors well described and preventable by weaning PPIs likely confounding effects; eradicate Helicobacter pylori if present in long-term PPI users theoretical risks and rodent studies no direct proven link but stop PPI in patients with carcinoid clinical benefits of gastroprotection outweigh risks dyskinesia (metoclopramide) and prolonged QT syndrome (domperidone). Failure of optimised therapy after four to eight weeks should suggest secondary-care referral. Following successful symptom control, step down to the lowest effective maintenance PPI dose should be tried. An algorithm for the management of reflux in primary-care adapted from National Institute for Health and Clinical Excellence (NICE) guidelines is presented in Figure 2. 9 Pregnancy Lifestyle, posture and diet should be addressed. Antacids or alginates can be used. Ranitidine is safe and omeprazole can be used for severe symptoms if required. Long-term PPI therapy Long-term PPI requirement should be reviewed at least annually. Remember rebound hyperacidity may be responsible for immediate symptom relapse and dependence that can be avoided by weaning down PPI therapy and using alginates to facilitate withdrawal. Long-term acid suppression may have adverse effects; 10,11 these should be discussed with patients, though the risk-benefit ratio is usually in favour of continued PPI use in patients who need them (see Table 4). Long-term use is recommended in reflux patients with: 24 Prescriber August

6 Key points reflux diagnosis depends on symptoms and medication response PPIs are first-line agents for troublesome symptoms lifestyle change and drug review are important endoscopy is not required for most patients tertiary investigations may include impedance studies to pick up nonacid reflux PPIs should be used 30 minutes before meals and escalated with twice-daily dosing alginates are helpful for PPI breakthrough symptoms and for weaning down PPIs consider adding H 2 -antagonists for nocturnal breakthrough rebound hyperacidity is a preventable cause of reflux symptom relapse potential long-term adverse effects should encourage PPI use review recurrent severe oesophagitis despite lifestyle modification previous dilatation of oesophageal strictures confirmed Barrett s oesophagus. Antireflux surgery Consider referral for assessment if: uncontrolled severe symptoms and PPI intolerant patient prefers to avoid long-term medication an option for failed medical therapy. Conclusion Reflux is a common disorder with usually typical symptoms, and a diagnostic trial with a PPI is often helpful. Prescription review GPs in England wrote 43 million scrips for PPIs in 2011, at a total cost of 153 million. Omeprazole remained the most popular PPI, with 54 per cent of the market by volume, closely followed by lansoprazole with 40 per cent. The average cost per scrip for omeprazole was greater than for lansoprazole, the cheapest PPI, and pantoprazole. This was due to high use of the 40mg capsule (costing three times more than the 10 or 20mg capsules) and the use of expensive special and liquid preparations, albeit in low numbers. Esomeprazole was the most expensive PPI. Prescribing decreased slightly to 3.0 per cent of all PPIs compared with 3.8 per cent in 2010 but, with an average cost per scrip 10 times greater than that of omeprazole, it accounted for 25 per cent of spending. Rabeprazole A common cause is increased tlosrs but other aggravating factors including lifestyle and drugs are important to recognise. Endoscopy is not generally needed unless there are alarm symptoms. PPI therapy is the gold standard for moderate to severe symptoms and their effects can be optimised by taking 30 minutes before a meal and by using twicedaily dosing for breakthrough symptoms. They should be weaned down after symptom control to avoid rebound hyperacidity and PPI dependence. Some patients will require maintenance therapy, including those with complications such as peptic strictures or Barrett s oesophagus. References 1. Hungin AP, et al. Digestive diseases 2001;19: Vakil N, et al. Am J Gastroenterol 2006;101: Fass R, et al. Arch Intern Med 1999;159: Malfertheiner, et al. Alimentary Pharmacol therap 2012; 35: Hvid-Jenson F, et al. N Engl J Med 2011;365: Reimer C, et al. Gastroenterol 2009;137: Evans N, et al. BJHCM 2007;13: Mainie I, et al. Gut 2006;55: NICE. Dyspepsia: management of dyspepsia in adults in primary care. CG17. August Norman A, et al. Frontline Gastroenterol 2011;2: McCarthy DM. Curr Opin Gastroenterol 2010;26: Declaration of interests Dr Basu has worked on reflux-based projects sponsored by Reckett Benckiser. Dr Basu is consultant gastroenterologist at Sheffield Teaching Hospitals NHS Foundation Trust Items Cost Cost per (000s) ( 000s) scrip ( ) esomeprazole rabeprazole omeprazole pantoprazole lansoprazole alginates Table 5. Number, total cost and average cost per scrip of prescriptions for PPIs and alginates in England, 2011 enteric-coated tablets were also relatively expensive. Most prescriptions for alginates were for Gaviscon preparations, with the sugar-free Advanced Liquid accounting for 41 per cent by volume and 47 per cent of spending. 26 Prescriber August

7 Resources Guidelines American Gastroenterology Association medical position statement on the management of gastro - esophageal reflux disease. Kahrilas PJ, et al. Gastroenterology 2008;135: Dyspepsia proven gastro-oesophageal reflux disease management. NHS Clinical Knowledge Summaries. Dyspepsia: managing dyspepsia in adults in primary care. CG17. NICE, August Organisations The British Society of Gastroenterology (BSG). Tel: ; t.smith@bsg.org.uk; website: Primary Care Society for Gastroenterology. secretariat@pcsg.org.uk; website: Patient information The BSG provide an online factsheet for patients on heartburn and reflux. general/heartburn-and-gastro-oesophageal-reflux.html. CPD: Management of GORD Answer these questions online at Prescriber.co.uk and receive a certificate of completion for your CPD portfolio. Utilise the Learning into Practice form to record how your learning has contributed to your professional development. 1. One of these statements is false which is it? a. Nocturnal heartburn predicts easier control of symptoms in a patient with suspected GORD b. Quality of life and functional impairment should be emphasised when asking the patient about the frequency, duration and severity of symptoms c. Nitrates are among the drugs that may potentiate reflux d. Patients may already have tried a PPI before seeking medical help 2. Which one of these statements about lifestyle change in patients who may have GORD is false? a. There is no clear evidence of the efficacy of lifestyle change in patients with severe GORD b. Patients should be encouraged to eat slowly c. Patients should try not lying down within three hours after drinking or eating d. Patients should try raising their heads when in bed by using an extra pillow 3. One of these statements is false which? a. Reflux of bile and pepsin may cause symptoms and oesophagitis b. Reflux is often due to increased tlosrs c. Forty per cent of patients with reflux develop oesophagitis d. Rebound hyperacidity after discontinuing PPI therapy resolves within a week 4. Which one of these statements about drug treatment of GORD is false? a. Moderate and severe symptoms should be treated with full-dose PPI therapy for four to eight weeks and maintained with the lowest effective dose or on an as-required basis b. Taking a PPI 30 minutes before a meal improves efficacy c. If omeprazole 20mg once daily is not effective, the dose should be increased to 40mg once daily d. PPIs are the most effective agents for stricture prevention 5. Which one of these statements about adjuvant therapy of GORD is false? a. Alginates reduce systemic PPI absorption by about 30 per cent b. When an H 2 -antagonist is indicated, it should be used on a two weeks on and two weeks off basis to avoid the development of tolerance c. Options for use during pregnancy include omeprazole, ranitidine and alginates d. Adding an H 2 -antagonist should be considered if nocturnal symptoms occur despite optimised PPI therapy 6. One of these statements is false which is it? a. Patients who have previously undergone dilatation of oesophageal strictures should be considered for long-term PPI therapy b. Most patients with suspected GORD should have an endoscopy c. Patients who do not want to take long-term medication should be referred for assessment for surgery d. Oesophageal impedance studies are the gold standard for reflux diagnosis in patients who are difficult to manage and have a suboptimal response to a PPI 28 Prescriber August