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| Trends in Prescribing of Antacids and Ulcer Healing Drugs in England (Chart 1) |
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Dyspepsia is common: in one UK survey 40% of adults reported having had one or more dyspeptic symptoms in the previous year1. It is unclear whether the prevalence of dyspepsia is increasing, however chart 1 shows that prescribing of drugs for dyspepsia is rising. This is due to use of proton pump inhibitors (PPIs) since prescribing of H2-receptor antagonists (H2RAs) and antacids has fallen. Although spending has fluctuated over the last 5 years (chart 2), the amount spent for the quarters to March 1997 and March 2002 was very similar. Increased expenditure on PPIs has been balanced by the falling cost of H2RAs.
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Urgent referral
Urgent referral for endoscopy is recommended for patients aged over 55 years with recent onset of dyspepsia and/or continuous symptoms because these patients have an increased risk of cancer2. Patients of any age who present with dyspepsia and any of the following "ALARM" symptoms should also be referred immediately: Anaemia (iron deficiency), Loss of weight (unexplained), Anorexia, Recurrent problems, Melaena, Swallowing problem.
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Gastro-oesophageal reflux disease (GORD)
If urgent referral is not required, there are a number of options for managing patients. Eradicating Helicobacter pylori in those with typical symptoms of GORD is of no benefit3. Patients who have severe GORD or a proven pathology should be treated with a healing dose of a PPI until symptoms have been controlled. After that has been achieved the dose should be "stepped down" to the lowest dose that maintains control of symptoms. In complicated oesophagitis (stricture, ulcer, haemorrhage), the full dose should be maintained4. Patients with mild GORD symptoms and/or those who do not have a proven pathology can often be managed by a "step up" strategy starting with general measures to reduce reflux, such as losing weight if overweight and raising the head of the bed; progressing to antacids, alginates or H2RAs if necessary. PPIs can then be reserved for those with poor symptom relief. The alternative in mild GORD is to start with a PPI and then "step down" but this is a more expensive option.
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| Trends in Spending on Antacids and Ulcer Healing Drugs in England (Chart 2) |
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Non-ulcer dyspepsia and peptic ulcer disease
Most patients seen by a GP will not have a diagnosed cause for their dyspepsia. Between 15 to 25% of patients will have peptic ulcer disease (PUD), another 15 to 25% GORD, less than 2% stomach cancer and the remainder (about 60%) are classified as non-ulcer dyspepsia (NUD)4. For those patients who do not require urgent referral and who do not have symptoms of GORD, a policy of providing empiric therapy could be followed or patients could be tested for H. pylori before deciding on treatment or they could be referred for endoscopy. None of these policies is ideal5. Referring all patients for endoscopy is unrealistic in most localities and it is unlikely to be cost-effective. Many patients find endoscopy an unpleasant experience.
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| Many GPs would treat dyspepsia with antacids, H2RAs or PPIs and only investigate those who fail to respond. NICE recommends that patients presenting with mild dyspepsia may be treated on either a "step-up" or "step-down" basis but they should not normally be treated long-term without a confirmed clinical diagnosis being made4. Patients diagnosed with NUD should not be routinely treated with PPIs. If the symptoms appear to be acid-related, an antacid or the lowest dose of an acid suppressor to control symptoms should be prescribed4. |
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| Patients who are H. pylori negative are unlikely to have PUD. However H. pylori tests have limitations and their use in patients on first presentation of dyspepsia is not recommended5. For patients with proven ulcer disease, eradication of H. pylori increases the proportion of healed ulcers and reduces the risk of recurrence3. Although H. pylori eradication can improve dyspeptic symptoms in a small proportion of patients with NUD compared to placebo (NNT 15), it also increases the prevalence of oesophagitis3 and the long-term effects of eradication are unknown. The gold standard non-invasive test for H. pylori is a carbon urea breath test. Laboratory-based serological tests are more likely to give false positive results. Near-patient serological tests are not recommended due to concerns about their accuracy5. One week triple therapy regimens that comprise a PPI, amoxycillin, and either clarithromycin or metronidazole, eradicate H. pylori in over 90% of cases3. For patients with an ulcer there is generally no need to continue treatment with a PPI after eradication of H. pylori unless the ulcer is complicated by haemorrhage or perforation. |
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Prevention of NSAID-induced ulcers
All NSAIDs, including Cox II selective drugs, cause gastro-intestinal (GI) adverse events and they should only be prescribed after careful consideration of their risks and benefits. Factors associated with a high risk of developing serious GI adverse events include:
- Age over 65 years
- Use of concomitant medicines known to increase the chance of upper GI adverse events
- Serious co-morbidity
- Prolonged use of maximum recommended doses of NSAIDs
- Previous history of PUD/dyspepsia7
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Where it is essential that patients at high risk of GI adverse events receive an NSAID, misoprostol or a PPI is usually co-prescribed. Only misoprostol has been shown to reduce the occurrence of serious upper GI complications and bleeding when used for gastro-protection6. Omeprazole and lansoprazole reduce the development of ulcers detected by endoscopy however there is as yet no evidence to show that PPIs reduce GI complications when prescribed with an NSAID6. Unfortunately misoprostol causes abdominal pain and diarrhoea in a significant minority of patients. Another approach to reducing the risk of NSAID-induced ulcers in high risk patients is to prescribe a Cox II selective inhibitor rather than a standard NSAID. However there remains some concern regarding the use of Cox II selective inhibitors in patients with cardiovascular disease. In patients who are taking low dose aspirin, the benefit of using Cox II selective agents to reduce GI toxicity is reduced7. The published analysis of one of the trials (Celecoxib Long Term Arthritis Safety Study) has also been criticised for reporting results over 6 rather than 12 months since almost all the ulcer complications that occurred in the second half of the trial were in users of celecoxib8.
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H. pylori infection and NSAID use independently increase the risk of PUD and ulcer bleeding9. In patients who are H. pylori positive and at high risk of NSAID-induced PUD, eradication before starting an NSAID will reduce their risk of developing PUD. However patients who are H. pylori positive and already taking an NSAID do not appear to benefit from eradication.
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Proton pump inhibitors and H2-receptor antagonists
PPI prescriptions have increased by 129% over the last 5 years to 3.5 million items in the quarter to March 2002. Spending on PPIs has increased by 47% to £95.7 million per quarter. Lansoprazole is now the most commonly prescribed PPI (50% of items, 41% of spending), followed by omeprazole (32% items, 43% spending). NICE recommends that in circumstances where it is appropriate to use a PPI and where healing is required, the optimal dose to achieve this should be prescribed initially. Once healing has been achieved or where it is not required, the lowest dose of the PPI that provides effective symptom relief should be used4. Over the last 5 years the prescribing of lower strength PPIs has increased more rapidly than the prescribing of higher strength PPIs. For example in the quarter to March 1997, 34% of all lansoprazole prescriptions were for the 15mg strength and this increased to 51% by the quarter to March 2002. H2RA prescriptions have fallen by 26% over the last five years to 1.3 million items (quarter to March 2002), whilst spending has decreased by 70% to £12.9 million. Ranitidine accounts for 70% of H2RA items and cost.
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| Cost For 28 Days Treatment |
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There is a small variation (2.6 fold) across health authorities in spending on ulcer healing drugs (NIC per 1,000 ulcer healing drug STAR-PUs, chart 3). The health authorities spending the most are in the North except for Cornwall and East Kent. Most higher spending health authorities also have high prescribing rates for ulcer healing drugs (DDD/STAR-PU) but whether this is related to a higher prevalence of dyspepsia is difficult to determine.
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Antacids
In the quarter to March 2002 there were 1.6 million items prescribed from the BNF section that includes antacids, dimethicone, compound alginates and other proprietary indigestion preparations. Prescribing of antacids and dimethicone has halved over the last 5 years to just over 200,000 items for the quarter to March 2002. However prescribing of compound alginates has hardly changed at 1.4 million items per quarter. Spending on antacids and dimethicone has fallen by 31% to just under £600,000 per quarter but spending on compound alginates has risen by 8% to £5.3 million.
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| Variation Between Health Authorities in Spending on H2-receptor Antagonists and Proton Pump Inhibitors (Quarter to March 2002) Chart 3 |
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References
- Logan R, Delaney B. Implications of dyspepsia for the NHS. BMJ 2001; 3232: 675-677.
- Department of Health. Referral guidelines for suspected cancer. www.dh.gov.uk/assetRoot/04/01/44/21/04014421.pdf
- Delaney B, Moayyedi P & Forman D. Helicobacter pylori infection. Clin Evid 2002; 7: 414-428
- National Institute for Clinical Excellence. Guidance on the use of proton pump inhibitors in the treatment of dyspepsia. Technology Appraisal Guidance No. 7, July 2000
- National Prescribing Centre. Managing dyspepsia: the role of Helicobacter pylori. MeReC Bulletin 2001; 12: 1-4
- Gotzsche P. Non-steroidal anti-inflammatory drugs. Clin Evid 2002; 7: 1063-1070
- National Institute for Clinical Excellence. Guidance on the use of cyclo-oxygenase (Cox) II selective inhibitors, celecoxib, rofecoxib, meloxicam and etodolac for osteoarthritis and rheumatoid arthritis. Technology Appraisal Guidance No. 27, July 2001
- Juni P, Rutjes A & Dieppe P. Are selective COX 2 inhibitors superior to traditional non steroidal anti-inflammatory drugs? BMJ 2002; 324: 1287-1288
- Huang J, Sridhar S & Hunt R. Role of Helicobacter pylori infection and non-steroidal anti-inflammatory drugs in peptic-ulcer disease: a meta-analysis. Lancet 2002; 359: 14-22
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Summary
- Refer urgently for further investigation patients aged over 55 years with recent onset of dyspepsia or continuous symptoms and patients with "ALARM" symptoms.
- Patients with severe GORD or who have a proven pathology should be treated with a proton pump inhibitor (PPI). Patients with mild GORD symptoms can often be managed by a "step up" strategy starting with general measures to reduce reflux and then progressing to antacids, alginates or H2-receptor antagonists if necessary.
- Patients with non-ulcer dyspepsia should not be treated routinely with PPIs.
- Eradicate H. pylori in patients with proven peptic ulcers. There is generally no need to continue treatment with a PPI after eradication of H. pylori.
- Near-patient serological tests for H. pylori are not recommended.
- Patients taking an NSAID who are at high risk of GI adverse events should either be prescribed a Cox II selective NSAID instead of a standard NSAID or they should receive misoprostol or a PPI in addition to a standard NSAID.
Treatment of Barrett's oesophagus
Following publication of this recent Centre Pages article on Drugs for Dyspepsia, a GP has contacted us to ask if we would comment on the treatment of patient's with Barrett's oesophagus. His concern was the increasing number of patients with Barrett's and whether they should be maintained on a low or high dose of a proton pump inhibitor.
The prevalence of Barrett's oesophagus varies in different reports according to how it is defined and the type of patients included. An incidence of 13% of Barrett's oesophagitis was found in a study of 428 patients with chronic GORD who received endoscopy as an initial screening procedure1. The main reason for identifying patients with Barrett's oesophagus is that they may develop oesophageal adenocarcinoma (the probability of this is between 1 in 50 and 1 in 200). There is a strong association between the severity and frequency of gastro-oesophageal reflux and the development of adenocarcinoma whether Barrett's oesophagus is present or not2.
Proton pump inhibitors are more effective than other acid suppressants for oesophagitis3. We are not aware of any studies that have shown that high doses of proton pump inhibitors prevent the transformation of Barrett's oesophagus to adenocarcinoma. Their use therefore is mainly to control symptoms. Other approaches to managing Barrett's such as endoscopic surveillance to detect early cancer have been shown to be of limited value4.
The NICE Technology Appraisal on the use of proton pump inhibitors in the treatment of dyspepsia recommends that patients who have a proven pathology such as Barrett's oesophagus should be treated with a healing dose of a proton pump inhibitor until symptoms have been controlled. After this has been achieved the dose should be stepped down to the lowest dose that maintains control of symptoms. If a patient has complicated oesophagitis (stricture, ulcer or haemorrhage), the full dose should be maintained5.
- Schnell T et al. Endoscopic screening for Barrett's oesophagitis, oesophageal adenocarcinoma and other mucosal changes in ambulatory subjects with symptomatic gastroesophageal reflux. Gastroenterol 1985; 88: 1576
- Lagergren J et al. Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 1999; 340: 825-831
- Moore RA et al. Reflux oesophagitis: quantitative systematic review of the evidence of effectiveness of proton pump inhibitors and histamine antagonists. Bandolier www.jr2.ox.ac.uk/bandolier/bandopubs/gordf/gord.htm
- Macdonald CE, Wicks AC and Playford RJ. Final results from 10 year cohort of patients undergoing surveillance for Barrett's oesophagus: observational study. BMJ 2000; 321: 1252-1255
- National Institute for Clinical Excellence. Guidance on the use of proton pump inhibitors in the treatment of dyspepsia. Technology Appraisal Guidance No. 7, July 2000
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