PACT Centre Pages - DRUGS FOR DYSPEPSIA


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Specialist referral or endoscopic investigation (to be seen within 2 weeks) is indicated for patients of any age with dyspepsia who present with any of the following alarm symptoms: chronic gastrointestinal (GI) bleeding, progressive unintentional weight loss, progressive dysphagia, persistent vomiting; or who have iron deficiency anaemia, epigastric mass or suspicious barium meal¹. Patients over 55 years with dyspepsia but no alarm symptoms do not require routine referral for endoscopy. However, they can be considered for endoscopy if symptoms persist despite Helicobacter pylori (H. pylori) testing and initial PPI therapy or where the risk of cancer is high¹. Of those patients with symptoms severe enough to require endoscopy, 40% will have GORD, 40% will have NUD and 13% will have an ulcer¹.

Uninvestigated dyspepsia
Self-treatment with an antacid and/or alginate therapy is appropriate for most patients with uninvestigated dyspepsia. However, additional therapy may be required if symptoms persistently affect a patient's quality of life. Initially patients with dyspepsia should be offered H. pylori 'test and treat' or a treatment dose of a PPI for one month; available evidence is insufficient to advise which should be offered first¹. A recent trial compared 'test and treat' to omeprazole treatment in 219 patients aged under 45 years presenting with dyspepsia without alarm symptoms. Patients received either omeprazole or eradication therapy after testing for H. pylori. The ‘test and treat’ strategy was more effective at improving symptoms and reducing referral rates for endoscopy than PPI therapy².

Gastro-oesophageal reflux disease (GORD)
GORD includes both oesophagitis determined by endoscope and endoscopy negative reflux disease. Patients with severe GORD should be offered a treatment dose of a PPI for one or two months. If symptoms recur following initial treatment then a PPI should be 'stepped down' to the lowest dose at which symptoms are controlled¹. After treatment with PPIs an increase in healing has been demonstrated compared with placebo or H2RAs³. There is no evidence that eradication of H. pylori is beneficial when symptoms of GORD recur⁴.

Lifestyle advice including avoidance of certain food or drink which exacerbates symptoms, losing weight if overweight, raising the head of the bed and stopping smoking should be offered to patients. There is limited evidence of success with these interventions in relieving GORD symptoms but they provide general health benefits.

Peptic ulcer disease (PUD)
Nearly all patients who have PUD will test positive for H. pylori: eradication therapy should be offered to these patients to reduce ulcer recurrence and increase ulcer healing¹. For patients taking NSAIDs, offer full dose PPI or H2RA therapy for one month and if H. pylori is present subsequently try eradication therapy¹. Where possible NSAIDs should be discontinued. Patients who are not receiving NSAIDs should be offered H. pylori eradication therapy first. A two-week wash out period following PPI use is necessary before testing for H. pylori. The gold standard for detecting H. pylori is a non-invasive carbon urea breath test. The breath test’s specificity results in fewer patients being inappropriately treated with eradication therapy. Laboratory based serology testing should only be used if it has already been locally validated because it performs less well than the breath test or stool antigen testing. Near patient testing is not recommended due to the inadequate performance of these tests. Patients testing positive should be prescribed a 7-day course of a PPI, and either metronidazole and clarithromycin 250mg, or an amoxicillin and clarithromycin 500mg regimen¹. Re-testing for H. pylori should always use a carbon urea breath test.

Reducing GI adverse events
NSAIDs including Cox II selective drugs cause GI adverse effects and before prescribing the risks versus benefits should be assessed. Prescribing of NSAIDs has increased by 13% in the last 5 years. In the quarter to March 2004, there were over 5 million NSAID items at a cost of £60.8 million; 1.6 million of these items were for Cox II selective drugs, costing £37.9 million. Prescription items for Cox II selective inhibitors have grown by over 500% in the past 5 years while costs have risen almost 10-fold. Using Cox II selective inhibitors rather than a standard NSAID may reduce the risk of serious GI adverse events in high risk patients. However, a recent population based study has shown that a 41% rise in NSAID use, entirely due to increased use of Cox II selective inhibitors, was accompanied by a 10% increase in hospitalisation rates for upper GI haemorrhage⁶. An observational study that investigated the burden of adverse drug reactions (ADR) as a cause of hospital admissions found NSAIDs were implicated in 30% of admissions due to an ADR (363 cases). Aspirin was the drug most often associated with adverse events. Other NSAIDs including rofecoxib and celecoxib also caused ADRs resulting in admission⁷.

The factors associated with a high risk of GI adverse events from NSAIDs include:

• age over 65 years
• use of other medicines known to increase the chance of upper GI adverse events
• serious co-morbidity
• prolonged use of maximum recommended doses of standard NSAIDs
• previous history of PUD/dyspepsia⁸.

Patients at high risk of GI adverse events who need to take an NSAID can be co-prescribed either a PPI or misoprostol, alternatively a Cox II selective NSAID can be prescribed. Compared with placebo, misoprostol significantly reduces NSAID associated gastric and duodenal ulcers found on endoscopy and reduces serious upper GI complications⁹. PPIs are the treatment of choice for H. pylori positive patients who present with a bleeding ulcer and who need to continue NSAIDs. Eradicating H. pylori before commencing an NSAID is useful in patients at high risk of PUD or with a previous history of PUD¹⁰.

Evidence from observational studies suggests that the use of selective serotonin re-uptake inhibitors (SSRIs) increases the risk of developing GI bleeding to around three times the risk for patients not using SSRIs. However, the absolute risk is small, around 3 extra episodes of upper GI bleeding requiring hospitalisation per 1,000 patient–years of treatment. SSRIs appear to carry a higher risk of bleeding in patients aged over 80 years or those with a history of GI bleeding, therefore, it is prudent to avoid SSRIs in these groups of patients or in those also taking aspirin or another NSAID¹¹.

Prescribing data
PPIs accounted for 63% (4.6 million) of items for drugs to treat dyspepsia and 86% of cost (£100.3 million), quarter to March 2004. Just over half of these items were for lansoprazole (Table 1). This drug accounted for 54% of spending on PPIs. Omeprazole was the next most commonly prescribed PPI followed by rabeprazole. During the past 5 years prescribing of PPIs has more than doubled (Chart 1). However, the increase in spending over the same period is more modest at just 29%. This is largely due to increased prescribing of lansoprazole. The Drug Tariff prices of omeprazole gastro-resistant capsules were reduced considerably in December 2003 (see price chart).

Prescribing of H2RAs has fallen by almost 28% during the past 5 years, with spending showing a 63% decrease. They now account for 16% of all items for drugs to treat dyspepsia and 9% of cost. 77% of H2RA prescribing in the quarter to March 2004 was for ranitidine (0.9 million items, £7.9 million). Cimetidine was the next most commonly prescribed at 16% of prescribing (0.2 million items) and 11% of cost (£1.1 million). Prescribing of drugs classified under the BNF section "Dyspepsia and GORD" is also decreasing (19% in the past 5 years). This group of drugs mainly consists of antacids and compound alginates. In the quarter to March 2004 there was a total of 1.5 million items, costing £5.5 million. Compound alginates accounted for 90% of items and cost. Prescribing of drugs in the BNF sub-section "Antacids and Simeticone" has almost halved in the past 5 years with only 150,000 items prescribed, quarter to March 2004.

SUMMARY

• Refer patients presenting with alarm symptoms immediately for further investigation. Patients aged over 55 years with dyspepsia but without alarm symptoms do not require routine initial referral for endoscopy.
  
• A full dose PPI should be initiated for one to two months in severe cases of GORD. If symptoms recur after initial therapy the PPI should be ‘stepped down’ to the lowest dose that controls symptoms.
  
• Treatment for non-ulcer dyspepsia should be on an ‘as needed’ basis at the lowest dose of a H2RA or PPI at which symptoms are controlled.
  
• H. pylori positive patients with peptic ulcers should receive eradication therapy.
  
• Patients who are at high risk of GI adverse events and who need to continue taking an NSAID can receive either misoprostol or a PPI with a standard NSAID or alternatively a Cox II selective NSAID.

1. National Institute for Clinical Excellence. Dyspepsia: managing adult patients in primary care. Final consultation draft. February 2004

2. Manes G, Menchise A, De Nucci C, Balzano A. Empirical prescribing for dyspepsia: randomized controlled trial of test and treat versus omeprazole treatment. BMJ 2003; 326: 1- 6

3. Clinical Evidence freelance writers. Gastro-oesophageal reflux disease. Clinical Evidence 2004;11: 588-590
4. Clinical Evidence freelance writers. Helicobacter pylori infection. Clinical Evidence 2004;11: 606-607

5. Anonymous. Should H. pylori be e radicated in non-ulcer dyspepsia? DTB 40; 3: 23-24

6. Mamdani M, Juurlink D, Kopp A, Naglie G, Austin P, Laupacis A. Gastrointestinal bleeding after the introduction of COX 2 inhibitors: ecological study. BMJ 2004; 217: 1415-1416

7. Pirmohamed M, James S, Meakin S, Green C, Scott A K, Walley T J, et al. Adverse drug reactions as a cause of admission to hospital: prospective analysis of 18,820 patients. BMJ 2004; 329: 15-19

8. 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

9. Rostom A, Dube C, Wells G, et al. Prevention of NSAID-induced gastroduodenal ulcers (Cochrane Review). In: The Cochrane Library, Issue 2, 2004

10. National Prescribing Centre. NSAIDs and gastroprotection. MeReC Briefing 2002; 20: 1-4

11. Anonymous. Do SSRIs cause gastrointestinal bleeding? DTB 42; 3: 17-18