1059 
Although the prevalence of H pylori is decreasing in western countries, patients are becoming increasingly older with more co-morbidity and drug use. Against
this background, PUD remains a common clinical problem
Lisette G Capelle MD Department of Gastroenterology and Hepatology Ernst J Kuipers MD PhD Professor/Head of Department Department of Gastroenterology and Hepatology/Department of Internal Medicine
Erasmus MC University Medical Centre Rotterdam The Netherlands
Although the incidence of peptic ulcer disease (PUD) is declining, it still remains a common clinical problem. Due to the increasing use of nonsteroidal antiinflammatory drugs (NSAIDs) and more elderly patients who often also suffer from co-morbidity, the incidence of hospital admissions for complicated ulcers remains relatively stable. Adequate treatment, including Helicobacter pylori eradication, withdrawal of NSAIDs or gastroprotective treatment, and early endoscopy in high-risk patients are essential to reduce the admission and mortality rate of PUD.
Background
PUD remains an important clinical problem in western countries. Although exact epidemiological data are lacking, it is estimated that at least 10% of the population suffers from PUD during a lifetime. PUD can affect the stomach and proximal duodenum, but peptic ulcers can also arise in the lower oesophagus, distal duodenum and, in particular after gastrojejunostomy, in the jejunum. The predominant causes of PUD are H. pylori infection and the use of NSAIDs. Patients with an H. pylori infection have an estimated lifetime risk of 5–15% for PUD, for patients who use NSAIDs daily this risk is even higher. The ulcers are thought to result from a combination of primary mucosal damage by H. pylori gastritis or drug-related effects, enhanced by damaging effects of acid and pepsin.
Typical clinical features of PUD are episodic or persistent epigastric pain, which may be relieved by food intake. However, patients may also present with other dyspeptic symptoms, vomiting, loss of appetite, intolerance of fatty foods and heartburn. Upper gastrointestinal endoscopy is the mainstay for diagnosis.
Up until 30 years ago, PUD was a common indication for hospital admission and abdominal surgery. This was due to the high prevalence of colonisation with H pylori, and the lack of therapeutic options. However, ever since then, the incidence of PUD and hospital admissions for this condition declined substantially. This was firstly caused by the introduction of acid-suppressive drugs, starting with H2-antagonists and later followed by proton pump inhibitors (PPIs). The second major cause for the decline was the recognition of H pylori as an important aetiologic factor for PUD. This offered opportunities for antimicrobial intervention, which changed PUD from a chronic, recurrent disorder into a curable condition. Further, it turned out that the prevalence of colonisation with this bacterium was steadily decreasing in many populations as a result of improved socioeconomic circumstances over the past decades.
In The Netherlands, the number of hospital admissions for PUD decreased between 1980 and 2003 from 32.4 to 16.2 per 100,000 in men and from 21.2 to 15.7 per 100,000 in women, an effect which was due to the decreased incidence of PUD as well as changes in hospital admission practice and improved treatment options.[1] Unfortunately, the admission rate for complicated ulcers remained relatively stable during this period.[1]
Complications of PUD are bleeding, obstruction and perforation. The mortality rates in patients with such a complication remain considerable, ranging from 5% to 15%. Probable explanations for the persistently high admission rates for complicated PUD are first the increasing use of NSAIDs, in particular in elderly patients who often also suffer from co-morbidity. This effect is enhanced by the lack of prescription and use of proper gastroprotective treatment in many of these patients.[2,3] Since complicated ulcer disease is accompanied by high mortality rates and the prevalence increases with advancing age, it is expected that this common disease will continue to have an important impact on healthcare in the coming decade.
Current treatments and guidelines: H pylori -associated ulcers
Initial ulcer healing H pylori-associated ulcers heal spontaneously, but frequently recur when the infection is not cured. A recent Cochrane review described a relative risk reduction of 54% and 38%, respectively, for the recurrence of duodenal ulcers and gastric ulcers in patients treated with H pylori eradication therapy compared with patients treated with an ulcer-healing drug.4 In H pylori-associated ulcers eradication therapy for 4 to 7 days seems sufficient for ulcer healing. Continuation of acid-suppressive treatment is only needed when H pylori infection persists, although it is often given for longer periods, in particular in patients with complicated PUD.
H pylori eradication
H pylori eradication can only be successfully achieved with a combination of drugs. Such combination treatment consists of a PPI and two antibiotics, in particular including amoxicillin, clarithromycin or metronidazole (Table 1). Combinations with four drugs are also made and sometimes include bismuth compounds and tetracycline. Duration of treatment ranges from 7 to 14 days, with 14-day treatment being more effective than 7 days of treatment.[5] Increased prevalence of antimicrobial resistance in populations throughout Europe impairs the efficacy of treatment. In populations with low clarithromycin resistance, the combination of a PPI with clarithromycin and either amoxicillin or metronidazole is recommended. In populations with low metronidazole resistance a combination of a PPI with clarithromycin and metronidazole is preferred.[5] The combination of PPI, amoxicillin or tetracycline and metronidazole is a second-choice treatment. Other antibiotics such as fluoroquinolones, rifabutin and furazolidone are alternatives for patients failing first and second treatments and for those residing in high-resistance areas.[5] Recently, sequential therapy consisting of five days of treatment with a PPI and an antibiotic (usually amoxicillin) followed by five days of PPI and two other antibiotics (usually clarithromycin and a 5-nitroimidazole) has been shown to be better than PPI triple therapy, with a mean increase in eradication rate of 13–18%.[5]
NSAID-associated ulcers
NSAID-associated ulcer disease primarily asks for the consideration as to whether the NSAID can be stopped. Acid suppression by means of a PPI or other gastroprotective therapy such as misoprostol promotes ulcer healing. If it is not possible to discontinue NSAIDs, patients may be switched to a selective COX-2 inhibitor or use additional PPI as maintenance therapy. It has been demonstrated that this strategy causes fewer ulcers and fewer other important upper gastrointestinal events compared with nonselective NSAIDs.[6–8] However, the initial high expectations of this therapy have been tempered since COX-2 inhibitors demonstrated a significant increase in cardiovascular events, resulting in a withdrawal of rofecoxib from the market.[9,10]
PPIs are also effective for ulcer healing. A previous study demonstrated a healing rate of 84% and 92%, respectively, in patients with gastric or duodenal ulcers when treated with 20 mg omeprazole daily for eight weeks, compared with 64% and 81% in patients who received 150 mg ranitidine twice a day for eight weeks. The use of a higher dose of omeprazole provided no obvious advantage.[11]
[[HHE.P28]]
Currently, it is recommended to test for H pylori in NSAID users with PUD, since both NSAIDs and H pylori can increase the risk of PUD recurrence after initial healing. If NSAID users are positive for H pylori, additional H pylori eradication is recommended.[5] When patients have to continue NSAIDs, H pylori eradication has no additional benefit over PPI therapy for prevention of ulcer recurrence.[12]
Prevention of PUD in high-risk patients using NSAIDs.
The prevention of NSAID-related PUD is essential in patients. This particularly pertains to highrisk patients, including patients with a previous history of PUD, patients using corticosteroids, anticoagulants or selective serotonine reuptake inhibitors (SSRIs), the elderly (>65 years) and those with severe concomitant disease.
As both nonselective NSAIDs and COX-2 inhibitors are also associated with increased cardiovascular risk, both the GI and cardiovascular risks should be taken into account when
prescribing NSAIDs to an individual patient. Patients with low cardiovascular risk and high GI risk may be treated with COX-2 inhibitors or another conventional NSAID in combination with a PPI or misoprostol.
In patients with high cardiovascular risk and high GI risk, NSAIDs and COX-2 inhibitors should be avoided. If this is not possible, naproxen and a PPI or misoprostol can be recommended. The latter is also recommended in patients with a high cardiovascular risk and a low GI risk. No specific advice is given for patients who have both low GI and cardiovascular risks.
Complicated ulcers
Bleeding
Peptic ulcers account for 50% to 70% of cases of acute nonvariceal upper GI bleeding.[13] Patients may have symptoms of anaemia or haematemesis, and may present with haemodynamic shock.
Treatment of patients with nonvariceal upper GI bleeding requires a multidisciplinary approach, including gastroenterology, radiology and surgery. Once the haemodynamic status is stabilised, early endoscopy is required both for identification and potential treatment of the bleeding source, and for risk assessment. This determines further management, including admission, level of hospital care, drug treatment and length of hospitalisation. All risk groups, including patients with a low risk of peptic ulcer bleeding or low risk for recurrent bleeding benefit from early endoscopy.[13] Endoscopic techniques include injection sclerotherapy, application of heat (thermal or laser coagulation) or compression with mechanical clips. Although endoscopic therapy leads in most patients to a reduction in recurrent bleeding and mortality, up to 10% of patients require further radiological or surgical treatment.[14]
Perforation
Perforation occurs in 2–10% of all peptic ulcers and usually involves the anterior wall of the duodenum. 15 Patients with acute perforation have symptoms of severe abdominal pain with peritoneal irritation. Patients are treated by laparotomy, in combination with broad-spectrum antibiotics against Gram-negative rods, anaerobes and oral flora. Mortality in these patients can be 5% to as high as 40% depending on age, co-morbidities and location of perforation.
Obstruction
Due to inflammation, oedema and scarring, recurrent ulcer disease can result in stenosis of the pylorus (gastric outlet obstruction). Patients with gastric outlet obstruction have symptoms of vomiting and/or anorexia. Treatment aims
at reducing the inflammation and oedema, thus H pylori eradication or H2-antagonists and PPIs are advised. If this does not lead to sufficient symptom resolution, endoscopic balloon dilation or surgery is indicated.
Current daily clinical practice
Patients with PUD should be tested for H pylori infection.[16] Diagnostic tests for H pylori include non-invasive methods such as the 13C-urea breath test, stool antigen tests and serum ELISA, but also invasive tests based on the use of endoscopic biopsy samples that can be cultured or seen for histology. If patients are H pylori-positive, eradication treatment should be prescribed.
In patients who are using NSAIDs, discontinuation with a switch to other medications or addition of a PPI is an effective therapy.
In most countries adherence to these strict guidelines is insufficient in daily clinical practice. A Dutch survey demonstrated that only 9.2% of high-risk NSAID users received gastroprotective treatment.[3] Instruction for adherence to this treatment is essential, as the risk of an NSAID associated complication increases 16% for every 10% decline in adherence among NSAID users.[3]
In patients older than 55 with alarm symptoms, early endoscopy with endoscopic biopsies is the preferred initial approach.[16] However, despite the multiple guidelines recommending early endoscopy, a considerable proportion of patients do not receive early endoscopy. Previous studies demonstrated that early endoscopy was performed in only 76% of Canadian and 78% of Dutch patients with upper GI bleeding.[13,17] Even more so, a recent national UK survey reported that approximately 40% of hospitals in the UK were not capable of offering out-of-hours emergency endoscopy to high-risk patients (UK comparative Audit of Upper Gastrointestinal Bleeding and the use of Blood, 2007).
It is important that a team consisting of a gastroenterologist, surgeon, radiologist and nursing staff is aware that endoscopy within the first 24 hours in patients at risk of complicated ulcer disease may result in safe and prompt discharge, improve outcome and reduce resource utilisation.[13,14]
Future expectations
Although the prevalence of H pylori is decreasing in western countries, patients are becoming increasingly older with more co-morbidity and drug use. Against this background, PUD remains a common clinical problem, with an increasing prevalence of complicated ulcers. We expect that the admission rate to hospitals and mortality caused by PUD will increase and that this disease will continue to have an important impact on healthcare in the coming decade.
Conclusions
Despite the decreasing incidence of peptic ulcers, admission rates and mortality remain stable. Adequate treatment could reduce the admission rate for PUD. This treatment should include: A PPI and H pylori eradication in patients positive for H pylori. Discontinuing NSAIDs or adding gastroprotective treatment in patients who use NSAIDs chronically. Early endoscopy in patients older than 55 years or in patients with alarm symptoms.
References
1. Post PN, Kuipers EJ, Meijer GA. Declining incidence of peptic ulcer but not of its complications: a nation-wide study in The Netherlands. Aliment Pharmacol Ther 2006;23:1587-93.
2. van Leerdam ME, Vreeburg EM, Rauws EA, et al. Acute upper GI bleeding: did anything change? Time trend analysis of incidence and outcome of acute upper GI bleeding between 1993/1994 and 2000. Am J Gastroenterol 2003;98:1494-9.
3. van Soest EM, Sturkenboom MC, Dieleman JP, et al. Adherence to gastroprotection and the risk of NSAID related upper gastrointestinal ulcers and haemorrhage. Aliment Pharmacol Ther 2007;26:265-75.
4. Ford AC, Delaney BC, Forman D, et al. Eradication therapy for peptic ulcer disease in Helicobacter pylori positive patients. Cochrane Database Syst Rev 2006:CD003840.
5. Malfertheiner P, Megraud F, O’Morain C, et al. Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report. Gut 2007;56:772-81.
6. Hawkey C, Laine L, Simon T, et al. Comparison of the effect of rofecoxib (a cyclooxygenase 2 inhibitor), ibuprofen, and placebo on the gastroduodenal mucosa of patients with osteoarthritis: a randomized, double-blind, placebocontrolled trial. The Rofecoxib Osteoarthritis Endoscopy Multinational Study Group. Arthritis Rheum 2000;43:370-7.
7. Hawkey CJ, Laine L, Simon T, et al. Incidence of gastroduodenal ulcers in patients with rheumatoid arthritis after 12 weeks of rofecoxib, naproxen, or placebo: a multicentre, randomised, double blind study. Gut 2003;52:820-6.
8. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen
in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000;343:1520-8.
9. Kearney PM, Baigent C, Godwin J, et al. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ 2006;332:1302-8.
10. Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005;352:1092-102.
11. Yeomans ND, Tulassay Z, Juhasz L, et al. A comparison of omeprazole with ranitidine for ulcers associated with nonsteroidal antiinflammatory drugs. Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-associated Ulcer
Treatment (ASTRONAUT) Study Group. N Engl J Med 1998;338:719-26.
12. Hawkey CJ, Tulassay Z, Szczepanski L, et al. Randomised controlled trial of Helicobacter pylori eradication in patients on non-steroidal antiinflammatory drugs: HELP NSAIDs study. Helicobacter Eradication for Lesion Prevention. Lancet 1998;352:1016-21.
13. Barkun A, Bardou M, Marshall JK. Consensus recommendations for managing patients with nonvariceal
upper gastrointestinal bleeding. Ann Intern Med 2003;139:843-57.
14. Palmer K. Non-variceal upper gastrointestinal haemorrhage: guidelines. Gut 2002;51 Suppl 4:iv1-6.
15. Behrman SW. Management of complicated peptic ulcer disease. Arch Surg 2005;140:201-8.
16. Talley NJ, Vakil NB, Moayyedi P. American Gastroenterological Association technical review on the evaluation of dyspepsia. Gastroenterology 2005;129:1756-80.
17. Vreeburg EM, Snel P, de Bruijne JW, et al. Acute upper gastrointestinal bleeding in the Amsterdam area: incidence, diagnosis, and clinical outcome. Am J Gastroenterol
1997;92:236-43.
