Peptic ulcer disease: Management

Treatment aims

• Eliminate the Hp-infection - today's treatment regimens have a success rate of 90% in clinical studies, but the success rate in clincal practice is lower³⁷, and has dropped further during the latest years³⁸
• Eliminate other risk factors in peptic ulcer disease - NSAIDs, salicylates, smoking, stress

Overview of management

• A valid diagnosis
  • Ideally, treatment should be based on an endoscopic diagnosis, otherwise a lot of patients will be treated unnecessary
  • Patients with an earlier endoscopically confirmed duodenal ulcer disease and still suffering from symptoms, should be considered as infected and can be treated without going through a new endoscopy
• Treatment failures
  • Most often caused by non-compliant patients or bacterial resistance^39-41
• Consider your treatment strategy according to the following guidelines:

Incident cases of Hp-infected duodenal or gastric ulcers

• The endoscopist prescribes triple therapy (or quadruple therapy)^42-44
• Treatment effect should be actively controlled in patients with gastric ulcer

Recurrence of known, uncomplicated duodenal ulcer disease

• Re-endoscopy and Hp-tests are not necessary
• All patients should be offered treatment
• The patients can be treated by the general practitioner
• Systematic control of treatment effect is unnecessary

Recurrence of known duodenal ulcer disease with earlier complication

• Prescribe anti-Hp-therapy
• Control that the eradication of Hp has been successful

Recurrence of known gastric ulcer disease

• Assess the risk of malignancy and decide on that background whether you will treat or refer the patient to endoscopy
• If you choose to treat, the effect of the treatment should be controlled

Self treatment

• There is no scientific evidence to recommend any dietary changes
• Stop smoking, since smoking delays the healing process and increases the risk of relapse
• Avoid salicylates and NSAIDs
• A moderate intake of alcohol is not harmful
• Advice the patient temporarilly to avoid foods and drinks the patient by personal experience knows may provoke symptoms

Patient involvement in drug treatment

• The recommended treatment regimens below have a maximum success rate of 90%
• Treatment success demands that the patient follows the treatment instructions strictly
• Any forgotten tablet reduces the chances for a successful result

Medications

• Currently, there is no ideal treatment available for Hp-positive patients. A combination therapy of at least three different drugs is needed

Treatment regimens

• In the regimens below, omeprazole may be replaced by another proton pump inhibotor. The numbering of the regimens does not indicate any priority
• Some experts warn that clarithromycin should be restricted to patients who have experienced a treatment failure. In spite of that, the majority of the most frequently applied regimens include clarithromycin
• Se avsnittet nedenfor om synkende suksessrater
• Course 1
  • Omeprazole (Losec^®) 20 mg x 2
  • Metronidazole (Flagyl^®) 400 mg x 2
  • Clarithromycin (Klacid^®) 500 mg x 2
• Course 2
  • Omeprazole (Losec^®) 20 mg x 2
  • Amoxicillin (Amoxicillin^®) 500 mg (750) mg x 2
  • Clarithromycin (Klacid^®) 500 mg x 2
• Course 3
  • Omeprazole (Losec^®) 20 mg x 2
  • Amoxicillin (Amoxicillin^®) 500 mg x 2
  • Metronidazole (Flagyl^®) 400 mg x 2
• Course 4
  • Bismuth subcitrate (Denol^®) 240 mg x 2
  • Metronidazole (Flagyl^®) 400 mg x 3
  • Tetracycline (Tetracyklin^®) 500 mg x 4
• Course 5
  • Ranithidine bismuth citrate (Pylorid^®)
  • Clarithromycin (Klacid^®) 500 mg x 2
  • Possibly + amoxicillin or metronidazole
• Course 6
  • Esomeprazole (Nexium^®) 20 mg x 2
  • Clarithromycin (Klacid^®) 500 mg x 2
  • Amoxicillin (Amoxicillin^®) 1 g x 2
• Quadruple course
  • Omeprazole (Losec^®) 20 mg x 2
  • Bismuth subcitrate (Denol^®) 240 mg x 2
  • Tetracycline (Tetracyklin^®) 500 mg x 4
  • Metronidazole (Flagyl^®) 400 mg x 2
• After ended triple therapy patients with large ulcers could benefit from furter 4 weeks of treatment with a proton pump inhibitor

Triple therapy - general information

• Duration of treatment
  • Usually 7-10 days
  • In a study it was shown that one week's treatment with omeprazole, amoxicillin and clarithromycin given twice a day was just as efficacious as to weeks of treatment. Besides, the costs become lower and the treatment is less cumbersome to the patient (Ib)⁴⁵
• Treatment failure
  • Which means that Hp is not eradicated, is mostly due to patients who do not comply with the treatment instructions
• Side-effects
  • Occur quite frequently, the worst is bismuth-medications, but they are seldom serious
• Bacterial resistance
  • Both metronidazole and clarithromycin resistance is a frequent cause of treatment failure^39-40
  • Prevalence of resistance to metronidazole is about 25%⁴⁶
  • Prevalence of resistance to clarithromycin is 10-20%⁴⁶
• Success rates are falling
  • International statistics show falling success rates with conventional triple therapy. The explanation can be the increasing use of eradication regimens in the treatment of functional dyspepsia, less pathogenic types of H pylori or an increased incidence of resistance to macrolids³⁸
  • A sequential regimen is recently shown to improve the results (Ib)⁴⁷
  • Example of a sequential regimen: Proton pump inhibitor + amoxicillin 1 g for 5 days, followed by proton pump inhibitor + clarithromycin + metronidazole for 5 days
• Increased gastrooesophageal reflux after Hp-eradication?
  • It has been claimed that eradication of H pylori will increase gastrooesophageal reflux, but recent studies find few signs of that^48-51

Hp + and peptic ulcer caused by NSAID

• Acute therapy
  • Stop, if possible, the treatment with NSAID⁵²
  • Give anti-Hp-therapy
• Patients who need longterm treatment with NSAIDs
  • If the patient needs to be treated with NSAID, both misoprostol, proton pump inhibitors and a double dose of H2-antagonists seems to provide effective prophylaxis against peptic ulcer (Ia)^53-54
    • Diarrhoea is a frequent side-effect of misoprostol
  • Eradication of Hp reduces the incidence of peptic ulcer among NSAIDs-users. However, eradication is less effective than maintenancetreatment with a proton pump inhibitor with regard to protection against ulcer (Ia)⁵⁵
• Longterm treatment with lowdose of salicylate^56-57
  • Hp-positive patients should have H pylori eradicated
  • Acid reducing agent should be used prophylactic when longterm treatment with salicylate is needed
  • Salicylic acid combined with a proton pump inhibitor lowers the risk of rebleeding compared to clopidogrel used alone. The combination is also a less expensive alternative than clopidogrel used alone⁵⁸
• COX-2 specific NSAIDs?
  • Be aware of the negative effects of this group of NSAIDs
    • There is serious doubt about the safety of this subgroup of NSAIDs in comparison to conventional NSAIDs, since COX-2-inhibitors increase the frequency of thromboembolic diseases, heart failure and other oedematous disorders, and reduced liver function¹⁶
  • Reduces the number of peptic ulcers, although the risk of symptomatic ulcers, perforation and bleeding is to a very little degree affected^59-60
    • NNT = 200, which means that 200 patients have to be treated for 1 year in order to hinder the development of one ulcer⁶¹
    • COX-2-agents is so far not studied as an alternative treatment in NSAID-induced ulcers
• NSAID + SSRI
  • Use of SSRI is associated with an increased risk (RR = 3.6) of bleeding in the digestive tract^14-15
  • This risk is significantly increased it NSAIDs are used together with SSRI (RR = 12.2)

Medication in Hp -negative ulcers

• Treatment alternatives, apply also for NSAID-induced ulcers
  • H2-antagonists
  • Proton pump inhibitors
• Acid reducing treatment
  • Seems to give a more rapid and better symptomatic relief the more potent the acid inhibition is
  • Proton pump inhibitors are definitely most potent, ex. Losec 20 mg x 1
• Treatment duration
  • Should be 4-6 weeks in duodenal ulcer and 6-8 weeks in gastric ulcer
  • Longterm treatment with an acid reducing agent can be necessary in such patients
• Antithrombotic therapy in patients with earlier bleeding ulcer
  • Combination therapy with aspirin + proton pump inhibitor twice daily was in one study found to be safer thant clopidogrel with regard to bleeding in the stomach (Ib)⁶²
  • The study raises doubt about the safety of using clopidogrel (Plavix) in such patients

Ongoing bleeding from a verified peptic ulcer⁶³

• First priority is given to handling a potential shock, to establish a correct diagnosis, risk assessment (i.e. Hp-status) and determination of relevant endoscopic treatment⁶⁴
• Endoscopic haemostasis
  • Many bleedings stop spontaneously
  • Potential interventions are use of hemoclips; injection of adrenalin, alcohol or a sclerosing agent, or a combination of the methods⁶⁵
  • Risk of rebleeding is highest from ulcers with "bleeding stigmata":
    • Visible vessels, clots, a bleeding point in the bottom of the ulcer crater
    • In such situations one aims at endoscopic treatment with infiltration of adrenalin 0.1 mg/ml attenuated 1:5 with NaCl 0.9%, potentially followed by aetoxysclerol
  • In one study pantoprazole was found to be more effective than somatostatin to prevent rebleeding after a successful endoscopic hemostasis (Ib)⁶⁶
• Intravenous proton pump inhibitor?
  • In vitro trials demonstrate that hemostatic mechanisms are enhanced with a neutral pH by improving the function of the thrombocytes and restrain the fibrinolysis⁶⁴
  • In cases with less bleeding, nausea, vomiting, stenosis og acute severe oesophagitis which causes dysphagia, a proton pumb inhibitor can be given, ex. Losec 20-40 mg x 1 intravenously until the patient take liquid food, followed by oral treatment
  • Reduced rebleeding (NNT 12) and reduced need for surgery (NNT 20), but did not affect the overall mortality (Ia)^67-68
  • Since the clinical significance of acid reduction is modest, it can be just as important to get started with conventional oral ulcer treatment as soon as the condition allows it - usually within one day
• Other surgical interventions in ongoing or rebleeding episodes
  • Angiographic embolisation or surgery can be indicated⁶⁵
  • Possible gastroduodenotomi and oversewing of blood vessels with or without vagotomi and drainage of duodenal ulcer; and excision of the ulcer with vagotomi and drainage or partial gastrectomi in bleeding gastric ulcer
• Anti-Hp-therapy
  • Hp-positives should have eradication treatment⁶⁹
• Longterm prophylaxis with proton pump inhibitor or misoprostol
  • If continued treatment with salicylate or NSAID is mandatory, the patient should also be given treatment with misoprostol or PPI^70-71
• Longterm prophylaxis with H2-antagonist?
  • In patients who have suffered from a bleeding ulcer, long term prophylaxis with H2-antagonist should be considered and Hp-diagnostics performed
  • A follow-up study of patients with bleeding ulcer who were eradicated of Hp, showed no difference in prognosis between those who got protective treatment and those who did not get such treatment⁷²

In therapeutic resistant cases^{63, 73}

• Check compliance - is the patient taking the drugs as instructed?
• Is the patient taking salicylate or NSAID?
• Smokers shoud stop smoking
• Zollinger Ellison's syndrome? Measure s-gastrin
• Consider the possibility of a submucosal tumor with ulceration
• Hp-tests should be repeated. Antigen test or urea breath test?
• Consider determination of bacterial resistance in connection with endoscopy
• A second treatment regimen should not include metronidazole if the drug has been given in the initial course

Surgery

• If recurrent treatment failures with medications, consider surgery in Hp-negative patients
• Hp-positive ulcer disease should not be operated

Indications⁶³

• Perforated ulcer
  • Has traditionally been treated with open surgery, but laparoscopic interventions seem to give at least as good results - although more evidence is needed (Ia)⁷⁴
  • Treatment is started with infusion of liquid, nasogastric suction and broadspectered antibiotics intravenously
• Severe bleeding
  • Associated with a fall in bloodpressure to below 100 mm Hg in spite of infusion of blood and saline and endoscopic therapy
  • Arterial embolization can often replace surgery in ulcer bleeding⁷⁵
• Rebleeding
  • Rebleeding after an initial stop in the acute bleeding og failed endoscopic haemostasis
  • Duodenal ulcer located on the posterior wall are sometimes associated with severe bleeding which often involves arteria gastroduodenale, and in this situation endoscopic therapy is seldom sufficient
• Prolonged bleeding
  • Bleeding which lasts more than 24h and with a need for bloodtransfusion that surpasses 6 units
• Suspicion of malignancy
• Retention/pyloric stenosis
  • Acute retension responds well on nasogastric decompression, use of H2-blocker or proton pump inhibitor and eradication of H. pylori
  • Endoscopic balloon dilatation of the pylorus or surgery - vagotomi or pyloriplastic, antrectomi or gastroenterostomi - are options to alleviate chronic obstruction⁷⁶
• Unsatisfactory effect of medical treatment

Gastric ulcer⁶³

• Methods
  • Resection of the ulcer and gastroduodenostomi a.m. Bilroth I
  • Alternatively, excision of the ulcer and suture in severely ill patients
• A perforated gastric ulcer
  • Is usually treated with tegmentatio
  • Several biopsies are needed, or even better, excision of the ulcer to exclude malignancy

Duodenal ulcer⁶³

• Nearly all these patients are Hp-infected, in principle the condition should not be operated on
• General strategy
  • PGV (proximal gastric vagotomi) and resections are done only in extraordinary cases wherein medical therapy has failed
  • The type of intervention which conserves most of the stomach, is preferred
• Perforation
  • Tegmentatio
  • Thorough irrigation of the peritoneal cavity (min 2 liters)
• Bleeding
  • Longitudinal incision of the pylorus and crossectional closure
  • Closure of the bleeding vessel and identification and ligature of a. gastroduodenal on the duodenal outside, preferably on both sides
  • Alternatively, Bilroth II-resection

Post operative regimen⁶³

• Nasogastric tube should not be used as routine
• Aspiration is performed if the patient is nauseous or there are signs of gastric retention
• Patients with perforation treated with just tegmentatio, should have proton pump inhibitor 80 mg x 1 i.v. for 3 days
  • Alternatively, 3 mg/h infusion with pump, followed by oral therapy with 20 mg x 1 for 3 weeks

Prophylactic treatment

• No known treatment with regard to Hp-infection, although good hygiene and sanitation in the childhood years is of obvious significance
• Research is ongoing with regard to immunization

Ulcers caused by NSAIDs

• In patients with a predisposition for peptic ulcer, and who require longterm therapy with NSAID, there are three alternatives⁵³:
  • (1) Shift to a COX-2-inhibitor? It is uncertain how useful this is
  • (2) Combine the NSAID with misoprostol
  • (3) Combine the NSAID with a double dose of H2-antagonist or a normal dose of proton pump inhibitor

Ulcers caused by salicylates

• Salicylate + proton pump inhibitor (esomeprazole) was significantly better than clopidogrel in the prevention of rebleeding (Ib)⁶²
• Results from studies indicate that patients in need of prophylactic treatment with salicylate against cardiovascular disease should continue with salicylate + PPI in stead of clopidogrel