Proton pump inhibitors as first-choice therapeutic agents

If alarm symptoms are present with reflux symptoms, esophagogastroduodenoscopy should be performed. Therapy is primarily by means of proton pump inhibitors (PPI). Probatory it is justifiable if there are no alarm symptoms. According to recent studies, PPI therapy seems to be slightly superior to the surgical approach. An ulcer can only be diagnosed on upper panendoscopy. Here, too, treatment involves several weeks of PPI therapy, in addition to which the cause of the ulcer must be sought and eliminated. Testing for Helicobacter pylori can be invasive or non-invasive; in either case, eradication should be the goal.

Up to 30% of the adult population suffer from regular reflux symptoms. Women and men are equally affected and there is no age peak in the occurrence of reflux disease. The main symptom is retrosternal burning (heartburn). Other typical complaints include regurgitation of food debris, retrosternal pressure, air regurgitation, dysphagia, or epigastric burning.

In addition to the esophageal symptoms mentioned above, chronic cough, hoarseness, asthmatic symptoms, or tooth enamel erosions may also represent extraesophageal manifestations of gastroesophageal reflux disease (Table 1) [1].

Predisposing factors for gastroesophageal reflux disease are hiatal hernias and visceral obesity. Hypotensive esophageal motility disorder (for example, in scleroderma) is also a risk factor due to inadequate esophageal clearance function.

24h-impedance pH-metry as gold standard

If a patient comes to the practice with reflux symptoms, he or she should first be asked specifically about alarm symptoms (Tab. 2) . If alarm symptoms are present, esophagogastroduodenoscopy should be mandatory. Endoscopically, alternative diagnoses (especially tumors, of course) can be excluded. Furthermore, the severity of the reflux esophagitis can be assessed, which is prognostic for the further course of the reflux disease and important for the expected response to therapy with proton pump inhibitors (PPI).

In the absence of alarm symptoms, probationary therapy with a PPI at a dosage of 20-40 mg/d for four weeks is primarily acceptable. In the absence of improvement after four weeks, the PPI should be increased to twice the standard dose and the patient should be scheduled for esophagogastroduodenoscopy.

Pathologic gastroesophageal reflux may still be present with unremarkable endoscopic findings. This is referred to as non-erosive gastroesophageal reflux disease (NERD). This diagnosis can only be made by 24h impedance pH-metry.  24-h impedance pH-metry is the gold standard in the diagnosis of gastroesophageal reflux disease. Also possible extraesophageal symptoms should – if the endoscopy is unremarkable – be further clarified with regard to gastroesophageal reflux disease by means of 24h impedance pH-metry due to the broad differential diagnosis.

Thus, this method demonstrated that PPIs suppress gastric acid but do not reduce the number of (nonacidic) reflux episodes. These are a common cause of persistent symptoms during therapy. Figure 1 shows an acid reflux episode during 24h impedance pH-metry.
Approximately 50% of patients with typical reflux symptoms but lack of PPI response and unremarkable endoscopy do not have gastroesophageal reflux disease [2].

Lifestyle measures and PPI

Lifestyle changes can reduce the frequency and severity of reflux symptoms. Non-drug therapeutic approaches aim at weight reduction, avoidance of meals shortly before going to bed, upper body elevation, and individual avoidance of triggering foods and beverages [3].

PPIs are the treatment of choice in patients with gastroesophageal reflux disease. PPIs are clearly superior to histamine-2 receptor blockers in terms of healing of reflux esophagitis and symptom relief. The efficacy of all available PPIs is essentially the same. If there is a good response to four to six weeks of therapy, an attempt may be made to pause the PPI and switch to on-demand therapy as needed. In patients with higher grade erosive reflux esophagitis, a recurrence rate of up to 80% can be expected within one year after discontinuation of the PPI [4]. In most cases, continuous therapy with the lowest still effective dose is necessary in these cases.

A recent study in subjects with only sporadic reflux symptoms demonstrated that increased reflux symptoms occurred after discontinuation of PPI [5]. The extent to which this so-called “acid rebound” has clinical relevance is still controversial at present.
A surgical procedure (fundoplicatio) should be evaluated if…

• … Patients exhibit uncontrollable volume reflux.
• … there is a pH-metrically documented lack of gastric acid suppression under high-dose PPI use.
• … there is a good response but severe PPI intolerance.

A new paper compares PPI therapy with laparoscopic antireflux surgery. Both approaches show high remission rates after five years, with PPI therapy (92%) appearing slightly superior to surgery (85%) [6].   

Gastroduodenal ulcer disease

In over 90% of cases, gastric or duodenal ulcer is caused by infection with Helicobacter pylori and/or non-steroidal anti-inflammatory drugs. The leading symptom of ulcer disease is a burning pain in the upper abdomen (dyspepsia). If no alarm signs (Tab. 2) are present, a trial of a PPI for several weeks can be performed primarily – as in gastroesophageal reflux disease.

However, an ulcer can ultimately only be diagnosed on upper panendoscopy. If one is present, six weeks of therapy with a PPI should be given. At the same time, the cause of the ulcer must be sought and eliminated.

In older people, it is often worth asking specifically about the use of non-steroidal anti-inflammatory drugs. These are often taken for years and are no longer perceived by the patient as an actual medication. For ulcer prophylaxis, concomitant use of a PPI is always recommended under NSAID therapy. Once an ulcer has been diagnosed, NSAIDs should not be used in affected individuals in the future.

Testing for Helicobacter pylori

Worldwide, about 50% of people are infected with Helicobacter pylori. A distinction is made between two forms of testing: invasive and non-invasive. That is, it must first be determined whether or not the patient requires upper panendoscopy. During upper panendoscopy, a biopsy can then be performed to look for Helicobacter pylori . If the findings are striking, a biopsy is obtained for histological examination; Helicobacter can be found with a sensitivity of 80-95%. If a histological examination of the gastric tissue is not absolutely necessary, Helicobacter pylori can be searched for by means of a rapid urease test, the sensitivity and specificity of which is 90-95%. Culture for Helicobacter pylori or search by PCR are rarely used in everyday life. Cultivation only makes sense if resistance is sought (sensitivity 70-90%, specificity 100%), PCR if uncertainty persists (sensitivity and specificity of 90-95%).

In the absence of alarm symptoms and especially if the patient originates from Asia, Africa or Southeast Europe, a non-invasive search for Helicobacter pylori is worthwhile, as the prevalence in this population group is significantly >20%. In Swiss men and women with dyspeptic complaints, the Helicobacter prevalenceis <20%. There are three options to choose from for non-invasive testing:

1. The determination of Helicobacter stool antigen(HpSA, sensitivity and specificity of 85-95%).
2. The performance of a urea breath test (sensitivity and  specificity also from 85-95%).
3. The serological clarification (sensitivity: 70-90%). 

The serological clarification is only suitable for the exclusion of an infection. The advantage of serological testing over all other invasive and non-invasive testing methods is the independence of the result from the use of a PPI. This leads to a reduction in Helicobacter activity, which is why the test can then be falsely negative. The PPI-free interval  should be at least two weeks, and after eradication, wait at least four weeks until retesting.
Whether a urea breath test or the determination of the stool antigen is performed is irrelevant with regard to sensitivity/specificity, and the costs for the two tests are also identical at around CHF 50.

Aim for eradication

In cases of proven Helicobacter infection, eradication should be pursued even in cases of low distress because of the carcinogenic potential. Longstanding standard regimens are the triple therapies with PPI 2× standard dose/d, clarithromycin 2×500 mg/d, and either amoxicillin 2×1 g/d (French regimen) or metronidazole 2×500 mg/d (Italian regimen). The optimal duration of therapy is 10-14 days.

Tolerance of antibiotic therapy is not good, so the most common reason for treatment failure is not actual antibiotic failure but insufficient patient compliance. Nevertheless, antibiotic resistance is also an increasing problem in the treatment of Helicobacter plyori infection. The most recent data show a resistance rate of 38% to clarithromycin in Austria, while the resistance rate to metronidazole is 34% throughout Europe [7]. Resistance to amoxicillin is rare at 1-2%. Table 3 summarizes recent eradication schemes. The recommendation for second-line treatment is PPI, amoxicillin, and either rifabutin (2× 150 mg/d) or levofloxacin (2× 500 mg/d) for ten days. Cultivation with resistance testing is recommended in cases of mandatory eradication success and lack of response to first- and second-line therapy. 

The necessary control of eradication success depends on the indication. In individuals with a history of ulcer disease or neoplasia, success must be monitored. In the case of purely dyspeptic complaints, retesting may be performed at recurrence.

Conclusion for practice

• In the absence of alarm symptoms, a four-week PPI trial may be tried for dyspepsia or reflux symptoms.
• The gold standard for confirming the diagnosis of gastroesophageal reflux disease is 24-hour impedance pH-metry.
• Erosive reflux disease often requires low-dose PPI continuous therapy.
• If you have upper abdominal symptoms, it is worth looking for Helicobacter pylori.
• Lack of compliance and resistance to clarithromycin and metronidazole are common causes of primary treatment failure.
• After eradication treatment, wait at least four weeks until the next test.

Literature:

1. Vakil N, et al: The Montreal definition and classification of gastroesophageal reflux disease: a global evidence-based consensus.  Am J Gastroenterol 2006; 101: 1900-1920.
2. Mainie I, et al: Acid and non-acid reflux in patients with persistent symptoms despite acid suppressive therapy: a study using combined ambulatory impedance-pH monitoring. Gut 2006; 55: 1398-1402.
3. Kahrilas PJ, et al: American Gastroenterological Association Institute technical review on the management of gastroesophageal reflux disease. Gastroenterology 2008; 135: 1392-1413.
4. Howden CW: Editorial: just how “difficult” is it to withdraw PPI treatment? Am J Gastroenterol 2010; 105: 1538-1540.
5. Reimer C, et al: Proton-pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy. Gastroenterology 2009; 137: 80-87.
6. Galmiche JP, et al: Laparoscopic antireflux surgery vs esomeprazole treatment for chronic GERD: the LOTUS randomized clinical trial. JAMA 2011; 305: 1969.
7. Megraud, et al: Helicobacter pylori resistance to antibiotics in Europe and its relationship to antibiotic consumption. Gut 2013; 62: 34-42.

HAUSARZT PRAXIS 2013; 8(9): 27-30