Peptic ulcer | Medicina Clínica (English Edition)

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          "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Eradication treatment of choice for <span class="elsevierStyleItalic">Helicobacter pylori</span>&#46;</p> <p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">&#42;PPIs&#58; proton pump inhibitors&#46; Double doses increase cure rates&#46;</p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">&#42;&#42;Pylera&#174;&#58; 1 tablet combines 140&#8239;mg bismuth subcitrate&#44; 125&#8239;mg tetracycline hydrochloride and 125&#8239;mg metronidazole&#46;</p> <p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">&#42;&#42;&#42;Dosage schedule as described in the SmPC&#59; data from the European <span class="elsevierStyleItalic">H&#46; pylori</span> Registry suggest that the dose of 4 capsules every 8&#8239;h is most effective and well tolerated&#46;</p>"
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of individuals will have a PU during their lifetime&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> The annual incidence ranges from 0&#46;3 to 1&#46;9 &#8240;&#46; Most epidemiological studies in recent decades show a decrease in the incidence of PU complications&#44;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> especially in developed countries&#46; In Europe&#44; both hospital admissions and mortality from PU have been significantly reduced over the last 20 years&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;6</span></a> This decline has been attributed to a decrease in the prevalence of <span class="elsevierStyleItalic">Helicobacter pylori &#40;H&#46; pylori&#41;</span> infection&#44; the widespread use of antisecretory drugs&#44; and a decrease in both smoking and the prescription of non-steroidal anti-inflammatory drugs &#40;NSAIDs&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#44;8</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Risk factors and pathophysiology</span><p id="par0015" class="elsevierStylePara elsevierViewall">The pathophysiology of PU is complex and multifactorial&#44; being the result of an imbalance between aggressive gastric factors&#44; such as acid and pepsin&#44; and mucosal protective factors that act as a defensive barrier&#44; such as mucus and bicarbonate&#46; Thus&#44; ulcer formation can be caused by both increased gastric acid secretion and dysfunction of the mucosal barrier&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The most important risk factors for PU are <span class="elsevierStyleItalic">H&#46; pylori</span> infection and the use of NSAIDs and&#47;or acetylsalicylic acid &#40;ASA&#41;&#46; More than 90&#37; of duodenal ulcers and more than 70&#37; of gastric ulcers are positive for <span class="elsevierStyleItalic">H&#46; pylori&#46;</span><a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a><span class="elsevierStyleItalic">H&#46; pylori</span> infection and NSAID use independently elevate the risk of ulcer bleeding&#44; increasing the risk 1&#46;79-fold and 4&#46;85-fold&#44; respectively&#46; Furthermore&#44; synergy between the two factors has been observed&#46;<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;11</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">However&#44; not all people with <span class="elsevierStyleItalic">H&#46; pylori</span> infection and&#47;or NSAID intake will develop PUs&#46; This could be due to differences in <span class="elsevierStyleItalic">H&#46; pylori</span> virulence&#44; individual susceptibility and local inflammatory response to infection&#46; In the case of NSAIDs&#44; in addition to individual susceptibility&#44; pharmacological characteristics will determine a significantly different ability to damage the gastroduodenal mucosa&#46;</p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Pathophysiology of <span class="elsevierStyleItalic">H&#46; pylori</span> damage</span><p id="par0030" class="elsevierStylePara elsevierViewall">The mechanism by which <span class="elsevierStyleItalic">H&#46; pylori</span> causes PU is not exactly known&#46; It is accepted that the pathophysiological mechanisms of duodenal ulcer and gastric ulcer are distinct and depend on the response to <span class="elsevierStyleItalic">H&#46; pylori</span> infection&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">H&#46; pylori</span> colonises the gastric mucosa from the pylorus to the cardia&#46; In patients with duodenal ulcer&#44; inflammation of the pyloric antrum would be common&#44; leading to increased gastrin production&#44; which in turn stimulates acid secretion&#46; On the other hand&#44; the mucosa of the body - which secretes gastric acid - would be preserved and the acid hypersecretion that occurs would damage the duodenal mucosa&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">In patients with gastric ulcer&#44; however&#44; inflammation would also significantly affect the mucosa of the body&#44; damaging the glands and decreasing acid secretion&#46; Mucosal damage in this case is attributed to decreased protective factors&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">On the other hand&#44; infection with <span class="elsevierStyleItalic">H&#46; pylori</span> strains expressing virulence factors is associated with an increased risk of PU&#44; with the expression of Cag A protein&#44; which induces a strong local inflammatory response&#44; and Vac A toxin&#44; which causes vacuolar degeneration and ulceration&#44; being the two most important factors&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;13</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Pathophysiology of NSAID damage</span><p id="par0050" class="elsevierStylePara elsevierViewall">The main ulcerogenic mechanism of NSAIDs is the inhibition of the enzyme cyclooxygenase &#40;COX&#41;&#44; which in turn is the molecular mechanism of their anti-inflammatory action&#46; This enzyme has two isoforms&#44; COX-1 and COX-2&#46; COX-1 inhibition - which is constitutive - decreases the synthesis of prostaglandins involved in gastrointestinal protection&#44; reduces bicarbonate and mucus secretion and affects the integrity of the mucosal barrier&#46; A second ulcerogenic mechanism of NSAIDs is direct damage to gastric mucosal cells by accumulation in the cytoplasm&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">All this favours the development of PU&#46; COX-2 -which is inducible- develops in tissues in response to local inflammation and produces mediators of pain and inflammation&#46; Inhibition of COX-2 is responsible for the beneficial effects of NSAIDs&#46; Unlike non-selective NSAIDs that similarly inhibit both isoenzymes &#40;COX-1 and COX-2&#41;&#44; COXIBs inhibit COX-2 to a greater extent and are therefore less ulcerogenic&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">A number of factors increase the risk of developing PU and its complications in patients receiving NSAIDs&#44; usually due to decreased mucosal barrier efficacy&#46; The main risk factors are age&#44; smoking&#44; the presence of comorbidities and the concomitant use of other drugs&#44; which may influence the development of PU and its clinical course&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Clinical signs and symptoms</span><p id="par0065" class="elsevierStylePara elsevierViewall">The usual clinical features consist of dyspepsia symptoms&#44; often non-specific&#44; such as epigastric pain or discomfort&#44; commonly described as &#39;burning&#39;&#44; sometimes with a feeling of painful hunger&#46; Irradiation to the flanks or retrosternal area is rare&#46; In duodenal ulcer&#44; the pain occurs daily&#44; developing 2&#8722;3&#8239;h after ingestion&#44; wakes the patient early in the morning and is usually relieved after taking antacids or food&#46; Radiation towards the back suggests a penetrating duodenal ulcer&#46; In patients with gastric ulcer the pattern tends to be more atypical and irregular and many or all of these features may be missing&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">In most cases&#44; peptic ulcer follows a chronic relapsing course with symptomatic flares lasting several weeks&#44; often with a clear seasonal relationship &#40;predominantly spring or autumn&#41; followed by spontaneous remissions with symptom-free periods of months or years&#46; Physical examination is usually normal&#44; except for the occasional and completely non-specific epigastric tenderness&#46; Most elderly patients with PU are asymptomatic or oligosymptomatic&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;16&#44;17</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Complications of peptic ulcer disease</span><p id="par0075" class="elsevierStylePara elsevierViewall">Complications include upper gastrointestinal bleeding &#40;UGB&#41;&#44; perforation&#44; penetration and stenosis&#46;</p><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Upper gastrointestinal bleeding</span><p id="par0080" class="elsevierStylePara elsevierViewall">It is the most common complication of PU and the most common cause of non-varicose UGB&#44; accounting for 40&#37;&#8211;50&#37; of cases&#46; The most common presentation is in the form of haematemesis and&#47;or melena&#44; with or without abdominal pain&#46; Up to 15&#37; of cases may develop as rectal bleeding due to rapid transit of blood along the intestine&#44; especially after major haemorrhages&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;3&#44;18&#44;19</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Hospital admissions for UGB due to PU have decreased worldwide&#46; In Spain&#44; the incidence of hospitalisation per 100&#44;000 person-years for non-varicose UGB decreased from 54&#46;6 in 1996 to 25&#46;8 in 2005&#46; Given the lower incidence&#44; overall mortality has decreased&#44; although hospital mortality remains stable at around 5&#37; of admissions&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> The persistently high in-hospital mortality is probably due to the fact that UGB patients are now older and more often present with severe comorbidities&#44; especially cardiovascular&#46;<a class="elsevierStyleCrossRefs" href="#bib0100"><span class="elsevierStyleSup">20&#44;21</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Adequate treatment of UGB reduces mortality and is based on&#58; &#40;a&#41; adequate treatment of haemodynamic status with early and non-aggressive crystalloid infusion&#44; &#40;b&#41; a restrictive transfusion policy&#44; &#40;c&#41; the use of high-dose intravenous PPI inhibitors&#44; &#40;d&#41; early reintroduction of antiplatelet and&#47;or antithrombotic therapy and &#40;e&#41; and performance of EGD within the first 24&#8239;h&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">In case of bleeding recurrence&#44; a second endoscopic treatment is recommended&#46; Arterial embolisation is reserved for cases of persistent bleeding after endoscopic treatment or a second recurrence after two endoscopic treatments&#46; Although it depends on local availability and experience&#44; embolisation is considered preferable to surgery because of its similar efficacy and lower morbidity and mortality&#46; Surgery is therefore currently reserved for exceptional cases&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Perforation and penetration</span><p id="par0100" class="elsevierStylePara elsevierViewall">Perforation is the PU complication with the highest mortality&#44; up to 30&#37; of cases&#44; with duodenal perforation being more common than gastric perforation &#40;60&#37; vs&#46; 40&#37;&#41;&#44; typically associated with NSAID treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> The triad of sudden abdominal pain&#44; tachycardia and abdominal splinting as a sign of peritoneal irritation is characteristic&#58; this is associated with the absence of peristalsis on physical examination and increased acute phase reactants on blood tests&#46; In up to 15&#37; of perforation cases&#44; a plain chest X-ray in the standing position will not show subdiaphragmatic free air&#46; In contrast&#44; abdominal CT scan is much more sensitive &#40;98&#37;&#41; and is considered the diagnostic technique of choice&#46; Early diagnosis&#44; haemodynamic resuscitation&#44; antibiotic treatment and urgent surgical intervention are essential<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> to increase survival&#59; thus&#44; one of the factors most strongly associated with mortality is surgery delay&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Penetration is defined as invasion of the ulcer by erosion of the intestinal wall into an adjacent organ or anatomical structure&#44; with no outflow of air or intestinal contents into the peritoneum&#46; The pancreas is the most common location&#46; Patients may notice changes in the characteristics of the pain&#44; e&#46;g&#46;&#44; an increase in intensity that does not improve with food or medication&#44; or back irradiation&#46; Diagnosis is confirmed by abdominal CT scan and treatment is usually surgical&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Stenosis</span><p id="par0110" class="elsevierStylePara elsevierViewall">Duodenal cap or pyloro-antral stenosis is the least common complication of PU&#44; accounting for 5&#37;&#46; Until the 1970s&#44; PU was the most common cause of gastric obstruction&#46; Today&#44; however&#44; the main cause of stricture is antral neoplasm&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> Symptomatology consists of nausea&#44; vomiting&#44; early satiety&#44; anorexia and weight loss&#46; Diagnosis is made by EGD and biopsy and initial treatment should be with high-dose intravenous PPIs&#46; Unresponsive patients should be assessed for endoscopic dilatation&#46; However&#44; in patients with scarring fibrosis&#44; endoscopic therapy may be ineffective&#46; In these cases&#44; direct surgery -pyloroplasty or gastro-jejunostomy- can either be chosen or reserved if dilatation fails&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a></p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Diagnosis</span><p id="par0115" class="elsevierStylePara elsevierViewall">PU symptoms are often non-specific and of low predictive value&#46; The most common are dyspepsia symptoms &#40;epigastric pain or burning&#44; bloating or early satiety&#41;&#46; In patients younger than 55 years&#44; without warning signs for neoplasm and uninvestigated dyspepsia&#44; as an alternative to EGD&#44; a <span class="elsevierStyleItalic">&#39;test and treat&#39;</span> strategy is recommended&#44; which consists of performing a non-invasive test for <span class="elsevierStyleItalic">H&#46; pylori</span> and in case of a positive result&#44; implement treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> On the other hand&#44; in patients older than 55 years or with warning signs or symptoms&#44; it is recommended to perform a baseline EGD to exclude malignancy&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">30&#44;31</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">EGD is the diagnostic test of choice&#44; allowing diagnosis of PU and biopsies to rule out malignancy in the case of gastric ulcer &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; It also allows detection of <span class="elsevierStyleItalic">H&#46; pylori</span> infection by histology&#44; rapid urease test or molecular techniques&#44; useful for further treatment planning&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0125" class="elsevierStylePara elsevierViewall">Endoscopic data not only allow the diagnosis to be made&#44; but also suggest whether the aetiology is benign or malignant&#46; Duodenal ulcers are very rarely malignant and therefore do not routinely require biopsy&#46; Gastric ulcers with inflammatory margins of regular appearance suggest a benign aetiology&#46; In contrast&#44; irregular or thickened margins and&#47;or the presence of a mass raised towards the lumen suggest a malignant aetiology &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Regardless of the endoscopic appearance&#44; biopsies of the base and margins of any gastric ulcer should be performed&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> Follow-up endoscopy is also recommended to check for healing and to rule out malignant aetiology&#44; even if the previous biopsy is benign&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Treatment</span><p id="par0130" class="elsevierStylePara elsevierViewall">Initially it will include PPIs at standard doses for 4 weeks in duodenal ulcer and for 8 weeks in gastric ulcer&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">In patients with <span class="elsevierStyleItalic">H&#46; pylori</span> infection&#44; the treatment of choice for PU is eradication therapy&#44; based on a combination of several antibiotics active against H<span class="elsevierStyleItalic">&#46; pylori</span> together with a PPI&#46; The target cure rate should be at least 90&#37;&#46; According to the most recent consensus&#44; the key points for the choice of eradication therapy are<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34&#44;35</span></a>&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0140" class="elsevierStylePara elsevierViewall">Use quadruple regimens&#46; Triple therapies are not recommended because of their low efficacy in our setting&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0145" class="elsevierStylePara elsevierViewall">Extend the duration of treatment to 14 days&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0150" class="elsevierStylePara elsevierViewall">Use high doses of PPIs&#46; Use of PPIs at double doses&#44; every 12&#8239;h&#44; increases cure rates&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0155" class="elsevierStylePara elsevierViewall">In salvage regimens&#44; do not repeat antibiotics with high rates of secondary resistance such as clarithromycin or levofloxacin&#46;</p></li></ul></p><p id="par0160" class="elsevierStylePara elsevierViewall">As treatment of choice&#44; a quadruple combination with bismuth using a PPI is recommended&#44; associated with the combination of bismuth&#44; tetracycline and metronidazole in a single capsule&#46; This combination is well tolerated and achieves cure rates of over 90&#37; with only 10 days of treatment&#46; A second alternative is concomitant quadruple therapy without bismuth &#40;PPI&#44; clarithromycin&#44; amoxicillin and metronidazole&#41; for 14 days&#46; If these first-line regimens fail to cure the infection&#44; salvage treatment includes a quadruple regimen with levofloxacin &#40;PPI&#44; amoxicillin&#44; levofloxacin and bismuth&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a> In penicillin-allergic patients&#44; a quadruple regimen with bismuth and salvage therapy with a quadruple regimen of levofloxacin PPI&#44; clarithromycin and bismuth is recommended&#46; Failure of two treatment regimens makes it necessary to reconsider the indication for eradication therapy and to assess causes of non-adherence before proceeding with further lines of treatment&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a> summarises the drugs&#44; doses and duration of <span class="elsevierStyleItalic">H&#46; pylori</span> eradication treatment recommended in our setting&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0170" class="elsevierStylePara elsevierViewall">In patients with uncomplicated duodenal ulcer who do not require NSAIDs or ASA&#44; it is not recommended to maintain antisecretory therapy after completion of <span class="elsevierStyleItalic">H&#46; pylori</span> treatment&#46; In contrast&#44; in patients with gastric ulcer who do not require NSAIDs or ASA&#44; it is recommended to maintain antisecretory therapy for four to eight weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Treatment and prevention of NSAID-induced peptic ulcers</span><p id="par0175" class="elsevierStylePara elsevierViewall">In patients with NSAID-induced PUs&#44; duodenal ulcers heal after 4 weeks of treatment with a PPI and gastric ulcers heal after 6&#8211;8 weeks&#44; even if anti-inflammatory treatment is maintained&#46; PPIs reduce the risk of developing a peptic ulcer in patients receiving NSAIDs or ASA in both acute &#40;OR 0&#46;70&#44; 95&#37; CI 0&#46;24&#8211;2&#46;04&#41; and chronic &#40;OR 0&#46;32&#44; 95&#37; CI 0&#46;15&#8722;0&#46;67&#41; treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">PPIs are the treatment of choice for the prevention of PU in patients receiving NSAIDs&#44; with PPIs being superior to placebo and anti-H2 agents and equally effective than misoprostol&#44; although with better tolerance&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;38</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">The available data suggest that all PPIs provide equivalent&#44; safe and effective prophylaxis&#46; They are effective at standard doses &#40;omeprazole 20&#8239;mg&#47;day&#44; lansoprazole 30&#8239;mg&#47;day&#44; pantoprazole 40&#8239;mg&#47;day&#44; rabeprazole 20&#8239;mg&#47;day or esomeprazole 20&#8239;mg&#47;day&#41;&#44; with no evidence that higher doses are superior for either treatment or prevention of NSAID-induced gastroduodenal lesions&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> Lower doses&#44; which may decrease the efficacy of prevention&#44; are also not recommended&#46; Given its lower cost&#44; omeprazole 20&#8239;mg is the PPI of choice&#46; In patients with one or more risk factors for gastrointestinal bleeding&#44; the benefits of PPI therapy -prevention of PU- far outweigh the risk of complications of these drugs&#46; Although several studies have suggested an association between long-term PPI treatment and multiple pathologies such as bone fractures or <span class="elsevierStyleItalic">Clostridium difficile</span> infection&#44; all of them are observational&#44; the increased risk is very modest and many of the associations can be explained by the presence of confounding factors&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> Moreover&#44; no study has shown an increase in mortality associated with PPI use&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">40&#44;41</span></a> Therefore&#44; there is no justification for under-therapeutic doses&#44; avoidance or discontinuation of these drugs in accepted indications&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> That said&#44; it is clear that we cannot completely rule out potential risks and that the drug should not be used if it is not indicated&#46; Therefore&#44; as with any medicine&#44; it is important to carefully assess the benefits and risks before prescribing&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">On the other hand&#44; it is important to define the gastrointestinal and cardiovascular risks of each patient &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#44; which will allow us to select the appropriate NSAID &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46; In this regard&#44; COXIBs are associated with a lower risk of peptic complications compared to non-selective NSAIDs&#46; Their risk of gastrointestinal complications is similar to that of the association of an NSAID with PPIs&#46; However&#44; the benefits of selective COX-2 inhibitors are reduced -in fact&#44; they practically disappear- with the co-administration of low doses of ASA&#46; In these cases&#44; it would be necessary to associate a PPI to the COXIB to prevent PU&#46; The association of NSAIDs and anticoagulants significantly increase the risk of bleeding&#59; again&#44; the risk is lower with COXIBs than with non-selective NSAIDs&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0195" class="elsevierStylePara elsevierViewall">In patients at cardiovascular risk&#44; it should first be assessed whether administration is strictly necessary&#46; If it is&#44; the minimum effective dose should be used for the shortest possible time&#46; Finally&#44; NSAIDs with the best cardiovascular safety profile should be used &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Eradication of <span class="elsevierStyleItalic">H&#46; pylori</span> in patients on NSAID&#47;ASA treatment</span><p id="par0200" class="elsevierStylePara elsevierViewall">It is highly controversial whether patients on chronic treatment with NSAIDs and&#47;or ASA should be treated for <span class="elsevierStyleItalic">H&#46; pylori</span>&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">There is some evidence in favour of eradication in patients who are about to start NSAID treatment &#40;<span class="elsevierStyleItalic">naive</span>&#41;&#46; Thus&#44; a meta-analysis showed that both <span class="elsevierStyleItalic">H&#46; pylori</span> infection and the use of non-selective NSAIDs are independent risk factors for the development of PU&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> The approach will depend on whether patients are <span class="elsevierStyleItalic">na&#239;ve</span> or already on chronic NSAID therapy and whether or not they have a history of previous PU&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a> Thus&#44; in <span class="elsevierStyleItalic">na&#239;ve</span> patients with no history of PU or complications&#44; eradication of <span class="elsevierStyleItalic">H&#46; pylori</span> significantly reduces the risk of PU and ulcer bleeding<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">45&#44;46</span></a> but not in those already on chronic NSAID therapy&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">47&#44;48</span></a></p><p id="par0210" class="elsevierStylePara elsevierViewall">In patients with a history of PU or complications&#44; on chronic NSAID treatment&#44; at least 2 randomised controlled trials &#40;RCTs&#41; show that chronic PPI treatment is superior to eradication<a class="elsevierStyleCrossRefs" href="#bib0245"><span class="elsevierStyleSup">49&#44;50</span></a> and a third RCT concludes that there is no difference between eradication and PPI treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a> In NSAID <span class="elsevierStyleItalic">na&#239;ve</span> patients&#44; one RCT<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> shows that eradication is clearly superior to non-eradication in preventing PU during the six months following treatment &#40;12&#46;1&#37; vs&#46; 34&#37;&#41;&#44; although neither group received prophylactic PPI treatment in this study&#46;</p><p id="par0215" class="elsevierStylePara elsevierViewall">Therefore&#44; it is recommended to investigate and treat <span class="elsevierStyleItalic">H&#46; pylori</span> in patients who are about to start NSAID therapy &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; Eradication should be associated with prophylaxis whenever patients have any gastrointestinal risk factors &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; It is not recommended to investigate <span class="elsevierStyleItalic">H&#46; pylori</span> in patients on chronic NSAID therapy&#44; especially in those already receiving PPI prophylaxis&#46; There are no studies showing that <span class="elsevierStyleItalic">H&#46; pylori</span> eradication provides additional efficacy in reducing the risk of PU or its complications in this group of patients&#46; On the other hand&#44; this is a generally older group&#44; with comorbidity and often polypharmacy&#46; In this context&#44; the risk of bleeding after temporarily stopping PPIs to assess <span class="elsevierStyleItalic">H&#46; pylori</span> and the risk of adverse effects or interactions of eradication therapy are likely to outweigh the possible -and unproven- benefits of <span class="elsevierStyleItalic">H&#46; pylori</span> eradication&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0220" class="elsevierStylePara elsevierViewall">In patients on chronic ASA treatment&#44; <span class="elsevierStyleItalic">H&#46; pylori</span> eradication has been shown to slightly reduce the risk of PU bleeding&#46;<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">53&#44;54</span></a></p><p id="par0225" class="elsevierStylePara elsevierViewall">However&#44; a meta-analysis<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a> showed that the evidence was not sufficient to conclude that <span class="elsevierStyleItalic">H&#46; pylori</span> is a risk factor for UGB in patients receiving ASA&#46; In addition&#44; an epidemiological study<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a> found neither additive nor potentiating effect between ASA and <span class="elsevierStyleItalic">H&#46; pylori</span> infection in patients with PU&#46; In an RCT in 250 high-risk patients -with a history of UGB for PU- and chronic ASA&#44; Chan et al&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> compared <span class="elsevierStyleItalic">H&#46; pylori</span> eradication versus chronic PPI&#44; with a 6-month follow-up&#46; The rate of bleeding was low in both groups&#44; 1&#46;9&#37; in patients receiving eradication treatment and 0&#46;9&#37; in patients with prophylactic PPI&#46; The differences were not significant&#44; probably due to the limited follow-up and the small number of patients&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">On the other hand&#44; there is strong evidence<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a> that the use of PPIs reduces the risk of PU and bleeding in patients on chronic treatment with NSAIDs or ASA&#46; Therefore&#44; treatment with PPIs is recommended in patients receiving ASA with gastrointestinal risk factors&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">On the other hand&#44; it is not recommended to systematically investigate and treat <span class="elsevierStyleItalic">H&#46; pylori</span> in patients receiving or about to receive ASA&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Peptic ulcer in <span class="elsevierStyleItalic">H&#46; pylori-negative</span> patients not taking NSAIDs&#47;ASA</span><p id="par0240" class="elsevierStylePara elsevierViewall">With the decreasing prevalence of <span class="elsevierStyleItalic">H&#46; pylori</span> infection&#44; some studies indicate an increased proportion of &#39;idiopathic&#39; PU&#44; i&#46;e&#46;&#44; <span class="elsevierStyleItalic">H&#46; pylori-</span>negative and not associated with NSAIDs or ASA&#46; However&#44; there is an important limitation in these studies&#44; and that is the fact that there is no objective method to assess ASA and NSAID intake&#46; In the studies&#44; this information is generally obtained during history-taking or from the medical records&#46; In a study conducted in our setting&#44; the prevalence of idiopathic PU was very low&#58; only 1&#46;6&#37; of all duodenal ulcers and 4&#46;1&#37; of all gastric ulcers were negative for NSAIDs and <span class="elsevierStyleItalic">H&#46; pylori&#46;</span><a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a></p><p id="par0245" class="elsevierStylePara elsevierViewall">The diagnosis of NSAID- and <span class="elsevierStyleItalic">H&#46; pylori-negative</span> PUs should be made only after careful exclusion of &#39;occult&#39; NSAID use and&#47;or a false negative diagnosis of <span class="elsevierStyleItalic">H&#46; pylori</span> infection&#46;</p><p id="par0250" class="elsevierStylePara elsevierViewall">In NSAIDs and <span class="elsevierStyleItalic">H&#46; pylori-negative</span> PUs&#44; the use of other drugs or toxins with ulcerogenic potential such as bisphosphonates&#44; cocaine&#44; radiotherapy or oral iron should be assessed&#46; Other causes to rule out are atypical herpes virus or cytomegalovirus infections&#44; other disorders such as Crohn&#39;s disease or malignant aetiology&#44; especially in the case of duodenal ulcers where biopsies should not be performed&#46; Lymphoma or Kaposi&#39;s sarcoma are very rare causes of ulceration and are usually related to a state of immunosuppression&#46; Another rare cause is gastrinoma &#40;Zollinger Ellison syndrome&#41;&#46; In this case&#44; patients usually have diarrhoea accompanying PU that responds to PPI treatment&#46; PU due to gastrinoma is usually severe&#44; multiple and often extends into the distal duodenum&#44; although the typical gastrinoma symptoms may be masked by previous PPI use&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Future challenges</span><p id="par0255" class="elsevierStylePara elsevierViewall">Important challenges remain in the treatment and prevention of PU&#46; These include determining the best medication combination in NSAID&#47;ASA users and&#44; above all&#44; addressing the increase in difficult-to-treat bleeding in patients with severe co-morbidity on anticoagulant therapy&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Conflict of interest</span><p id="par0260" class="elsevierStylePara elsevierViewall">Xavier Calvet has received lecture fees from Allergan&#46; Pilar Garc&#237;a-Iglesias and Isabel Laucirica declare no conflicts of interest in relation to this review&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Peptic ulcer disease &#40;PUD&#41; is a frequent pathology&#59; although the incidence has decreased in recent years&#44; it continues to be an important cause of morbidity and mortality associated with high healthcare costs&#46; The most important risk factors are <span class="elsevierStyleItalic">Helicobacter pylori</span> infection and the use of non-steroidal anti-inflammatory drugs &#40;NSAID&#41;&#46; Most patients with PUD remain asymptomatic&#44; with dyspepsia being the most frequent and often characteristic symptom&#46; It can also debut with complications such as upper gastrointestinal bleeding&#44; perforation or stenosis&#46; The diagnostic technique of choice is upper gastrointestinal endoscopy&#46; Treatment with proton pump inhibitors &#40;PPIs&#41;&#44; eradication of <span class="elsevierStyleItalic">H&#46; pylori</span> and avoiding the use of NSAIDs are the basis of treatment&#46; However&#44; prevention is the best strategy&#44; it includes an adequate indication of PPIs&#44; investigation and treatment of <span class="elsevierStyleItalic">H&#46; pylori</span>&#44; avoiding NSAIDs or using those that are less gastrolesive&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">La enfermedad ulcerosa p&#233;ptica &#40;UP&#41; es una patolog&#237;a frecuente&#59; aunque su incidencia ha disminuido en los &#250;ltimos a&#241;os&#44; sigue siendo una causa importante de morbimortalidad asociada a un elevado gasto sanitario&#46; Los factores de riesgo m&#225;s importantes son la infecci&#243;n por <span class="elsevierStyleItalic">Helicobacter pylori</span> y el uso de antiinflamatorios no esteroideos &#40;AINE&#41;&#46; La mayor&#237;a de los pacientes con UP permanecen asintom&#225;ticos&#44; siendo la cl&#237;nica m&#225;s frecuente la dispepsia&#44; a menudo caracter&#237;stica &#40;dispepsia ulcerosa&#41;&#46; Tambi&#233;n puede debutar con complicaciones como hemorragia digestiva alta&#44; perforaci&#243;n o estenosis&#46; La t&#233;cnica diagn&#243;stica de elecci&#243;n es la endoscopia digestiva alta&#46; El tratamiento con inhibidores de la bomba de protones &#40;IBP&#41;&#44; la erradicaci&#243;n de <span class="elsevierStyleItalic">H&#46; pylori</span> y evitar el consumo de AINE son la base del tratamiento&#46; Sin embargo&#44; la prevenci&#243;n es la mejor estrategia&#44; incluye una adecuada indicaci&#243;n de IBP&#44; la investigaci&#243;n y tratamiento de <span class="elsevierStyleItalic">H&#46; pylori</span>&#44; evitar los AINE o utilizar aquellos menos gastrolesivos&#46;</p></span>"
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#60;1&#46;5&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Moderate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">1&#46;5&#8722;10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">High&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Investigate and treat <span class="elsevierStyleItalic">H&#46; pylori</span>&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Do not investigate or treat <span class="elsevierStyleItalic">H&#46; pylori</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Do not investigate or treat <span class="elsevierStyleItalic">H&#46; pylori</span>&#46; PPI&nbsp;\t\t\t\t\t\t\n
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