Riesgo de resultados negativos asociados a inhibidores de la bomba de protones: revisión de las prescripciones electrónicas en pacientes polimedicados / Risk of negative results associated with proton pump inhibitors: review of electronic prescription in polymedicated patients

Introducción: El elevado consumo de inhibidores de la bomba de protones (IBP) puede incrementar la probabilidad de aparición de interacciones clínicamente relevantes. Pacientes mayores, polimedicados y pluripatológicos representan un grupo de alto riesgo. Se espera que la revisión sistemática de las prescripciones electrónicas (PE) permita detectar potenciales interacciones farmacológicas. Material y métodos: Estudio retrospectivo, transversal y observacional: revisión de las PE de IBP dispensadas entre enero y diciembre de 2015 en una farmacia comunitaria rural. Resultados: 1.186 PE, 164 pacientes (edad 65,7±17,2). Mayor número de pacientes en rango de edad 71-80 (n=52). Medicamentos por paciente: 11,0±5,6. PE IBP sin indicación aprobada: 27%. Indicación mayoritaria: protección frente a gastrolesión (77%). 29 pacientes (30%) con riesgo de resultados negativos asociados a la medicación (RNM) por omeprazol, 15 de ellos sin indicación. Patologías concomitantes más prevalentes: hipertensión arterial (n=81), dislipemia (n=61) y diabetes (n=36). Principios activos implicados: acenocumarol, hierro, cianocobalamina, escitalopram, benzodiazepinas y clopidogrel. Discusión: El 80% de las PE de omeprazol corresponde a pacientes entre 61 y 90 años, la mayoría con comorbilidad y polifarmacia, y supera el tiempo de tratamiento recomendado. Relacionamos la cronificación y el aumento del riesgo de RNM con la ausencia de un seguimiento adecuado. Muchos fármacos corresponsables del riesgo tratan los problemas de salud (PS) más prevalentes de nuestra población: la probabilidad de interacción resulta independiente de la correcta indicación del IBP. Conclusiones: La revisión de las PE permite valorar el riesgo de RNM y evaluar la información básica relativa al riesgo de interacción. Se detectaron RNM de no necesidad y de inseguridad en proporciones comparables. Un número elevado de PE de omeprazol tienden a cronificarse. Las interacciones más relevantes registradas ocurren a nivel metabólico (AU)

Introduction: Extensive use of proton pump inhibitors (PPI) can result in an increased risk of drug interactions. Aged polypharmacy patients are a source of particular concern. A systematic electronic prescription (EP) review allows detection of potential drug - drug interactions. Material and methods: Retrospective, transversal, observational study: review of e-prescription orders received during 2015 in our community pharmacy. Results: 1186 EP dispensed to 164 patients (age 65.7±17.2), 52 patients in 71-80 range. 11.0±5.6 medicines per patient. 27% IBP EP with no approved indication. 77% EP used as gastroprotective agent. As far as omeprazole is concerned, risk of negative outcomes associated with medication (NOM) detected in 29 patients (30%), 15 of them taking the drug without approved indication. Most prevalent comorbidities: hypertension (n=81), dyslipidemia (n=61) and diabetes (n=36). Drugs responsible for potential interaction: acenocoumarol, iron, cyanocobalamin, escitalopram, benzodiazepines and clopidogrel. Discussion: 80% of omeprazole EP were dispensed to patients aged 61-90. Coupled with multimorbidity and polypharmacy, the duration of the treatment exceeded directions for use in most of the cases. Chronification and increase of NOM may be due to lack of an appropriate patient follow-up procedure. Many of the drugs responsible for omeprazole interactions were prescribed to treat most prevalent health problems. Thus, risk of NOM does not appear to depend on PPI appropriate indication. Conclusions: EP review let us to assess the risk of suffering from a NOM. Reviewing pharmacokinetic PPI interaction profile allows to depict the basics for a later intervention. During EP review, safety and necessity NOMs were recorded in similar percentages. Most relevant interactions found for omeprazole occur during metabolism of the drugs (AU)

Laryngopharyngeal reflux: A confounding cause of aerodigestive dysfunction.

BACKGROUND: Laryngopharyngeal reflux (LPR) is one of the most common and important disorders of upper airway inflammation. It causes significant impairment to quality of life, and can predict serious laryngeal and oesophageal pathology, yet it remains under-diagnosed and under-treated. OBJECTIVE: This paper attempts to unravel the diagnostic dilemma of LPR and provide a practical, discriminating approach to managing this common condition. DISCUSSION: Historical red flags mandating early referral for specialist review are identified, and pathophysiology, symptomatology and common signs are reviewed. In addition, a comprehensive treatment plan consisting of lifestyle modifications, counselling aids and empirical medical therapy is proposed. A strategy for tracking clinical improvement using Belfasky's validated symptom index is included to aid counselling, compliance and follow-up.

Cost-effectiveness of histamine receptor-2 antagonist versus proton pump inhibitor for stress ulcer prophylaxis in critically ill patients*.

OBJECTIVE: To examine the cost-effectiveness of using histamine receptor-2 antagonist or proton pump inhibitor for stress ulcer prophylaxis. DESIGN: Decision analysis model examining costs and effectiveness of using histamine receptor-2 antagonist or proton pump inhibitor for stress ulcer prophylaxis. Costs were expressed in 2012 U.S. dollars from the perspective of the institution and included drug regimens and the following outcomes: clinically significant stress-related mucosal bleed, ventilator-associated pneumonia, and Clostridium difficile infection. Effectiveness was the mortality risk associated with these outcomes and represented by survival. Costs, occurrence rates, and mortality probabilities were extracted from published data. SETTING: A simulation model. PATIENTS: A mixed adult ICU population. INTERVENTIONS: Histamine receptor-2 antagonist or proton pump inhibitor for 9 days of stress ulcer prophylaxis therapy. MAIN MEASUREMENTS AND RESULTS: Output variables were expected costs, expected survival rates, incremental cost, and incremental survival rate. Univariate sensitivity analyses were conducted to determine the drivers of incremental cost and incremental survival. Probabilistic sensitivity analysis was conducted using second-order Monte Carlo simulation. For the base case analysis, the expected cost of providing stress ulcer prophylaxis was $6,707 with histamine receptor-2 antagonist and $7,802 with proton pump inhibitor, resulting in a cost saving of $1,095 with histamine receptor-2 antagonist. The associated mortality probabilities were 3.819% and 3.825%, respectively, resulting in an absolute survival benefit of 0.006% with histamine receptor-2 antagonist. The primary drivers of incremental cost and survival were the assumptions surrounding ventilator-associated pneumonia and bleed. The probabilities that histamine receptor-2 antagonist was less costly and provided favorable survival were 89.4% and 55.7%, respectively. A secondary analysis assuming equal rates of C. difficile infection showed a cost saving of $908 with histamine receptor-2 antagonists, but the survival benefit of 0.0167% favored proton pump inhibitors. CONCLUSIONS: Histamine receptor-2 antagonist therapy appears to reduce costs with survival benefit comparable to proton pump inhibitor therapy for stress ulcer prophylaxis. Ventilator-associated pneumonia and bleed are the variables most affecting these outcomes. The uncertainty in the findings justifies a prospective trial.

Diagnosing gastro-oesophageal reflux disease or lactose intolerance in babies who cry a lot in the first few months overlooks feeding problems.

This paper explores two areas in which the translation of research into practice may be improved in the management of cry-fuss behaviours in the first few months of life. Firstly, babies who cry excessively are often prescribed proton pump inhibitors, despite evidence that gastro-oesophageal reflux disease is very rarely a cause. The inaccuracy of commonly used explanatory mechanisms, the side-effects of acid-suppressive medications, and the failure to identify treatable problems, including feeding difficulty when the diagnosis of 'reflux' is applied, are discussed. Secondly, crying breastfed babies are still prescribed lactase or lactose-free formula, despite evidence that the problem of functional lactose overload is one of breastfeeding management. The mechanisms and management of functional lactose overload are discussed. These two problems of research translation need to be addressed because failure to identify and manage other causes of cry-fuss problems, including feeding difficulty, may have adverse outcomes for a small but significant minority of families.

Optogenetic inhibition of cocaine seeking in rats.

Inhibitory optogenetics was used to examine the roles of the prelimbic cortex (PL), the nucleus accumbens core (NAcore) and the PL projections to the NAcore in the reinstatement of cocaine seeking. Rats were microinjected into the PL or NAcore with an adeno-associated virus containing halorhodopsin or archaerhodopsin. After 12 days of cocaine self-administration, followed by extinction training, animals underwent reinstatement testing along with the presence/absence of optically induced inhibition via laser light. Bilateral optical inhibition of the PL, NAcore or the PL fibers in the NAcore inhibited the reinstatement of cocaine seeking.

Increasing the duration of dual amoxicillin plus omeprazole Helicobacter pylori eradication to 6 weeks: a pilot study.

BACKGROUND AND AIM: Helicobacter pylori infections have become increasingly difficult to treat as antimicrobial resistance has increased. The aim of this study was to test the hypothesis that a 6-week dual regimen of amoxicillin 1 gm and omeprazole 20 gm therapy b.i.d. would cure at least 90% of treatment-naïve H. pylori infections. METHODS: This was an open-label prospective pilot study in which treatment-naïve subjects with active H. pylori infection (positive by two tests) received dual amoxicillin 1 g and omeprazole 20 mg, b.i.d. daily for 6 weeks. Success was accessed by urea breath test 4-6 weeks later. A tentatively effective therapy was defined as a per-protocol treatment success of 90% or greater; treatment success of 80% or less was prespecified as unacceptable. RESULTS: Sixteen patients were included in the study (14 men, two women) with an average age of 49 years. At 16 patients, the prespecified stopping rule of six treatment failures was achieved (i.e. the 95% confidence interval excluded achieving the required 90% success rate even if 50 patients were entered). As per protocol, enrollment was stopped. Per-protocol and intention-to-treat treatment success were both 62.5% (95% confidence interval, 35-84%). Compliance was greater than 99%. Five patients (31%) reported side-effects, all of which were mild and none interrupted therapy. CONCLUSION: Despite the theory and pre-existing data from Japan, in the USA, prolonging the duration of dual amoxicillin-PPI therapy did not improve treatment outcome in 90% or more of our patients.

Seguridad e interacciones de los IBP / Security and interactions of PPIs

Los IBP han demostrado ser fármacos relativamente seguros después de muchos años de una amplia utilización. Las reacciones adversas con las que más frecuentemente se han asociado son leves y con escasa repercusión clínica. Inducen hipergastrinemia pero esta no se ha relacionado con una capacidad para inducir lesiones malignas Parece que pueden facilitar determinadas infecciones bacterianas a nivel digestivo y del aparato respiratorio, aunque este hecho no limita su prescripción dada la facilidad de su tratamiento. Desde el punto de vista farmacocinético se han descrito la posibilidad de interacciones con otros fármacos a nivel del citocromo P450, pero ello no parece tener mayor trascendencia clínica y terapéutica en general. Sin embargo, recientemente se está incidiendo por las agencias reguladoras en la hipotética interacción de los IBP (sobre todo omeprazol) con el clopidogrel generando una reducción en su efecto antiagregante. Aunque se debe seguir esta recomendación, necesitaria ser evaluado de forma específica para poder determinar su realidad clínica y las posibles alternativas existentes en los pacientes con riesgo de sangrado gastrointestinal. En último lugar se revisa su administración en situaciones especiales, objeto de discusión, como en la mujer embarazada o durante la lactancia materna...

Actualización en enfermedad gastrointestinal relacionada con antiinflamatorios no esteroideos / Update on gastrointestinal disorders associated with non-steroidal antiinflammatory drugs

Los estudios más recientes presentados en el congreso americanode 2008 en relación con el uso de antiinflamatoriosno esteroideos (AINE) o el ácido acetilsalicílico (AAS) y eltracto gastrointestinal han señalado un creciente interés delos investigadores por los efectos secundarios que estos fármacosinducen en el tracto gastrointestinal inferior. Así seha señalado que existe una creciente incidencia temporalde estos eventos que casi alcanza la señalada para los deltracto gastrointestinal superior, un efecto que parece extensiblea los asociados a AINE y AAS. Otro aspecto de interésse ha centrado en la deficiente cobertura gastroprotectoraque reciben las personas con factores de riesgotratadas con AINE o AAS. Diversos estudios han estudiadodiversos aspectos relacionados y han señalado que más del50% de estos pacientes no reciben terapia apropiada. Elanálisis personal indica que la edad sería el principal factorde éste déficit. El conocimiento de los factores de riesgoy las potenciales medidas de prevención entre los médicosque prescriben AINE parece adecuado al término de la residencia,pero no parece que después se ponga en práctica.La solución a este problema no parece fácil, ya que ni aundisponiendo de recordatorios y de fármacos gratuitos se alcanzanlos objetivos deseables. Una manera de cubrir estedéficit podría venir de los preparados comerciales combinados(AINE + inhibidores de la bomba de protones) queen un estudio se ha demostrado conllevan menos daño gastroduodenal,con lo que se obviaría el problema de la necesidadde prescribir ambos y el incumplimiento de los pacientes(AU)

The most recent studies presented at Digestive Disease Week2008 on non-steroidal anti-inflammatory drugs (NSAIDs)and aspirin have revealed the growing interest of investigatorsin the adverse effects of these drugs in the lower gastrointestinal(GI) tract. Some studies have shown that thereis an increasing time trend of lower GI events and a decreasingtime trend of upper GI events, and that the number ofevents associated with NSAIDs and/or aspirin located in thelower GI tract is approaching that of events located in theupper GI tract.Another area of growing research interest is the lack of appropriategastroprotective therapy in patients with risk factorswho received NSAIDS or aspirin. Several studies haveinvestigated diverse aspects related to this area and most indicatethat at least 50% of at-risk patients treated withNSAIDs (or aspirin) do not receive appropriate gastroprotectivetherapy.A personal analysis of the data suggests thatthe risk factor most frequently associated with lack of gastroprotectionis age.Knowledge of risk factors and potential therapeutic measuresare appropriate among senior residents, but is not subsequentlytranslated into clinical practice.There is no easysolution to this problem since, even within the best conditionsof a mega-trial (MEDAL trial) with free available gastroprotectionand intervention during the trial, investigatorscould not reach reasonable gastroprotection rates inat-risk patients.One potential solution may come from combinationpills (e.g. NSAID+proton pump inhibitor). Onestudy showed that this combination was associated with fewergastroduodenal lesions and could avoid the need toprescribe a gastroprotective agent and poor compliance(AU)

Cisapride and ventricular arrhythmia.

AIMS: We aimed to examine the association between cisapride and ventricular arrhythmia, and examine the relationship to dose and CYP3A4 inhibitors. METHODS: A nested case-control study was conducted in Medicaid beneficiaries exposed to cisapride, metoclopramide or a proton pump inhibitor (PPI) from 1999 to 2000. Cases were hospitalized with a principal International Classification of Diseases-9 code indicating sudden cardiac death or ventricular arrhythmia. Controls had at least as much event-free person time following the study prescription as its matched case. RESULTS: A total of 145 cases and 7250 controls were identified. The unadjusted rate ratio for cisapride vs. PPIs was 1.49 (95% confidence interval 0.96, 2.25). The adjusted odds ratio (OR) for cisapride vs. PPIs was 2.10 (1.34, 3.28). Excluding persons in managed care, the adjusted OR for cisapride was 2.92 (1.55, 5.49). In the initial prescription period, the adjusted OR for cisapride vs. PPIs was 7.85 (1.95, 31.60). Non-arrhythmogenic CYP3A4 inhibitors were not associated with an increased risk in users of cisapride or PPI inhibitors. The OR for potentially arrhythmogenic CYP3A4 inhibitors was 3.79 (1.76, 8.15) in cisapride users and 3.47 (2.06, 5.83) in PPI users. CONCLUSIONS: Cisapride was associated with a doubling to tripling of the risk of hospitalization for ventricular arrhythmia, and a nearly eightfold risk in the initial prescription period. Although use of potentially arrhythmogenic CYP3A4 inhibitors was associated with an increased risk, this appears to be due to a direct effect of the drugs themselves rather than an interaction with cisapride.

Systematic review: maintenance treatment of gastro-oesophageal reflux disease with proton pump inhibitors taken 'on-demand'.

BACKGROUND: Proton pump inhibitors (PPI) therapy 'on-demand' is often used as an alternative to continuous maintenance therapy in gastro-oesophageal reflux disease (GERD). AIM: We conducted a systematic review with the specific objectives to ascertain whether on-demand PPI therapy was effective in preventing symptomatic relapse and to assess the relative efficacy of on-demand vs. continuous PPI maintenance strategy. METHODS: Randomized-controlled clinical trials comparing on-demand PPI vs. placebo or on-demand vs. continuous PPI therapy in GERD patients were identified by searching the Medline database and the Cochrane Controlled Trials Register. RESULTS: Seventeen studies were found which met inclusion criteria. Out of the 17 studies: five investigated exclusively patients with non-erosive reflux disease (NERD), four patients with NERD and mild oesophagitis, two patients with erosive oesophagitis only, and two patients with uninvestigated GERD symptoms, respectively. Four further studies were not investigating the effectiveness of the therapies but primarily pharmacoeconomic or quality of life parameters. CONCLUSIONS: On the basis of the analysis of 17 studies, we can conclude that on-demand therapy with currently available PPI appears to be effective in the long-term management of patients with NERD or mild and uninvestigated forms of GERD, but not in patients with (severe) erosive oesophagitis.

Predictors of inappropriate utilization of intravenous proton pump inhibitors.

BACKGROUND: Inappropriate use of intravenous proton pump inhibitors is prevalent. AIM: To assess appropriateness of intravenous proton pump inhibitor prescribing. METHODS: Retrospective review of in-patient prescribing of intravenous pantoprazole over a 2-month period in 2004, in an academic centre. Prescribing was deemed appropriate before and after endoscopic haemostasis, and in fasting individuals requiring a proton pump inhibitor. RESULTS: Amongst 107 patients, 49 (46%) had upper gastrointestinal bleeding. Overall, 33 (31%, 95% CI: 22-41%) received appropriate therapy (indication, dose and duration), 61 (57%, 95% CI: 47-67%) had an inappropriate indication, and 13 (12%, 95% CI: 7-20%) had an incorrect treatment dose or duration. Therapy was appropriate in 20 (41%, 95% CI: 27-55%) with upper gastrointestinal bleeding, and 13 (22%, 95% CI: 12-33%) in the non-upper gastrointestinal bleeding group. Appropriate prescribing rates decreased (from 41% to 16%, 95% on difference CI: 14-38%) when considering intravenous proton pump inhibitor use while awaiting endoscopy as inappropriate. Significant predictors of inappropriate use were increasing age and decreasing mean daily dose, with a trend for prescriptions written during evening shifts. CONCLUSION: Inappropriate intravenous proton pump inhibitor utilization was most frequent in the non-upper gastrointestinal bleeding group, mostly for unrecognized indications. Educational interventions to optimize utilization should target prescribing in older patients, those receiving lower mean daily doses, and, perhaps, prescribing outside regular hours.

Application of lag-time into exposure definitions to control for protopathic bias.

PURPOSE: To control for protopathic bias, some studies have incorporated the concept of lag-time into their exposure definition (time period before the index date that was not considered in assessing exposure). The objective of this study was to introduce a procedure to identify the best lag-time to be applied in studies where control for protopathic bias is required. METHODS: We used data from a case-control study carried out to assess the association between exposure to proton pump inhibitors (PPIs) and risk of gastric cancer, using RAMQ databases. Exposure was defined as the number of defined daily doses of PPIs dispensed during the 5-year period prior to the index date (divided into four quartiles). Thirty-one different lag-times were applied (0-30 months) based on 1-month intervals. Logistic regression was used to estimate the matched odds ratio (OR) for each lag-time. The change point in the ln(ORs) was identified by applying a two-compartmental model and a segmented regression model. RESULTS: A trend of decreasing ORs was found with the application of an increasing lag-time. As an illustration, the ORs for the 1st quartile of defined daily doses, when applying the 31 different lag-times, ranged between 3.52 when applying a 0 lag-time and 0.97 when applying a 30 months lag-time. Applying the two methods for the different lag-times showed that the ORs stabilized at around 6 months. CONCLUSION: For the purpose of controlling for protopathic bias in pharmacoepidemiological studies, we have provided a method to assess the most appropriate lag-time that should be applied for the assessment of drug exposure.

A comparative study of intragastric acidity during post-breakfast and pre-dinner administration of low-dose proton pump inhibitors: a randomized three-way crossover study.

BACKGROUND: The absorption and bioavailability of proton pump inhibitors is influenced by food intake. Proton pump inhibitors bind to the parietal cell active proton pump, which is maximally stimulated after dinner: usually the largest meal of the day. However, it has not been fully clarified whether the efficacy of proton pump inhibitors differs between post-breakfast and pre-dinner dosing. AIM: To perform a pH-monitoring study to clarify this issue for two low-dose proton pump inhibitors. SUBJECTS AND METHODS: The subjects were 20 healthy male volunteers (seven Helicobacter pylori-positive and 13 H. pylori-negative), who were divided into two groups of 10 and administered 15 mg lansoprazole or 10 mg rabeprazole, respectively. All subjects underwent ambulatory intragastric 24-h pH- monitoring under three conditions allocated randomly: (i) without medication, (ii) seventh day of post-breakfast administration and (iii) eighth day of pre-dinner administration of each drug. RESULTS: There was no significant difference in the percentage time during which pH > or =4.0 in the 24-h period between post-breakfast and pre-dinner administration of both drugs (56.6% vs. 55.8%; P = 0.557), although intragastric acidity during administration of both drugs was significantly lower than that without medication. CONCLUSIONS: The timing of drug administration does not significantly influence the efficacy of low-dose proton pump inhibitors.

Atypical symptoms of GORD in Belgium: epidemiological features, current management and open label treatment with 40 mg esomeprazole for one month.

UNLABELLED: Frequency of atypical symptoms in patients suffering from gastro-oesophageal reflux disease (GORD) is not well known, and the optimal management of such symptoms has not been well established. Our aims were to set up an observatory of these atypical symptoms of GORD in Belgium and to study the efficacy of one month treatment with esomeprazole 40 mg. PATIENTS AND METHODS: Gastroenterologists participating in this observational survey were asked to register every new outpatient with symptoms of GORD during a period of 20 consecutive working days. All patients who reported predominant presence of atypical manifestations of GORD were documented and characterized more in detail. In patients with dominant chest pain or ENT symptoms, a treatment with esomeprazole 40 mg daily during 4 weeks was proposed. RESULTS: 90 gastroenterologists included 2864 patients consulting for symptoms suggestive of GORD, including 776 (27.1%) with dominant atypical symptoms. Endoscopy (performed in 2800 patients) showed significantly less oesophagitis in atypical than in typical GORD patients (68% vs. 81.1%; P < 0.0001). Management of atypical GORD patients appeared to be very heterogeneous. Overall 516/776 patients were included in the open phase of treatment with esomeprazole 40 mg, but data for analysis are only available in 228 patients. After one month, symptoms had disappeared in 57.1% and significantly improved in 26.6%. CONCLUSION: Atypical GORD represents a large number of consultations in gastroenterology in Belgium. It is associated with less endoscopic lesions than typical GORD. Its management is heterogeneous reflecting the lack of guidelines on this topic. Response rate after esomeprazole 40 mg for one month in this open uncontrolled trial was high. This result warrants confirmation in a placebo-controlled trial.