Grigorios I. Leontiadis

Proton Pump Inhibitors and Risk of Fracture: A Systematic Review and Meta-Analysis of Observational Studies

OBJECTIVES:Proton pump inhibitors (PPIs) are widely used in several acid-related gastrointestinal disorders. In vivo studies have suggested that gastric suppression by PPIs could result in decreased intestinal calcium absorption. Subsequently, there have been concerns that the chronic use of a PPI is associated with an increased risk of bone fracture. However, the results of clinical studies are conflicting.METHODS:We performed a systematic review and meta-analysis of controlled observational studies to evaluate the risks of PPI use on fracture outcome. All controlled observational studies that compared fracture outcome in patients with PPI therapy with a control group were included. We calculated pooled odds ratios (ORs) using a random-effects model.RESULTS:Of 1,668 identified studies, 10 (4 cohort and 6 case–control) with 223,210 fracture cases were included in our analysis. In PPI users, compared with non/past users, the OR for hip fracture (n=9) was 1.25 (95% confidence interval (CI)=1.14–1.37). The OR for vertebral fracture (n=4) was 1.50 (95% CI=1.32–1.72) and for wrist/forearm fracture (n=3) was 1.09 (95% CI=0.95–1.24). In subgroup analysis of hip fracture, this association was observed in both high-dose and low-dose PPI exposure. When stratified by duration of exposure, the short duration of PPI use was associated with increased risk of developing hip fracture (OR=1.24; 95% CI=1.19–1.28), whereas there was no significant increase in risk of hip fracture in long-term PPI users (OR=1.30; 95% CI=0.98–1.70). There was significant statistical and clinical heterogeneity among studies for the main analysis and most of the subgroup analyses.CONCLUSIONS:Our results should be interpreted with caution. We found a modest association between PPI use and increased risk of hip and vertebral fractures, but no evidence of duration effect in subgroup analysis. However, observational studies cannot clarify whether the observed epidemiologic association is a causal effect or a result of unmeasured/residual confounding. Thus, randomized controlled studies are required to confirm or refute these results.

Clinical Practice Guidelines for the Medical Management of Nonhospitalized Ulcerative Colitis: The Toronto Consensus

BACKGROUND & AIMS The medical management of ulcerative colitis (UC) has improved through the development of new therapies and novel approaches that optimize existing drugs. Previous Canadian consensus guidelines addressed the management of severe UC in the hospitalized patient. We now present consensus guidelines for the treatment of ambulatory patients with mild to severe active UC. METHODS A systematic literature search identified studies on the management of UC. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an iterative online platform and then finalized and voted on by a working group of specialists. RESULTS The participants concluded that the goal of therapy is complete remission, defined as both symptomatic and endoscopic remission without corticosteroid therapy. The consensus includes 34 statements focused on 5 main drug classes: 5-aminosalicylate (5-ASA), corticosteroids, immunosuppressants, anti-tumor necrosis factor (TNF) therapies, and other therapies. Oral and rectal 5-ASA are recommended first-line therapy for mild to moderate UC, with corticosteroid therapy for those who fail to achieve remission. Patients with moderate to severe UC should undergo a course of oral corticosteroid therapy, with transition to 5-ASA, thiopurine, anti-TNF (with or without thiopurine or methotrexate), or vedolizumab maintenance therapy in those who successfully achieve symptomatic remission. For patients with corticosteroid-resistant/dependent UC, anti-TNF or vedolizumab therapy is recommended. Timely assessments of response and remission are critical to ensuring optimal outcomes. CONCLUSIONS Optimal management of UC requires careful patient assessment, evidence-based use of existing therapies, and thorough assessment to define treatment success.

ACG Clinical Guideline: Treatment of Helicobacter pylori Infection

Helicobacter pylori (H. pylori) infection is a common worldwide infection that is an important cause of peptic ulcer disease and gastric cancer. H. pylori may also have a role in uninvestigated and functional dyspepsia, ulcer risk in patients taking low-dose aspirin or starting therapy with a non-steroidal anti-inflammatory medication, unexplained iron deficiency anemia, and idiopathic thrombocytopenic purpura. While choosing a treatment regimen for H. pylori, patients should be asked about previous antibiotic exposure and this information should be incorporated into the decision-making process. For first-line treatment, clarithromycin triple therapy should be confined to patients with no previous history of macrolide exposure who reside in areas where clarithromycin resistance amongst H. pylori isolates is known to be low. Most patients will be better served by first-line treatment with bismuth quadruple therapy or concomitant therapy consisting of a PPI, clarithromycin, amoxicillin, and metronidazole. When first-line therapy fails, a salvage regimen should avoid antibiotics that were previously used. If a patient received a first-line treatment containing clarithromycin, bismuth quadruple therapy or levofloxacin salvage regimens are the preferred treatment options. If a patient received first-line bismuth quadruple therapy, clarithromycin or levofloxacin-containing salvage regimens are the preferred treatment options. Details regarding the drugs, doses and durations of the recommended and suggested first-line and salvage regimens can be found in the guideline.

The Toronto Consensus Statements for the Management of Inflammatory Bowel Disease in Pregnancy

BACKGROUND & AIMS The management of inflammatory bowel disease (IBD) poses a particular challenge during pregnancy because the health of both the mother and the fetus must be considered. METHODS A systematic literature search identified studies on the management of IBD during pregnancy. The quality of evidence and strength of recommendations were rated using the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. RESULTS Consensus was reached on 29 of the 30 recommendations considered. Preconception counseling and access to specialist care are paramount in optimizing disease management. In general, women on 5-ASA, thiopurine, or anti-tumor necrosis factor (TNF) monotherapy for maintenance should continue therapy throughout pregnancy. Discontinuation of anti-TNF therapy or switching from combination therapy to monotherapy may be considered in very select low-risk patients. Women who have a mild to moderate disease flare while on optimized 5-ASA or thiopurine therapy should be managed with systemic corticosteroid or anti-TNF therapy, and those with a corticosteroid-resistant flare should start anti-TNF therapy. Endoscopy or urgent surgery should not be delayed during pregnancy if indicated. Decisions regarding cesarean delivery should be based on obstetric considerations and not the diagnosis of IBD alone, with the exception of women with active perianal Crohns disease. With the exception of methotrexate, the use of medications for IBD should not influence the decision to breast-feed and vice versa. Live vaccinations are not recommended within the first 6 months of life in the offspring of women who were on anti-TNF therapy during pregnancy. CONCLUSIONS Optimal management of IBD before and during pregnancy is essential to achieving favorable maternal and neonatal outcomes.

Recent safety concerns with proton pump inhibitors.

There have been recent concerns about the safety of proton pump inhibitors (PPIs). We focus here on 3 specific concerns-the possible interaction between PPIs and clopidogrel, the postulated link between PPI use and fractures, and the possibility that long-term PPI use might lead to hypomagnesemia. There is evidence for an in vitro interaction between clopidogrel and at least some PPIs. The Food and Drug Administration (FDA) has warned against the use of certain PPIs by patients on clopidogrel. However, a randomized controlled trial that compared clopidogrel alone with the combination of clopidogrel and omeprazole found no increase in adverse cardiovascular outcomes and a reduction in the rate of adverse gastrointestinal outcomes attributable to omeprazole. PPI use may be a weak risk factor for certain fractures, but the quality of evidence is relatively poor and there is a strong possibility of confounding. The mechanism whereby PPI use might increase fracture risk is unknown. Currently, no additional measures concerning calcium supplementation or bone mineral density monitoring are recommended for patients on a PPI. The FDA has suggested monitoring serum magnesium levels in patients on PPI therapy. The mechanism and frequency of PPI-induced hypomagnesemia are unclear. PPI treatment should not be withheld from patients who genuinely require it, but the PPI should be taken in the lowest effective dose and only for as long as clinically indicated. The same is, of course, true for all medicines. The benefits of PPI therapy greatly outweigh the risks.

Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis.

OBJECTIVES:There is emerging concern that selective serotonin reuptake inhibitors (SSRIs) may be associated with an increased risk of upper gastrointestinal (GI) bleeding, and that this risk may be further increased by concurrent use of nonsteroidal anti-inflammatory (NSAID) medications. Previous reviews of a relatively small number of studies have reported a substantial risk of upper GI bleeding with SSRIs; however, more recent studies have produced variable results. The objective of this study was to obtain a more precise estimate of the risk of upper GI bleeding with SSRIs, with or without concurrent NSAID use.METHODS:MEDLINE, EMBASE, PsycINFO, the Cochrane central register of controlled trials (through April 2013), and US and European conference proceedings were searched. Controlled trials, cohort, case–control, and cross-sectional studies that reported the incidence of upper GI bleeding in adults on SSRIs with or without concurrent NSAID use, compared with placebo or no treatment were included. Data were extracted independently by two authors. Dichotomous data were pooled to obtain odds ratio (OR) of the risk of upper GI bleeding with SSRIs +/− NSAID, with a 95% confidence interval (CI). The main outcome and measure of the study was the risk of upper GI bleeding with SSRIs compared with placebo or no treatment.RESULTS:Fifteen case–control studies (including 393,268 participants) and four cohort studies were included in the analysis. There was an increased risk of upper GI bleeding with SSRI medications in the case–control studies (OR=1.66, 95% CI=1.44,1.92) and cohort studies (OR=1.68, 95% CI=1.13,2.50). The number needed to harm for upper GI bleeding with SSRI treatment in a low-risk population was 3,177, and in a high-risk population it was 881. The risk of upper GI bleeding was further increased with the use of both SSRI and NSAID medications (OR=4.25, 95% CI=2.82,6.42).CONCLUSIONS:SSRI medications are associated with a modest increase in the risk of upper GI bleeding, which is lower than has previously been estimated. This risk is significantly elevated when SSRI medications are used in combination with NSAIDs, and physicians prescribing these medications together should exercise caution and discuss this risk with patients.

Canadian Association of Gastroenterology consensus guidelines on safety and quality indicators in endoscopy

BACKGROUND Increasing use of gastrointestinal endoscopy, particularly for colorectal cancer screening, and increasing emphasis on health care quality, highlight the need for clearly defined, evidence-based processes to support quality improvement in endoscopy. OBJECTIVE To identify processes and indicators of quality and safety relevant to high-quality endoscopy service delivery. METHODS A multidisciplinary group of 35 voting participants developed recommendation statements and performance indicators. Systematic literature searches generated 50 initial statements that were revised iteratively following a modified Delphi approach using a web-based evaluation and voting tool. Statement development and evidence evaluation followed the AGREE (Appraisal of Guidelines, REsearch and Evaluation) and GRADE (Grading of Recommendations, Assessment, Development and Evaluation) guidelines. At the consensus conference, participants voted anonymously on all statements using a 6-point scale. Subsequent web-based voting evaluated recommendations for specific, individual quality indicators, safety indicators and mandatory endoscopy reporting fields. Consensus was defined a priori as agreement by 80% of participants. RESULTS Consensus was reached on 23 recommendation statements addressing the following: ethics (statement 1: agreement 100%), facility standards and policies (statements 2 to 9: 90% to 100%), quality assurance (statements 10 to 13: 94% to 100%), training, education, competency and privileges (statements 14 to 19: 97% to 100%), endoscopy reporting standards (statements 20 and 21: 97% to 100%) and patient perceptions (statements 22 and 23: 100%). Additionally, 18 quality indicators (agreement 83% to 100%), 20 safety indicators (agreement 77% to 100%) and 23 recommended endoscopy-reporting elements (agreement 91% to 100%) were identified. DISCUSSION The consensus process identified a clear need for high-quality clinical and outcomes research to support quality improvement in the delivery of endoscopy services. CONCLUSIONS The guidelines support quality improvement in endoscopy by providing explicit recommendations on systematic monitoring, assessment and modification of endoscopy service delivery to yield benefits for all patients affected by the practice of gastrointestinal endoscopy.

The risks of PPI therapy

PPIs have become one of the most commonly used medications worldwide, as they are the treatment of choice for several acid-related gastrointestinal disorders. However, concerns have been raised about PPI therapy, including the risk of pneumonia, bone fractures and enteric infections, and a possible interaction with clopidogrel that could increase the risk of cardiovascular events. Observational studies have shown very modest associations between PPI therapy and these risks, although the association between PPI treatment and the risk of enteric infections seems to be stronger than the association with other risk factors. However, given the inherent limitations of observational studies, these associations could be attributable to bias and/or confounding factors. In addition, evidence from randomized, controlled trials does not support a clinically significant effect of PPI therapy on the risk of cardiovascular events in patients taking clopidogrel or the risk of pneumonia. Nevertheless, it is impossible to exclude the possibility that some of these associations might be causal or indeed that PPI therapy has an as yet unknown long-term adverse effect. As with any therapy, therefore, it is advisable to prescribe PPIs only to patients for whom these drugs have been proven beneficial.

Systematic Review of the Symptom Burden, Quality of Life Impairment and Costs Associated with Peptic Ulcer Disease

BACKGROUND Management of peptic ulcer disease has improved over the past few decades. However, the widespread use of nonsteroidal anti-inflammatory drugs and low-dose acetylsalicylic acid means that the burden of peptic ulcer disease remains a relevant issue. METHODS We systematically searched PubMed and EMBASE for articles published 1966-2007 that reported symptoms, impairment of well-being or health-related quality of life, and costs associated with peptic ulcer disease. RESULTS Thirty studies reported the prevalence of patient-reported gastrointestinal symptoms in individuals with endoscopically diagnosed symptomatic peptic ulcer disease. Average prevalence estimates, weighted by sample size, were 81% (95% confidence interval [CI], 77%-85%) for abdominal pain (11 studies), 81% (95% CI, 76%-85%) for pain specifically of epigastric origin (14 studies), and 46% (95% CI, 42%-50%) for heartburn or acid regurgitation (11 studies). On average, 29% (95% CI, 25%-34%) of patients with peptic ulcer disease presented with bleeding, often as the initial symptom (11 studies). Patients with peptic ulcer disease had significantly lower health-related quality of life than the general population, as measured by the Psychological General Well-Being index (P <.05; 7 studies) and the Short-Form-36 questionnaire (P <.05; 2 studies). Direct medical costs of peptic ulcer disease based on national estimates from several countries were USD163-866 per patient. The most costly aspects of peptic ulcer disease management were hospitalization and medication. Complicated peptic ulcer disease is particularly costly, estimated to be USD1883-25,444 per patient. CONCLUSION Peptic ulcer disease significantly impairs well-being and aspects of health-related quality of life, and is associated with high costs for employers and health care systems.

Effect of comorbidity on mortality in patients with peptic ulcer bleeding: systematic review and meta-analysis.

OBJECTIVES:By systematic review and meta-analysis, we sought to assess the impact of comorbidity on short-term mortality in patients with peptic ulcer bleeding (PUB).METHODS:We conducted systematic searches in PubMed and Embase (January 1989–January 2010). Relative risks (RRs) were pooled across selected studies and an analysis of diagnostic test accuracy was performed to validate the results further.RESULTS:Of 1,572 identified studies, 16 were eligible for inclusion. Only three had a low risk of bias and the overall quality of evidence was low. The risk of death (30-day or in-hospital mortality) was significantly greater in PUB patients with comorbidity than in those without (RR: 4.44; 95% confidence interval (CI): 2.45–8.04). The pooled sensitivity for comorbidity predicting death in patients with PUB was 0.86 (95% CI: 0.66–0.95) and the pooled specificity was 0.53 (95% CI: 0.40–0.65). PUB patients with three or more comorbidities had a greater risk of dying than those with one or two (RR: 3.46; 95% CI: 1.34–8.89). All individual comorbidities that we assessed significantly increased the risk of death associated with PUB. However, RRs were higher for hepatic, renal, and malignant disease (range: 4.04–6.33; no significant heterogeneity) than for cardiovascular and respiratory disease and diabetes (2.39, 2.45, and 1.63, respectively; no significant heterogeneity).CONCLUSIONS:Underlying comorbidity is consistently associated with increased mortality in patients with PUB. The number and type of comorbidities in patients with PUB should be carefully evaluated and factored into initial management strategies.