Proton pump inhibitors increase significantly the risk of Clostridium difficile infection in a low-endemicity, non-outbreak hospital setting

Background  Proton pump inhibitors (PPI) have been linked to higher risk of Clostridium difficile infection (CDI). The relevance of this association in hospitals with low disease activity, where an outbreak strain is nondominant, has been assessed in relatively few studies.
Aim  To assess the association of PPI and CDI in a setting of low disease activity.
Methods  A retrospective cohort study was conducted at two hospitals. Patients admitted for ≥7 days receiving antibiotics were included. Demographics, exposure to PPI, antibiotics and other drugs in relation to diagnosis of CDI were assessed by univariate and multivariate analyses.
Results  Of 14 719 patients, 149 (1%) first episode CDI were documented; PPI co-exposure increased CDI [1.44 cases/100 patients vs. 0.74 cases/100 non-exposed (OR: 1.96, 95% CI: 1.42–2.72)]. By logistic regression, PPI days (adjusted OR: 1.01 per day, 95% CI: 1.00–1.02), histamine-2 blockers, antidepressants, antibiotic days, exposure to medications, age, admission service and length of admission were significant predictors.
Conclusions  A statistically significant increase in CDI was observed in antibiotic recipients who received PPI, but the absolute risk increase is modest. In settings of with low rates of CDI, the benefit of PPI therapy outweighs the risk of developing CDI. These data support programmes to decrease inappropriate use of PPI in hospitalized patients.     

Comparison of risk factors and clinical responses to proton pump inhibitors in patients with erosive oesophagitis and non-erosive reflux disease

Background  There has been no report on the response to proton pump inhibitor (PPI) therapy and on-demand or the relapse rate of non-erosive reflux disease (NERD) and erosive oesophagitis in Korea.
Aim  To compare the risk factors, clinical symptoms and PPI responses between patients with erosive oesophagitis and NERD patients.
Methods  A survey was performed prospectively in the erosive oesophagitis (205 patients) and NERD group (200 patients). Clinical symptoms, risk factors and PPI responses were analysed. On-demand therapy and the relapse rate of GERD symptoms were investigated during a one-year follow-up.
Results  BMI ≥ 25 (OR 3.0, 95% CI 1.1–8.3), alcohol use (OR 2.9, 95% CI 1.0–8.3), hiatal hernia (OR 5.0, 95% CI 1.2–20) and triglyceride ≥150 mg/dL (OR 4.0, 95% CI 1.7–10) were more common in the erosive oesophagitis group than in the NERD group by multivariate analysis. The ratio of oesophageal to extra-oesophageal symptoms was higher in the erosive oesophagitis group compared with the NERD group ( P  <   0.001). The PPI response rates at 8 weeks were different ( P  =   0.02); refractory rates were higher in the NERD group (16.7%) compared with the erosive oesophagitis group (6.0%). However, there was no significant difference between the two groups in on-demand therapy or the relapse rate.
Conclusion  These results suggest that the underlying pathogenic mechanisms of erosive oesophagitis and NERD are distinct.     

Factors influencing long-term changes in mental health after interferon-alpha treatment of chronic hepatitis C

Background  Antiviral treatment with interferon-alpha (IFN-α) is associated with several acute psychiatric side effects. Little is known about long-term effects on mental health after treatment independent from viral response and the influence of pre-existing psychiatric risk-factors.
Aim  To evaluate long-term effects of antiviral treatment with interferon-alpha (IFN-α) on mental health in patients with psychiatric risk factors.
Method  We prospectively investigated long-term mental health changes in 81 hepatitis C virus-infected patients. Psychiatric outcome was measured with the Montgomery–Asberg Depression Scale (MADRS), Brief Psychiatric Rating Scale, the Global Social Functioning Scale and the Global Clinical Impression Scale 6 months after the end of antiviral treatment with IFN-α and ribavirin.
Results  Six months after antiviral therapy, 49% of the patients showed a worsening and 27.2% an improvement of depression scores. The most important predictor for a long-term improvement of depression scores was a pre-treatment MADRS score ≥5 (OR 14.21, 95% CI: 2.51–81.30). Patients with pre-existing psychiatric disorders (OR = 0.117, 95% CI: 0.024–0.558), methadone substitution (OR = 0.20, 95% CI: 0.045–0.887) or genotype 2/3 (OR = 0.341, 95% CI: 0.138–0.845) were significantly less likely to show a long-term worsening of depressive symptoms.
Conclusions  Pre-existing psychiatric risk factors increase the chance for a long-term improvement and reduce the risk for a long-term worsening of mental health after antiviral treatment of chronic hepatitis C with IFN-α.     

Increased health costs from mandated Therapeutic Substitution of proton pump inhibitors in British Columbia

Background  In 2003, British Columbia's PharmaCare programme implemented a drug reimbursement policy called Therapeutic Substitution, which required patients with acid-related diseases, primarily gastro-oesophageal reflux disease (GERD), to make a medically unnecessary switch from their prescribed proton pump inhibitor (PPI) to the cheapest available brand name PPI (Pariet, rabeprazole sodium), comprising a different (nongeneric) chemical.
Aim  To evaluate the independent effects of PPI Therapeutic Substitution on individual healthcare utilization among those complying with the policy.
Methods  We used the BC Ministry of Health Services' individual-level linked data, allowing isolation of healthcare utilization for the entire population of PPI consumers from 2002 to 2005.
Results  After controlling for individual case variation in age, gender and a proxy for pre-existing health status, regression analysis revealed statistically significant greater overall use of PPIs, physician services and hospital services independently associated with patients who complied with Therapeutic Substitution. Over the 3-year period 2003–2005, this represented net healthcare expenditures totalling approximately C$43.51 million (C$9.11 million in total PPI drug expenditures, C$24.65 million for physician services and C$9.75 million for hospital services).
Conclusion  Medically unnecessary drug switching caused by compliance with Therapeutic Substitution policy appears to be independently associated with higher overall healthcare utilization.     

Underutilization of gastroprotective strategies in aspirin users at increased risk of upper gastrointestinal complications

Background  Aspirin use is with an increased risk of upper gastrointestinal complications (UGICs). Proton pump inhibitors (PPIs) decrease the risk of UGICs among aspirin users. The distribution of risk factors for UGIC and PPI utilization among aspirin users remains uncharacterized.
Aim  To determine the prevalence and predictors of PPI use in high-risk aspirin users.
Methods  Using questionnaires and administrative records, we collected information on aspirin and PPI utilization and risk factors for UGICs from a stratified random sample of subjects with established cardiovascular disease. We calculated the proportion of aspirin users with UGIC risk factors and determined the prevalence of PPI use among aspirin users with risk factors. Regression analysis was used to determine predictors of PPI use among aspirin users.
Results  Overall response rate was 35%, of whom 86% were regular aspirin users. Seventy-one per cent of aspirin users had at least one risk factor (in addition to cardiac disease) for the development of UGICs. Although a history of UGIC was predictive of PPI use, 44% of aspirin users with a prior history of UGICs did not receive a concomitant PPI, and only 23% of subjects with additional UGIC risk factors were prescribed a PPI.
Conclusion  There is a high prevalence of UGIC risk factors among aspirin users, and many are not prescribed PPIs as a gastroprotective strategy.     

Risk of recurrent myocardial infarction with the concomitant use of clopidogrel and proton pump inhibitors

Aliment Pharmacol Ther 2011; 33: 77–88

Summary

Background The association between myocardial infarction (MI) and co‐administration of proton pump inhibitors (PPIs) and clopidogrel remains controversial. Aim To quantify the association between concomitant use of PPIs and clopidogrel and occurrence of recurrent MI. Methods We conducted a case–control study within a cohort of acute MI patients in PHARMO Record Linkage System (1999–2008). The cases were patients readmitted for MI. PPI exposure was categorized as current (3–1 days before MI), past (30–3 days before MI), or no use (>30 days before MI). We used conditional logistic regression analyses. Results Among 23 655 patients hospitalized following MI, we identified 1247 patients readmitted for MI. Among clopidogrel users, current PPI use was associated with an increased risk of recurrent MI (OR: 1.62, 95% CI: 1.15–2.27) when compared with no PPI use, but not when compared with past PPI use (OR: 0.95, 95% CI: 0.38–2.41). Among clopidogrel non‐users, current PPI use was associated with an increased risk of recurrent MI (OR: 1.38, 95% CI: 1.18–1.61) when compared with no PPI use. Conclusions The apparent association between recurrent MI and use of PPIs with clopidogrel depends on the design, and is affected by confounding by indication. The association is not present when (un)measured confounding is addressed by design.     

Epidemiological study of gastro-oesophageal reflux disease: reflux in spouse as a risk factor

Background  Gastro-oesophageal reflux disease (GERD) is a growing health-care problem with variable distribution.
Aim  To assess GERD prevalence and risk factors and their possible correlation with pathophysiology in a population-based study.
Methods  Individuals aged 18–65 years were enrolled through random cluster sampling in Tehran. Previously validated self-administered questionnaires were used.
Results  Of the 2500 questionnaires, 2057 were analysed (mean age: 34.8 ± 13.0 years, 55.1% female). Frequent GERD was seen in 18.2%. Minor symptoms increased prevalence. Female gender (OR: 1.55, 95% CI: 1.01–2.41), BMI >30 kg/m² (OR: 1.79, 95% CI: 1.03–3.12), less education (OR: 1.52, 95% CI: 1.02–2.27), smoking (OR: 1.83, 95% CI: 1.12–2.99), NSAID use (OR: 4.23, 95% CI: 1.66–10.74) and GERD in spouse (OR: 1.82, 95% CI: 1.18–2.82) were associated with frequent GERD on multivariable analysis. GERD in first-degree relatives (OR: 1.73, 95% CI: 1.23–2.43) and asthma (OR: 4.09, 95% CI: 1.27–13.15) correlated with infrequent GERD. Minor symptoms correlated with GERD history in first-degree relatives, coffee consumption and NSAID use. Prevalence in the past 3 months was similar to that in the past 12 months ( P  < 0.05).
Conclusions  Gastro-oesophageal reflux disease is common in Tehran. The association of 'infrequent symptoms' with GERD history in first-degree relatives and 'frequent symptoms' with GERD history in spouse may point to the presence of yet unknown precipitating environmental factors inducing GERD in a genetically susceptible host. Minor GERD symptoms seem to have independent contribution to GERD. Assessing GERD in the past 3 months predicts prevalence in the past year.     

Proton pump inhibitors reduce the long-term risk of recurrent upper gastrointestinal bleeding: an observational study

Background  Between 3% and 40% of patients surviving an episode of upper gastrointestinal bleeding (UGIB) experience a recurrence within 1 year.
Aim  To characterize further the recurrence rate of UGIB and to investigate the role of long-term acid suppressive therapy in its secondary prevention.
Methods  Recurrent cases of UGIB were identified among patients registered in The Health Improvement Network in the UK. A nested case–control analysis provided relative risk (RR) estimates of factors associated with recurrence.
Results  Of 1287 patients included, 67 (5.2%) were identified with a recurrent UGIB episode, corresponding to a recurrence rate of 17.5 per 1000 person-years during a mean follow-up of 3 years. The greatest risk of recurrence was in patients prescribed the oral anticoagulant warfarin (RR: 5.38; 95% confidence interval: 2.02–14.36). Use of a single proton pump inhibitor (PPIs) was associated with a reduced risk of recurrence (RR: 0.51; 95% confidence interval: 0.26–0.99), even in patients taking warfarin, while current use of H₂-receptor antagonists was not. After the first episode of UGIB, use of nonsteroidal anti-inflammatory drugs and aspirin was greatly reduced, preventing estimation of the risk associated with these drugs.
Conclusion  Long-term PPI therapy reduces the risk of UGIB recurrence.     

Ethnic differences in drug therapy: a pharmacogenomics perspective

This study was presented at the American College of Chest Physicians meeting in Pittsburgh (PA, USA) in October 2011. The study objective was to evaluate the association of proton pump inhibitors (PPIs) and community-acquired pneumonia (CAP). The design was a meta-analysis of nine case–controlled and cohort studies. 120,863 pneumonia cases from 1987 to 2006 were included in the meta-analysis. PubMed and Ovid Medline were searched from inception through May 2011 by two investigators independently using keywords: PPI, pneumonia, CAP, anti-ulcer, antacid, omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole. This meta-analysis only included case–controlled and cohort studies that were published in full in English and evaluated PPI use and CAP incidence. Studies were excluded if they included the following patients: pediatric, Helicobacter pylori treatment and critically ill. Bibliographies of recent review articles and systematic reviews were hand-searched. Quality of studies was assessed using the Newcastle–Ottawa Quality Assessment Scale. Two investigators independently extracted data into standardized data collection forms that were confirmed by a third investigator. Data were analyzed based on current use of PPIs, duration of PPI use (<30 days or >180 days) and PPI dose (high vs low). Overall association of PPI and CAP was analyzed using the random effects model (Comprehensive Meta analysis^® Version 2.0). Nine studies met all criteria for the primary outcome. Newcastle–Ottawa Quality Assessment Scale scores ranged from 4 to 8 out of 9. Current use of PPIs (odds ratio [OR]: 1.39; 95% CI: 1.09–1.76), PPI use <30 days (OR: 1.65; 95% CI: 1.25–2.19), PPI high dose (OR: 1.50; 95% CI: 1.33–1.68) and PPI low dose (OR: 1.17; 95% CI: 1.11–1.24) were significantly associated with CAP. There was no association between CAP and PPI use >180 days (OR: 1.10; 95% CI: 1.00–1.21). In conclusion, patients currently receiving PPIs, particularly <30 days or high dose, showed an association with CAP. Practitioners need to be vigilant about adverse effects of PPIs and consider alternative therapies.     

Are proton pump inhibitors associated with the development of community-acquired pneumonia? A meta-analysis

This study was presented at the American College of Chest Physicians meeting in Pittsburgh (PA, USA) in October 2011. The study objective was to evaluate the association of proton pump inhibitors (PPIs) and community-acquired pneumonia (CAP). The design was a meta-analysis of nine case-controlled and cohort studies. 120,863 pneumonia cases from 1987 to 2006 were included in the meta-analysis. PubMed and Ovid Medline were searched from inception through May 2011 by two investigators independently using keywords: PPI, pneumonia, CAP, anti-ulcer, antacid, omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole. This meta-analysis only included case-controlled and cohort studies that were published in full in English and evaluated PPI use and CAP incidence. Studies were excluded if they included the following patients: pediatric, Helicobacter pylori treatment and critically ill. Bibliographies of recent review articles and systematic reviews were hand-searched. Quality of studies was assessed using the Newcastle-Ottawa Quality Assessment Scale. Two investigators independently extracted data into standardized data collection forms that were confirmed by a third investigator. Data were analyzed based on current use of PPIs, duration of PPI use (<30 days or >180 days) and PPI dose (high vs low). Overall association of PPI and CAP was analyzed using the random effects model (Comprehensive Meta analysis(?) Version 2.0). Nine studies met all criteria for the primary outcome. Newcastle-Ottawa Quality Assessment Scale scores ranged from 4 to 8 out of 9. Current use of PPIs (odds ratio [OR]: 1.39; 95% CI: 1.09-1.76), PPI use <30 days (OR: 1.65; 95% CI: 1.25-2.19), PPI high dose (OR: 1.50; 95% CI: 1.33-1.68) and PPI low dose (OR: 1.17; 95% CI: 1.11-1.24) were significantly associated with CAP. There was no association between CAP and PPI use >180 days (OR: 1.10; 95% CI: 1.00-1.21). In conclusion, patients currently receiving PPIs, particularly <30 days or high dose, showed an association with CAP. Practitioners need to be vigilant about adverse effects of PPIs and consider alternative therapies.     

Systematic review: standard- and double-dose proton pump inhibitors for the healing of severe erosive oesophagitis – a mixed treatment comparison of randomized controlled trials

Background  No randomized controlled trial (RCT) has compared all European-licensed standard- and double-dose PPIs for the healing of severe erosive oesophagitis.
Aim  To compare the effectiveness of licensed doses of PPIs for healing severe erosive oesophagitis (i.e. esomeprazole 40 mg, lansoprazole 30 mg, omeprazole 20 mg and 40 mg, pantoprazole 40 mg and rabeprazole 20 mg).
Methods  Systematic review of CENTRAL, EMBASE and MEDLINE for RCTs in patients with erosive oesophagitis (completed October 2008). Endoscopically verified healing rates at 4 and 8 weeks were extracted and re-calculated if not analysed by intention-to-treat. A mixed treatment comparison was used to combine direct treatment comparisons with indirect trial evidence while maintaining randomization. Odds ratios (OR) are reported compared to omeprazole 20 mg.
Results  A total of 3021 papers were identified in the literature search; 12 were of sufficient quality to be included in the analysis. Insufficient data were available to included rabeprazole. Esomeprazole 40 mg was found to provide significantly higher healing rates at 4 weeks [OR 1.84, 95% Credible Interval (95% CrI): 1.50 to 2.22] and 8 weeks (OR 1.91, 95% CrI: 1.13 to 2.88). No other PPI investigated had significantly higher healing rates than omeprazole 20 mg.
Conclusion  Esomeprazole 40 mg consistently demonstrates higher healing rates compared with licensed standard- and double-dose PPIs.     

Prescription rates of protective co-therapy for NSAID users at high GI risk and results of attempts to improve adherence to guidelines

Background  Protective co-therapy is recommended in NSAID users with GI risk factors, but adherence is poor.
Aim  To assess the proportion of NSAID users receiving co-therapy and strategies to improve adherence.
Methods  Arthritis patients ≥50 years of age received etoricoxib or diclofenac in a double-blind randomized trial. Reminders that high-risk patients (age ≥ 65; previous ulcer/haemorrhage; corticosteroid, anticoagulant, aspirin use) should receive co-therapy were given at study initiation. Free PPI was provided. An intervention midway through the study included a written reminder and required written response regarding co-therapy.
Results  16 244/23 504 (69%) patients had GI risk factors. Pre-intervention, co-therapy was most common with previous ulcer/haemorrhage [706/1107 (64%)] and 3–4 risk factors [331/519 (64%)]. In the 10 026 patients enrolled pre-intervention and remaining in the study ≥6 months after, co-therapy in high-risk patients increased from 2958/6843 (43%) to 4177/6843 (61%) (difference = 18%; 95% CI 16%,19%). The increase was greater outside the US (22%; 19%,24%) than in the US (15%; 13%,17%).
Conclusions  Less than 50% of NSAID users with GI risk factors are given protective co-therapy – even if prescribers are given reminders and cost is not an issue. Direct communication requiring written response significantly increased adherence to guidelines, but achieving higher levels of adherence will require additional strategies.     

Low body mass not vitamin D receptor polymorphisms predict osteoporosis in patients with inflammatory bowel disease

Background  Osteoporosis is a recognized complication of inflammatory bowel disease (IBD).
Aim  To investigate the role of environmental factors and vitamin D receptor (VDR) variants on the prevalence of osteoporosis.
Methods  DEXA scans and case note review were performed on 440 IBD patients from 1997 to 2006. All the IBD patients and 240 healthy controls were genotyped for VDR variants Taq -1 and Apa -1 using PCR-RFLP.
Results  Osteoporosis and osteopenia rates were 15% and 18% for IBD, 16% and 18% for Crohn's disease (CD) and 13% and 19% for ulcerative colitis, respectively. On univariate analysis of the CD patients, low body mass index (BMI, <18.5) and smoking status ( P  = 0.008 and 0.005 respectively) were associated with osteoporosis and osteopenia. Low BMI was also associated with osteoporosis on multivariate analysis in CD ( P  = 0.021, OR 5.83, CI 1.31–25.94). No difference was observed between Taq -1 and Apa -1 VDR polymorphisms in IBD, CD, ulcerative colitis and healthy controls. However, CD males were more likely to carry the variant Taq -1 polymorphism than healthy controls males ( P  = 0.0018, OR 1.94, CI 1.28–2.92) and female CD patients ( P  = 0.0061, OR 1.60, CI 1.17–2.44).
Conclusions  In this well-phenotyped cohort of IBD patients, a relatively low prevalence of osteoporosis was observed. Low BMI was the only independent risk factor identified to be associated with osteoporosis.