Prevalence Of Proton Pump Inhibitors Use Research Articles

Inappropriate Use of Proton Pump Inhibitor Among Elderly Patients in British Columbia: What are the Long-term Adverse Events?

Proton pump inhibitors (PPIs) are one of the most used classes of drugs. For most indications, PPIs are only recommended up to 8 weeks duration. However, PPI use continues to expand. Regular and prolonged use of PPIs should be avoided because of the risk of adverse events. The main objective of this study was to (1) investigate the extent of PPI usage in people aged 65 or older in the province of British Columbia (BC), Canada, (2) provide an overview of the harms associated with the long-term use of PPIs. We examined utilization trends of the PPIs in BC since the year 2009 using PharmaNet, BC's medication dispensing database where the information is accessible to community pharmacists. We performed a comprehensive literature search for relevant reviews reporting harms associated with long-term use of PPIs. A search was conducted from January 2014 to June 2022. Between 2000 and 2018 BC's population grew by 20%, but the use of PPIs escalated to 257%. Of these older British Columbians, 62% had a cumulative exposure exceeding 2 years and 42% exceeded 5 years. This is alarming because the recommended treatment duration is 4-12 weeks for common indications including reflux esophagitis, and duodenal and gastric ulcers. Only 13.5% were dispensed PPIs for 90 days or less. Patients on long-term PPI therapy should be reassessed. Adverse events of PPI use are common among older adults. We identified over 217 systematic reviews published during the last 8 years of specific harms associated with long-term daily usage of PPIs. These harms include increased risks of death, cardiovascular disease, acute renal injury, chronic kidney disease, dementia, fractures, hypomagnesemia, iron deficiency, vitamin B12 deficiency, enteric infection (including C. difficile), pneumonia, and neoplasia (gastric cancer, carcinoids, and colon cancer), and drug interactions. This study revealed a high prevalence of PPI use among elderly populations in BC, Canada. The overutilization of PPIs is often a result of failure to re-evaluate the need for continuation of therapy. Published studies identified signals of serious harm from long-term PPI exposure. Healthcare providers with patients can reverse the relentless expansion of long-term PPI exposure by discussing the expected benefits and potential harms.

Abstract P500: Proton Pump Inhibitor Use and Incident Cardiovascular Disease in Postmenopausal Women, Results From the Women’s Health Initiative

Introduction: Evidence from in-vitro and animal studies suggests that proton pump inhibitor (PPI) use is associated with incident cardiovascular disease (CVD). Observational studies in humans have shown conflicting results and didn’t account for relevant confounders such as diet and physical activity or confounding by indication. Methods: This study included 148,452 postmenopausal women without history of CVD at enrollment into the Women’s Health Initiative (WHI) observational study and clinical trials in 1993-1998. The primary exposure was PPI use (no, yes) determined by medication inventory conducted at baseline. The main outcome was incident primary CVD defined as a composite endpoint of physician-adjudicated myocardial infarction, coronary revascularization, stroke, and CVD mortality. Follow-up time was to September 2010. Cox proportional hazards regression was used to estimate hazards ratios (HR) and 95% confidence intervals (CI) for the association of PPI use and CVD. All models were adjusted for baseline age and stratified according to WHI study component. Additional models were further adjusted for demographics (education, income), lifestyle (smoking, alcohol, diet quality, physical activity, sleep duration), and major CVD risk factors (body mass index, family history of CVD, treated hypercholesterolemia, treated diabetes, treated hypertension). Results: Baseline prevalence of PPI use was 1.91%. After a mean follow-up of 11.3 years, there were 10,944 CVD events. PPI use was associated with a 28% higher risk of CVD compared to non-use in the age adjusted model (HR: 1.28, 95%CI: 1.13-1.45). The association was attenuated but remained significant after adjusting for potential confounders and was materially unchanged when using propensity score adjustment to better address confounding by indication (Table). Conclusions: PPI use was associated with higher risk of incident CVD in postmenopausal women. Further investigations are warranted to confirm this finding and identify potential mechanisms.

The Impact of Sex on the Response to Proton Pump Inhibitor Treatment.

Proton pump inhibitor (PPI) treatment is responsible for substantial gastrin elevation secondary to reduced intragastric acidity. Due to the increasing global prevalence of PPI users, concerns have been raised about the clinical significance of continuous gastrin elevation and its potential long-term side effects. Hypergastrinemia secondary to PPIs has trophic effects on gastric mucosa, leading to enterochromaffin-like cell hyperplasia and gastric (fundic) polyp formation, and it is believed to provoke acid rebound following PPI withdrawal that induces PPI overutilization. Previous studies have found higher gastrin release following PPI therapy in females compared with males, and sex differences have also been demonstrated in pharmacokinetic parameters and dose requirements for acid reflux. It is conceivable that females might be at increased risk of PPI overuse, because they often receive higher milligram-per-kilogram doses. The prevalence of PPI use is more common among females, and the female sex is a risk factor for adverse drug reactions. This non-systematic review outlines the current knowledge of the impact of biological sex on the response to PPIs. The aim is to highlight the female sex as a potential risk factor that could be a step toward precision medicine and should be considered in future research on the response to PPI treatment.

Proton Pump Inhibitors Increases Longitudinal Risk of Mortality, Decompensation, and Infection in Cirrhosis: A Meta-Analysis.

Proton pump inhibitors (PPIs) are frequently prescribed to cirrhotic patients, but there is limited longitudinal evidence regarding their effects. This study aimed to assess the impact of PPIs on adverse events in cirrhotic patients. A comprehensive search was conducted using the Medline and Embase databases to identify relevant articles. Pooled hazard ratios (HRs) using DerSimonian and Laird random-effects model were calculated to evaluate the risk of adverse events such as long-term mortality, hepatic decompensation, hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP), and overall infection in cirrhotic patients with PPI use. The analysis included 28 studies with 260,854 cirrhotic patients. The prevalence of PPI use among cirrhotic patients was 55.93%. The use of PPIs was not significantly associated with short-term mortality in cirrhotic patients. However, long-term mortality (HR 1.321, 95% CI 1.103-1.581, P = 0.002), decompensation (HR 1.646, 95% CI 1.477-1.835, P < 0.001), HE (HR 1.968, 95% CI 1.372-2.822, P < 0.001), SBP (HR 1.751, 95% CI 1.649-1.859, P < 0.001), and infection (HR 1.370, 95% CI 1.148-1.634, P < 0.001) were significantly associated with PPI use. Sensitivity analysis with prospective studies yielded similar results. PPIs should be reserved for appropriate indications at lowest effective dose for cirrhotic patients due to the potential harm.

Current management of gastro-oesophageal reflux disease-treatment costs, safety profile, and effectiveness: a narrative review.

The purpose of this study was to review the current management of gastro-oesophageal reflux disease (GORD), including treatment costs, safety profile and effectiveness. A literature review was performed of randomized-controlled trials, systematic reviews, Cochrane reports and National/Societal guidelines of the medical, endoscopic and surgical management of GORD. Proton pump inhibitor (PPI) prescribing patterns and expenditure were reviewed in different countries, including Australia, Canada, New Zealand, UK and USA. Proton pump inhibitors (PPIs) are primarily indicated for control of GORD, Helicobacter pylori eradication (combined with antibiotics), preventing NSAID-induced gastrointestinal bleeding and treating peptic ulcer disease. There is widespread overprescribing of PPIs in Western and Eastern nations in terms of indication and duration, with substantial expense for national health providers. Despite a favourable short-term safety profile, there are observational associations of adverse effects with long-term PPIs. These include nutrient malabsorption, enteric infections and cardiovascular events. The prevalence of PPI use makes their long-term safety profile clinically relevant. Cost-benefit, symptom control and quality-of-life outcomes favour laparoscopic fundoplication rather than chronic PPI treatment. Laparoscopic fundoplication in long-term management of PPI-responsive GORD is supported by SAGES, NICE and ACG, and PPI-refractory GORD by AGA and SAGES guidelines. The importance of establishing a definitive diagnosis prior to invasive management is emphasized, especially in PPI-refractory heartburn. We examined evidence-based guidelines for PPI prescribing and deprescribing in primary care and hospital settings and the need for PPI stewardship and education of health professionals. This narrative review presents the advantages and disadvantages of surgical, endoscopic and medical management of GORD, which may assist in shared decision making and treatment choice in individual patients.This paper was presented (GS020) at the 88th RACS Annual Scientific Conference, 6-10 May, 2019.

Assessment of proton-pump inhibitor use at a tertiary teaching hospital in Nigeria.

Background:Proton-pump inhibitor (PPI) is a widely used medication class globally. Because of its good safety profile, there is a huge likelihood of inappropriate use.Objectives:To determine the prevalence of PPI use and indications, describe its pattern of usage, and identify factors associated with inappropriate prescriptions at a federal tertiary teaching hospital in Maiduguri, Nigeria.Methods:PPI prescriptions were retrospectively assessed in the General Outpatients’ Department (GOPD) and Gastroenterology Unit (GITU) of a teaching hospital. Relevant data for the study were extracted from the patients’ medical records. Chi-square or Fisher’s exact tests where appropriate were used to identify factors associated with inappropriate PPI prescriptions. A p < 0.05 was considered to be significant.Results:PPIs were prescribed to 73.3% (220/300) of patients, while inappropriate prescriptions were noted in 91.4% (201/220) of these patients. Epigastric pain (49.5%) was the most common PPI indication, while omeprazole was the highest prescribed (53.4%). Nearly all inpatients (98.2%), those with epigastric pain (95.7%), and patients who were prescribed intravenous PPIs had more inappropriate PPI prescriptions compared to others.Conclusion:This study revealed a high prevalence of PPI use and inappropriate prescriptions at the study hospital. As a result, these findings highlight the importance PPI-based stewardship program at the study hospital.

Long-term use of proton-pump inhibitors: whole-of-population patterns in Australia 2013-2016.

Background:Proton-pump inhibitors (PPIs) are among the most prescribed medicines worldwide and concern about their long-term use is growing. We used dispensing claims for every person in Australia dispensed publicly subsidized PPIs between 2013 and 2016 to determine the incidence and prevalence of PPI use and to examine the patterns and durations of PPI treatment among individuals continuing treatment beyond the guideline-recommended maximum 12 weeks.Methods:We estimated annual prevalence and incidence per 100 people and duration of treatment for every Australian dispensed publicly subsidized PPIs between 2013 and 2016. We examined patterns of PPI treatment in three patient subgroups using PPIs for more than 12 weeks duration; people receiving maintenance, long-term continuous or long-term intermittent treatment. We calculated the proportion in each subgroup stepping down from higher to lower PPI strengths, stepping up from lower to higher PPI strength and discontinuing treatment.Results:PPIs were dispensed to 4,388,586 people; 60% were women; median age at initiation was 52 years [interquartile range (IQR): 36–65]. Standard and high strength PPIs accounted for 95% of dispensings. Annual incidence and prevalence were 3.9/100 and 12.5/100, respectively, in 2016 and highest among individuals over 65 years (prevalence range: 33–43/100). Most people (67%) stopped treatment after one dispensing; while 25%, 6% and 10% continued on maintenance, long-term continuous and long-term intermittent treatment, respectively. Median duration of treatment in people continuing treatment was 501 days (IQR: 180–not reached) for maintenance treated individuals and ‘not reached’ for long-term treated individuals. We observed 35%, 20% and 47% of people stepping down from higher to lower treatment strengths on maintenance, long-term continuous and long-term intermittent treatment, respectively.Conclusions:Longer-term treatment with higher strength PPIs is common. Targeted regulation of PPI prescribing may improve the uptake of lower strength formulations and reduce both harms and costs associated with long-term PPI treatment.

Demographic and health-related predictors of proton pump inhibitor (PPI) use and association with chronic kidney disease (CKD) stage in NHANES population.

Reports of adverse outcomes with use of Proton Pump Inhibitors (PPIs) and recent associations between PPI use and Chronic Kidney Disease (CKD) suggest the need to examine PPI use in the general population. The purpose of this study was to examine PPI use in the general U.S. population with a focus on CKD stages. This was a retrospective database study of the National Health and Nutrition Examination Survey (NHANES) for years 2009-2013. Inclusion criteria were age ≥ 18 years and having a serum creatinine value. The Andersen Behavioral Model of Health Services Utilization and previous research were used to identify the independent variables. Dependent variable was self-reported prescription medication use. Multinomial logistic regression models were used to examine factors associated with PPI use. Overall, the weighted prevalence of PPI use was 8.7%. Only 4.5% of the sample had stage 3 or 4 CKD. PPI use was highest among whites (10.5%) compared to minorities. PPI users were significantly older (mean = 59.8years), with a majority (80%) being 50 years and over. In multivariate analyses, PPI use was associated with having two or more comorbidities (OR = 3.8, CI: 2.85-5.13), and having fair/poor health (OR 4.6 (3.5-5.9). Stage 3 and 4 CKD patients had higher odds of using PPIs (stage 3 OR = 3.8 CI: 2.5-5.8, stage 4 OR = 6.5 CI: 1.6-25.8) compared to stage 1 patients. /Relevance: This is the first study to examine both predictors and racial disparities in PPI use in the general US population. While PPI use was low, there were racial disparities in PPI use. Multiple comorbid conditions, lower quality of life, and stage 3/4 CKD were associated with PPI use. Awareness of these predictors will enable clinicians to target key patient groups for tailored education and closer monitoring of PPI use.

Systematic review with meta-analysis: fundic gland polyps and proton pump inhibitors.

A causal association between proton pump inhibitor (PPI) use and fundic gland polyps has been suggested, but the data are conflicting. To clarify the relationship through a meta-analysis of the existing data. A systematic retrieval and selection of records was performed. The main inclusion criteria were original studies reporting the prevalence of fundic gland polyps in PPI users or the reverse, compared to controls. Key outcomes were the odds ratios (OR) for fundic gland polyp prevalence in association with PPI use, prevalence of PPI use amongst subjects with fundic gland polyps and fundic gland polyp prevalence among PPI users. Statistical analysis was performed using Mix 2.0 Pro. The initial search using electronic databases and manual searching retrieved 339 peer-reviewed articles and abstracts. Twenty articles metall inclusion and exclusion criteria, with a total of 40218 subjects included. The meta-analysis of 12 studies revealed an increase in fundic gland polyps amongst PPI users compared to controls (OR 2.46, 95% CI 1.42-4.27, P=0.001), particularly among individuals taking PPIs for at least 6months (OR: 4.71, 95% CI 2.22-9.99, P<0.001) or 12months (OR: 5.32, 95% CI 2.58-10.99, P<0.001). Proton pump inhibitor usage is associated with a significantly increased prevalence of fundic gland polyps, and there is a trend for this to increase with longer length of PPI exposure. However, the meta-analysis is limited mainly to cohort studies.

Use of proton-pump inhibitors among adults: a Danish nationwide drug utilization study.

The use of proton-pump inhibitors (PPIs) has increased over the last decade. The objective of this study was to provide detailed utilization data on PPI use over time, with special emphasis on duration of PPI use and concomitant use of ulcerogenic drugs. Using the nationwide Danish Prescription Registry, we identified all Danish adults filling a PPI between 2002 and 2014. Using descriptive statistics, we reported (i) the distribution of use between single PPI entities, (ii) the development in incidence and prevalence of use over time, (iii) measures of duration and intensity of treatment, and (iv) the prevalence of use of ulcerogenic drugs among users of PPIs. We identified 1,617,614 adults using PPIs during the study period. The prevalence of PPI use increased fourfold during the study period to 7.4% of all Danish adults in 2014. PPI use showed strong age dependency, reaching more than 20% among those aged at least 80 years. The proportion of users maintaining treatment over time increased with increasing age, with less than10% of those aged 18-39 years using PPIs 2 years after their first prescription, compared with about 40% among those aged at least 80 years. The overall use of ulcerogenic drugs among PPI users increased moderately, from 35% of users of PPI in 2002 to 45% in 2014. The use of PPIs is extensive and increasing rapidly, especially among the elderly.

Proton pump inhibitor prescribing patterns in the UK: a primary care database study.

To determine the prevalence and pattern of proton pump inhibitor (PPI) prescription and the practices employed to reduce PPI use in the UK general population. The UK's Clinical Practice Research Database was used to identify individuals who were issued with ≥1 PPI prescription during the period 1990-2014. Point and period prevalence of PPI use were estimated annually. Additionally, new users of PPI therapy who had 5 years of follow-up data were included in a cohort analysis to describe patterns of cessation and duration of PPI use. Both the period and point prevalence of PPI use increased between 1990 and 2014 (period prevalence increased from 0.2 to 15.0% and point from 0.03 to 7.7%). A total of 596 334 new users of PPI therapy in the cohort study received 8 784 272 prescriptions. Of these, 26.7% used PPI therapy long term (≥1 year continuously), while 3.9% remained on PPI therapy for 5 years. Clear attempts to step down dose were identified in 39.9% of long-term users, while this was 47% in patients whose initial indication did not mandate long-term use. A considerable increase in PPI use was observed in UK general practice. Of long-term PPI users, 60% did not have an attempt to discontinue or step down. Considerable opportunities may therefore exist to reduce the cost and side effects of PPI use through improving adherence to recommended withdrawal strategies. Copyright © 2016 John Wiley & Sons, Ltd.

Quiz Page March 2016: A 60-Year-Old Man With Fever, Night Sweats, and Acute Kidney Injury

Quiz Page March 2016: A 60-Year-Old Man With Fever, Night Sweats, and Acute Kidney Injury

Proton pump inhibitor co-prescription with dual antiplatelet therapy among patients with acute coronary syndrome in Qatar.

There are increasing concerns about clinically significant interactions between proton pump inhibitors (PPIs) and clopidogrel, resulting in adverse cardiovascular outcomes in patients with acute coronary syndromes (ACS). However, published evidence on the prevalence and predictors of PPI use with dual antiplatelet therapy (DAPT) is scarce. This study investigated the prevalence of PPI use among patients with ACS receiving DAPT and possible predictors of co-prescribing the PPIs with the DAPT. Heart Hospital, a specialized tertiary care center in Qatar. A retrospective observational study of a prescription database was conducted. Subjects included 626 patients admitted between January and December 2012 with the diagnosis of ACS who received DAPT and discharged with or without a PPI. Univariate analysis and multivariate binary logistic regression analysis were performed to determine the predictors of PPI-DAPT co-prescription. Prevalence of PPI co-prescribing with DAPT in proportions and percentages and odd ratios for the predictors of PPI-DAPT co-prescribing. A total of 626 patients were analyzed for PPI prevalence, with 200 patients (32 %) being prescribed PPI with DAPT upon discharge. After controlling for confounders, PPI use on admission (aOR 14.5; 95 % CI 7.6-27.6, p < 0.001), nationality (aOR 3.2; 95 % CI 1.1-9.9, p = 0.041), and having a history of diabetes (aOR 0.5; 95 % CI 0.24-0.99, p = 0.046) significantly influenced PPI-DAPT co-prescribing. Users of PPI on admission compared to nonusers were about 15 times more likely to be prescribed PPI with DAPT upon discharge; likewise, having Qatari nationality increased the likelihood of co-prescribing PPI with DAPT upon discharge by three folds. Lastly, patients with a history of diabetes were 50 % less likely to be prescribed PPIs upon discharge compared to those with no history of diabetes. The rate of PPI co-prescribing with DAPT in the population studied was relatively high. The strongest predictor of PPI co-prescription with DAPT upon discharge was PPI use on admission. Furthermore, PPI prescribing was significantly predicted by nationality and not having diabetes. Further studies are warranted to better predict the factors associated with PPI-DAPT co-prescription and to investigate rational prescribing of PPIs among ACS patients.

Prevalence of Gastroesophageal Reflux Disease (GERD) Symptoms and Proton Pump Inhibitor (PPI) Use in Patients With Crohn Disease (CD) Treated at a Tertiary Care Inflammatory Bowel Disease Center

Introduction: GERD is commonly diagnosed by improvement of upper gastrointestinal (UGI) symptoms on PPI therapy. Similar symptoms are reported in patients with CD and whether this is a manifestation of UGI CD or GERD is unclear. Data on the prevalence of GERD in CD do not exist. A preliminary study of patients with CD has shown gastroduodenal histologic findings of granulomas and focally enhanced gastritis, which are more specific to UGI CD, in 12% of patients with upper endoscopy (Diaz et al, 2015). Given the potential long-term side effects of PPIs, our aim was to evaluate the prevalence of PPI use and reported GERD symptoms in patients with CD. Methods: We performed a retrospective chart review of 499 patients with CD seen between September 2009 to May 2015 and grouped them using the Montreal Classification (MC). Each encounter was evaluated for pyrosis, regurgitation, globus, dysphagia, odynophagia, chest pain, postprandial abdominal pain, early satiety, bloating, and nausea. Use of acid suppressive therapy prior to the first visit and current use were also recorded, as were gastric emptying and pH studies if available. Results: The mean age of our 499 patient cohort was 39 years (range: 17-80), 49% males, mean BMI= 24.7 (range: 13-52). By MC criteria, 186 (37%) were L1, 80 (16%) were L2, 218 (44%) were L3, and 15 (3%) had upper and lower GI CD. Less than 5% of patients had gastric emptying or pH studies. 108 (21.6%) patients were on medications prior to their first visit with indications unknown and 111 (22.2%) patients were on acid suppressive therapy. Of the patients on acid suppressive therapy, 61% were not assessed for pyrosis, 88% were not assessed for regurgitation, and 82% were not assessed for postprandial abdominal pain. Other classic GERD symptoms were not assessed at higher rates (Table 2). Bloating and nausea were reported in 43 and 45% of patients on acid suppressive therapy, respectively.Table 2: Upper GI Symptoms Assessed While on Acid Suppressive TherapyConclusion: Many patients with CD are on PPI therapy without proper symptom screening or existing indications. Nausea and bloating are commonly reported in these patients and whether that is related to UGI CD, dyspepsia, or true GERD is unknown. Given the potential side effects of PPIs and the complications of CD, appropriate screening should be done to minimize PPI use. Further studies should prospectively evaluate CD patients through validated GERD questionnaires and endoscopic biopsies to better analyze which CD patients would benefit from PPI use.Table 1: Baseline Characteristics

Clinical Significance of the Clopidogrel–Proton Pump Inhibitor Interaction After Peripheral Endovascular Intervention for Claudication

Despite numerous studies in the cardiology literature, the clinical impact of proton pump inhibitor (PPI) administration on the antiplatelet effect of clopidogrel remains controversial. The objective of this study is to evaluate the effects of concurrent PPI and clopidogrel administration on outcomes after percutaneous transluminal angioplasty and stenting (PTA&S) of the superficial femoral artery (SFA) for claudication. Retrospective review of a prospectively maintained database (2004-2010) identified patients undergoing PTA&S of the SFA for lifestyle-limiting claudication (Rutherford Class III). Statistical analysis included univariate comparison (Wilcoxon, chi-square) of demographics, lesion characteristics, complication rates, and outcome measures. Patency comparisons were made with Cox-PH multivariable models and Kaplan-Meier survival analysis. Totally, 109 limbs were treated in 103 patients. All were prescribed clopidogrel for 1 month; concurrent PPI use (+PPI) was identified after 42 (38.5%) interventions. There were no statistically significant differences in demographics, comorbidity prevalence, lesion length, degree of stenosis, or runoff associated with PPI use. There were no cases of early thrombosis in either group. There were more instances of patency loss (28 [50%] vs 21 [42%]; P = .40) in patients with +PPI, and a trend toward reduced primary patency that did not achieve statistical significance (P = .5). By multivariate analysis only TransAtlantic Inter-Society Consensus (TASC) D lesions were independent predictors of primary (hazards ratio [HR] = 4.366; [95% confidence interval (CI): 1.291-14.764; P = .018) and assisted patency loss (HR = 6.815 [1.181-39.327]; P = .032). The clinical significance of the clopidogrel-PPI interaction is a controversial topic that has been the subject of numerous studies in the cardiology literature. This is the first report to examine this medication interaction after peripheral intervention. While there is no apparent association between PPI coadministration with clopidogrel in this series, the high prevalence of PPI use among patients prescribed clopidogrel following peripheral intervention warrants ongoing attention to this purported medication interaction.

Is proton pump inhibitor use a significant confounder for chromogranin A levels in sepsis? Reply to Haranath and Jakkinaboina

Dear Editor, In their letter Drs. Haranath and Jakkinaboina make some comments relevant to our recently published article ‘‘Prognostic value of chromogranin A in severe sepsis: data from the FINNSEPSIS study’’ [1]. Regrettably, we have inverted the data for hospital survivors and non-survivors concerning use of proton pump inhibitor (PPI) in Table 1, and a correction has been posted. This has no effect on the results of the study and there are no other errors in the table. The FINNSEPSIS study is one of the largest severe sepsis cohorts with serial blood sampling currently assembled and a strength of the study is the unbiased inclusion of patients. Hence, we did not exclude patients on the basis of prior medical history or the use of medication. We lack information on patients with previous neuroendocrine tumors, but considering a prevalence of 35/100,000 for all neuroendocrine tumors [2] it is unlikely that a high number of patients with neuroendocrine tumors were included in our cohort of patients with severe sepsis. Moreover, we report hospital mortality as our primary endpoint and this was sepsis-related in all patients. Finally, there are comments relating to the use of PPI and chromogranin A (CgA) measurements. Information regarding previous use of PPI was not collected in FINNSEPSIS, but we report the prevalence of PPI use during the hospitalization for severe sepsis in our patients. PPI use clearly influences CgA levels, also after short-term use [3], but given the prevalent use of PPI as a protective measure against stressinduced ventricular ulcers in patients with severe sepsis (84 % overall in our cohort), it would clearly not be of clinical interest to only report data for patients not treated with PPIs.

The effect of proton pump inhibitors on fracture risk: report from the Canadian Multicenter Osteoporosis Study

A large Canadian cohort was studied over 10 years to see if proton pump inhibitor (PPI) use increased the risk of sustaining a fragility fracture. We found an increased risk of fracture in individuals who used PPIs. The risk remained after controlling for other known fracture risk factors. Multiple retrospective studies have linked proton pump inhibitor use with increased risk of fragility fracture. We prospectively studied the association between PPI use and fracture in a large cohort over a 10-year period while controlling for known fracture risk factors. We studied 9,423 participants in the Canadian Multicenter Osteoporosis Study. The cohort was formed in 1995-1997 and followed for 10 years with monitoring for incident nontraumatic fracture and PPI use. Cox regression analyses were used to assess the association between PPI use and incident fracture risk. PPI use, coded as a time-dependent variable, was associated with a shorter time to first nontraumatic fracture, hazard ratio (HR)=1.75 (95% confidence interval (CI) 1.41-2.17, p<0.001). After controlling for multiple risk factors, including femoral neck bone density, the association remained significant, HR=1.40 (95% CI 1.11-1.77, p=0.004). Similar results were obtained after controlling for bisphosphonate use, using PPI "ever" use, or when the outcome was restricted to hip fracture. In this large prospective population-based cohort study, we found an association between PPI use and increased risk of fragility fracture. Although the increased risk found was modest, this finding is important, given the high prevalence of PPI use and the excess morbidity and mortality associated with osteoporosis-related fractures.

Re-prescribing of causative drugs in persons discharged after serious drug-induced upper gastrointestinal bleeding

Several drug classes are known to be associated with serious upper gastrointestinal bleeding (UGIB), among others NSAID, low-dose acetylsalicylic acid (ASA), vitamin K antagonists (VKA), clopidogrel and selective serotonin reuptake inhibitors (SSRIs). There are few data on how and to what extent these drugs are reintroduced in patients who have been discharged after a bleeding episode related to any of them. To assess if physicians re-prescribed potential causative drugs after an episode of UGIB and to explore whether drugs with antihaemostatic action (DAHA) are re-prescribed without a gastro-protective agent. By use of the Kaplan-Meyer method, we estimated the time from UGIB to re-prescribing for 3652 cases who were all admitted to hospital with a diagnosis of serious upper gastrointestinal bleeding from 1995 to 2006. Data on drug exposure were retrieved from a Danish prescription database, a recent study on drug-related UGIB, and The National Board of Health in Denmark. One-year rates of re-prescribing after UGIB were; 82%, 25%, 43%, 68%, 55%, 71% for SSRIs, NSAID, low-dose ASA, VKA, clopidogrel and dipyridamol, respectively. However, re-prescribing rates without proton pump inhibitors (PPIs) were markedly lower 25%, 3%, 5%, 1%, 17% and 6%, respectively. Non-users of DAHA had a prevalence of PPI use of about 30% a few months after an UGIB. Drugs with antihaemostatic action are re-prescribed to a large extent after an episode of upper gastrointestinal bleeding, but usually covered by PPIs. This use of PPI is specific for users of drugs with antihaemostatic action.

Use of proton pump inhibitors and H2 blockers and risk of pneumonia in older adults: a population-based case-control study

To examine whether use of proton pump inhibitors (PPIs) and H2 blockers is associated with increased pneumonia risk. We conducted a population-based, nested case-control study within Group Health, an integrated healthcare delivery system. Among community-dwelling, immunocompetent adults aged 65-94, we identified presumptive cases of ambulatory and hospitalized community-acquired pneumonia in 2000-2003 from ICD-9 codes and validated them by medical record review (N = 1125). Controls were selected, matched to cases on age, sex, and calendar year (N = 2235). Current PPI or H2 blocker use was ascertained from computerized pharmacy records. Comorbid illnesses and other characteristics were ascertained by medical record review. Multivariable conditional logistic regression was used to examine the association between medication use and pneumonia risk. We conducted sensitivity analyses using only administrative and pharmacy data to assess how these results differed from our primary results. The prevalence of PPI or H2 blocker use was 21% (241/1125) for pneumonia cases and 16% (350/2235) for controls (adjusted odds ratio [OR] 1.03, 95% CI 0.86-1.24, compared to nonuse). No increased risk was seen for recent initiation. The prevalence of PPI use was 12% (132/1125) for cases and 7% (160/2235) for controls (adjusted OR 1.13, 95% CI 0.88-1.44). Analyses using only administrative and pharmacy data yielded risk estimates farther from the null (adjusted OR 1.32, 95% CI 1.17-1.49, for current PPI use versus nonuse). Use of PPIs and H2 blockers is not associated with increased pneumonia risk in older adults. The increased risk observed in some prior studies may reflect confounding.

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

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. To determine the prevalence and predictors of PPI use in high-risk aspirin users. 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. 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. There is a high prevalence of UGIC risk factors among aspirin users, and many are not prescribed PPIs as a gastroprotective strategy.