Current Use Of Proton Pump Inhibitors Research Articles

Long-term use of proton pump inhibitors, dose-response relationship and associated risk of ischemic stroke and myocardial infarction.

Use of proton pump inhibitors (PPIs) has been associated with cardiovascular disease amongst patients not on antiplatelet therapy. The associations of PPI use, duration and dose, with risk of first-time ischemic stroke and myocardial infarction (MI) are poorly understood. All Danish individuals with no prior history of MI or stroke, who had an elective upper gastrointestinal endoscopy performed between 1997 and 2012, were identified from nationwide registries. We used multiple Poisson regression to test associations with current PPI use and its dose and used multiple cause-specific Cox regression and g-formula methods to analyze long-term use. Amongst 214998 individuals, during a median follow-up of 5.8years, there were 7916 ischemic strokes and 5608 MIs. Current PPI exposure was associated with significantly higher rates of both ischemic stroke (Hazard ratio (HR) 1.13; 95% confidence interval (CI) 1.08-1.19) and MI (HR 1.31, CI 1.23-1.39) after adjusting for age, sex, comorbidities and concomitant medication. High-dose PPI was associated with increased rates of ischemic stroke (HR 1.31, CI 1.21-1.42) and MI (HR 1.43, CI 1.30-1.57). Histamine H2 receptor antagonists (H2RAs) use was not significantly associated with ischemic stroke (HR 1.02, CI 0.84-1.24) or MI (HR 1.15, CI 0.92-1.43). Long-term users of PPIs, compared with nonusers, had a 29% (CI 5%-59%) greater absolute risk of ischemic stroke and a 36% (CI 7%-73%) greater risk of MI within a 6-month period. Use of PPIs was associated with increased risks of first-time ischemic stroke and MI, particularly amongst long-term users and at high doses.

Proton-Pump Inhibitor Use and the Risk of First-Time Ischemic Stroke in the General Population: A Nationwide Population-Based Study.

An increased risk of adverse cardiovascular events was reported for concomitant use of proton-pump inhibitors (PPIs) in patients taking antiplatelet agents. The present study aimed at determining whether PPI use alone could be associated with first-time ischemic stroke. This was a retrospective nationwide study using database from Taiwan National Health Insurance and involved subjects aged ≥20 years. In propensity score-matched analysis, patients with current PPI use were compared with propensity score-matched PPI non-use controls at a 1:1 ratio. Patients with prior stroke or hospitalization before the index date were excluded. The primary outcome measure was hospitalization with a primary diagnosis of ischemic stroke during 120-day follow-up. A parallel analysis adopting a nested case-control design was carried out. Patients hospitalized for a first-time ischemic stroke were identified and were compared with matched controls using conditional logistic regression analyses focusing on PPI use before the index date. The propensity score-matched analysis included 198,148 PPI treatment courses and control periods without PPI use. PPI use was associated with a higher risk of hospitalization due to ischemic stroke with a hazard ratio of 1.36 (95% confidence interval (CI) 1.14-1.620, P=0.001). Based on subgroup analysis, patients aged <60 years were more susceptible (P=0.043 for interaction), whereas gender, history myocardial infarction, diabetes mellitus, hypertension, use of antiplatelet agents of non-steroidal anti-inflammatory drugs, or type of PPIs had no effect on the risk. In the nested case-control analysis, 15,378 patients hospitalized owing to ischemic stroke were identified and were compared with 15,378 matched controls. An association between PPI use and increased cerebrovascular risks was identified, and the adjusted odds ratios for PPI use were 1.77 (95% CI 1.45-2.18, P<0.001) within 30 days, 1.65 (95% CI 1.31-2.08, P<0.001) between 31 and 90 days, and 1.28 (95% CI 1.03-1.59, P=0.025) between 91 and 180 days before the onset of first-time ischemic stroke. PPI use is associated with an increased risk of first-time ischemic stroke in the general population, and the risk is independent of antiplatelet agents. However, caution should be exercised when considering its clinical relevance as the magnitude of association was modest and a cause-and-effect relationship remained to be established.

P720 Use of proton pump inhibitors associated with a markedly increased risk of microscopic colitis

Background: Microscopic colitis (MC) is a chronic inflammatory bowel disease with unknown etiology. Proton pump inhibitor (PPI) use has been consistently linked to an increased risk of MC. The specific role of the different classes of PPI is unknown. Based on the nationwide Danish registries we explored the association between MC and use of PPI and in addition the effect of different classes of PPIs and dose-dependency. Secondly we explored the effect of concomitant use of PPI and NSAID. Methods: In a ten-year period (January 2004 to December 2013) we identified 10652 patients with a first-time recorded diagnosis of MC including 6254 (59%) with collagenous colitis (CC) and 4398 (41%) with lymphocytic colitis (LC). MC cases were identified via the Danish Pathology Registry. For each MC case, we sampled 10 population controls. Information on PPI use was obtained from the Danish Prescription Register. The analysis conformed to a case-control design, estimating the odds ratio (OR) for the association between PPI use and the risk MC using conditional logistic regression, while adjusting for potential confounders. Results: We found strong associations between current PPI use and both CC (adjusted OR [aOR] 8.75; 95% CI: 8.12–9.43) and LC (aOR 5.03; 95% CI: 4.61–5.49). This association was seen across all individual PPIs, however, the strongest association was seen with current use of lansoprazole, for both CC (aOR 20.10; 95% CI: 18.05–22.37) and LC (aOR 7.70; 95% CI: 6.79–8.73). When considering timing, ORs were highest for current use of PPI, while the association quickly diminished when considering recent or past exposure. When analyzing the prescribed strength of PPI, we found no apparent dose-response pattern. The use of NSAID was associated with a modest increased risk of CC (aOR 1.70; 95% CI: 1.55–1.87). However, the combination of NSAID and PPI and was associated with a higher risk for CC (aOR 9.72; 95% CI: 8.65–10.92) compared to the use of one of the drugs alone. Conclusions: In a large comprehensive case-control study based on nationwide Danish registries we found an increased risk of MC associated with the use of PPI and especially an increased risk with the use of lanzoprazole. The combination of NSAID and PPI and was associated with a high risk for CC.

Use of proton pump inhibitors and the risk of listeriosis. A nationwide registry-based case-control study

Recent studies suggest that proton pump inhibitors (PPIs) may increase the risk for listeriosis. We investigated a potential association in cases of nonpregnancy-associated listeriosis using registry data. We conducted a population-based, case-control study using Danish health registries. Cases (n = 721) were defined as patients aged ≥45 years notified with listeriosis from July 1994 to December 2012. We selected 34800 controls using risk-set sampling. Controls were individually matched for age, sex, and municipality. Data on use of PPIs and other drugs and hospitalization diagnoses over a 5-year period were extracted from nationwide health registries. A comorbidity index (CMI) was constructed. We calculated the association between use of PPIs and related drugs within 30 days (current use) and other time windows before the index date. Using conditional logistic regression, matched odds ratios (ORs) adjusted for CMI and confounders were estimated. The adjusted OR for current use of PPIs and development of listeriosis was 2.81 (95% confidence interval [CI], 2.14-3.69). PPI usage up to 90 days before the index date remained statistically significant. Subgroup analyses revealed increasing ORs with decreasing age and level of comorbidity and an increased OR for concurrent glucocorticoid treatment (OR, 4.61; 95% CI, 3.01-7.06). No significant association was found for current use of histamine-2-receptor antagonists (adjusted OR, 1.82; 95% CI, 0.89-3.71). Prescribed PPIs were associated with increased risk of listeriosis. The risk waned with time since last prescription redemption. PPIs may have unwanted side effects in vulnerable populations.

Risk of seizure associated with use of acid-suppressive drugs: An observational cohort study.

Previous, large, prescription-event monitoring studies in patients receiving PPI therapy recorded instances of convulsion or seizure. The objective of this study was to quantify the relative risk of seizure associated with the use of proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) in a general population, overall and stratified by epilepsy status, and to determine the effects of demographics and comorbidities. In this observational study (NCT01744301), patients aged 20-84years in the study period from 1 January 2005 to 31 December 2011 were identified from The Health Improvement Network. In a nested case-control analysis, 8605 patients with seizure were matched to 40000 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using logistic regression. After adjustment, there were no associations between current PPI use and seizure risk in the overall population (OR: 1.05; 95% CI: 0.87-1.27), the subcohort with epilepsy (OR: 0.87; 95% CI: 0.49-1.53), and the subcohort without epilepsy (OR: 1.05; 95% CI: 0.87-1.28). There were no associations between current H2RA use and seizure risk in the overall population (OR: 1.16; 95% CI: 0.62-2.18) and the subcohort without epilepsy (OR: 1.02; 95% CI: 0.51-2.01). Seizures were less frequent in women than in men. Dementia/psychosis, anxiety, depression, and use of anxiolytics, antidepressants, and paracetamol were associated with an increased seizure risk. Our study revealed that the use of PPIs and the use of H2RAs were not associated with an increased risk of seizures in the overall population or in the cohorts stratified by epilepsy status.

High risk of drug-induced microscopic colitis with concomitant use of NSAIDs and proton pump inhibitors.

Microscopic colitis (MC) is a chronic bowel disorder characterised by watery diarrhoea. Nonsteroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), selective serotonin reuptake inhibitors (SSRIs) and statins have been associated with MC. However, underlying mechanisms remain unclear. To study the association between exposure to these drugs and MC, with attention to time of exposure, duration, dosage and combined exposure, and to test hypotheses on underlying pharmacological mechanisms. A case-control study was conducted using the British Clinical Practice Research Datalink. MC cases (1992-2013) were matched to MC-naive controls on age, sex and GP practice. Drug exposure was stratified according to time of exposure, duration of exposure or dosage. Conditional logistic regression analysis was applied to calculate adjusted odds ratios (AORs). In total, 1211 cases with MC were matched to 6041 controls. Mean age was 63.4 years, with 73.2% being female. Current use of NSAIDs (AOR 1.86, 95% CI 1.39-2.49), PPIs (AOR 3.37, 95% CI 2.77-4.09) or SSRIs (AOR 2.03, 95% CI 1.58-2.61) was associated with MC compared to never or past use. Continuous use for 4-12 months further increased the risk of MC. Strongest associations (fivefold increased risk) were observed for concomitant use of PPIs and NSAIDs. Statins were not associated with MC. Current exposure to NSAIDs, PPIs or SSRIs and prolonged use for 4-12 months increased the risk of MC. Concomitant use of NSAIDs and PPIs showed the highest risk of MC. Acid suppression related dysbiosis may contribute to the PPI effect, which may be exacerbated by NSAID-related side-effects.

Risk of Out-of-Hospital Sudden Cardiac Death in Users of Domperidone, Proton Pump Inhibitors, or Metoclopramide: A Population-Based Nested Case-Control Study.

IntroductionEpidemiological studies have linked domperidone use with serious cardiac arrhythmias, including sudden cardiac death, but data on age, dose, and duration of use are limited.ObjectivesThe aim of this study was to assess the risk of out-of-hospital sudden cardiac death associated with domperidone use versus proton pump inhibitors (PPIs), metoclopramide, or non-use of all three medications, and to evaluate the risk of sudden cardiac death in relation to age and domperidone dose.MethodsThis was a population-based case-control study nested in a cohort of subjects aged ≥2 years in the Clinical Practice Research Datalink with one or more prescriptions for domperidone, any PPI, or metoclopramide from 2005 to 2011. Out-of-hospital sudden cardiac death was assessed by linkage with Hospital Episode Statistics and death certificates. Controls were matched on age, sex, and medical practice. The risk of sudden cardiac death in domperidone users versus risk in users of PPIs or metoclopramide was evaluated with multivariable conditional logistic regression; case-crossover analysis addressed possible residual confounding.ResultsFrom the study cohort (n = 681,104), 3239 sudden cardiac death cases were matched to 12,572 controls. The adjusted odds ratio (95 % confidence interval) for sudden cardiac death with current use of domperidone alone was 1.71 (0.92–3.18) versus non-use of study medications, 1.26 (0.68–2.34) versus current PPI use, and 0.40 (0.17–0.94) current metoclopramide use. The adjusted odds ratio (95 % confidence interval) relative to exposure to no study drug for domperidone >30 mg/day (eight cases, five controls) was 3.20 (0.59–17.3) and 1.65 (0.89–3.07) for age ≥61 years (27 cases, 49 controls). The odds ratio (95 % confidence interval) was 3.17 (1.72–5.83) for within-person periods of domperidone use versus non-use in the case-crossover analysis.ConclusionsCompared with non-use of any study drug, current domperidone use was associated with sudden cardiac death in nested case-control and case-crossover analyses, with a suggestion of higher risk in older persons and users of higher daily doses.Electronic supplementary materialThe online version of this article (doi:10.1007/s40264-015-0338-0) contains supplementary material, which is available to authorized users.

English

Patients surviving with a stroke have an increased risk for recurrent stroke. Clopidogrel is widely used to prevent recurrent stroke. However, clopidogrel may cause gastrointestinal bleeding (GIB). Therefore, proton pump inhibitors (PPIs) is recommended to reduce the side effect of clopidogrel. Unfortunately, these both drugs are metabolized in the liver by the same enzyme i.e. cytochrome P4502C19 (CYP219) that may reduce the effect of clopidogrel. The aim of this study was to evaluate the influence of PPIs on the effect of clopidogrel in the prevention of recurrent stroke. It was a hospital-based case control study conducted in Bethesda Private Hospital, Yogyakarta involving 392 patients with recurrent stroke as cases and 784 patients with first-ever stroke as controls. The exposure of PPIs during clopidogrel therapy on both cases and controls groups were recorded from prescription records for at least six months before index date. The duration of PPIs exposure were categorized as current expoure (less than two months before the index date) and recent exposure (2-6 months before the index date). The result showed there was no influence of PPIs exposure on the effect of clopidogrel on the risk of recurrent ischemic stroke (OR: 1.00; 95% CI: 0.56-1.79). Moreover, the current use of PPIs and clopidogrel could decrease the risk of recurrent ischemic stroke (OR: 0.04; 95% CI: 0.01-0.41). In conclusion, there is no association between PPI exposure and the risk of recurrent stroke in patients receiving clopidogrel.

Proton pump inhibitor use significantly increases the risk of cryptogenic liver abscess: a population-based study.

Proton pump inhibitors (PPIs) increase gastric pH and impair defence mechanisms against ingested pathogens, which may result in the overgrowth of virulent Klebsiella pneumoniae in the intestine and subsequent liver abscess. We investigated the possible association between PPIs use and cryptogenic liver abscess in Taiwan. We conducted a population-based case-control study using data from the National Health Insurance Research Database. A total of 958 adult cases of liver abscess and 3832 age- and sex-matched control patients were enrolled during 2000-2010. Conditional logistic regression was used to estimate the adjusted odds ratios (ORs) in patients using PPIs before cryptogenic liver abscess. The adjusted OR associating current use of PPIs (prescription within thepast 30days) with cryptogenic liver abscess was 4.7 [95% confidence interval (CI), 2.9-7.8], and recent use of PPIs (prescription within the past 31-90days) with cryptogenic liver abscess was 2.9 (95% CI, 1.4-6.1). A dose-response relationship was apparent for cumulative dose of PPIs within 90days. Adjusted OR was highest among the patients receiving PPIs more than 60 cumulative defined daily dose (OR=6.5, 95% CI, 2.8-14.9). Proton pump inhibitor therapy within the past 90days was associated with an increased risk of cryptogenic liver abscess.

OP010. Medication-induced microscopic colitis: do recency and duration of use matter?

Background: Microscopic colitis (MC) is a colonic disorder characterised by chronic watery diarrhoea. There is increasing evidence (table present) that exposure to commonly prescribed drugs like non-steroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), selective serotonin reuptake inhibitors (SSRIs), and statins is associated with an increased risk of MC. However, the attributive risk of recent or longer use and the effect of higher dosages has never been investigated, although this information would give more insight in the possible mechanism of medication-induced MC. Methods: A case-control study was conducted using the British Clinical Practice Research Datalink. Cases were diagnosed with microscopic, lymphocytic (LC) or collagenous (CC) colitis between 1992-2013. For each case, up to 5 randomly selected controls without MC were matched by year of birth, gender, and practice. The index date of the case defined that of the controls. Prescriptions within 60 days prior to index date were excluded to take into account a latency (lag) time and to minimize reverse causality. Exposure status was classified as current (61-90 days), recent (91-150 days), and past use (>150 days) according to the time since most recent prescription prior to index date. In current users, duration of continuous use and average daily dose was assessed. Conditional logistic regression analysis was applied to quantify the strength of the associations and to correct for confounders. Results: In total, 1.211 cases with MC (394 CC, 292 LC, 525 undefined MC) and 6.041 controls were identified. Current use of NSAIDs (OR 1.79, 95% CI 1.36-2.36), PPIs (OR 3.93, 95% CI 2.25-4.74), and SSRIs (OR 2.27, 95% CI 1.79-2.89) was associated with an increased risk of MC compared to never and past use. Especially a 4-12 months continuous use of NSAIDs, PPIs, and SSRIs increased the risk of MC. Long-term use (>24 months) attenuated this risk. Exposure to more than 1.25 standardised daily dosages was associated with an elevated risk of MC in PPI (OR 6.90, 95% CI 3.82-12.49) and SSRI users (OR 4.15, 95% CI 2.47-6.97). Analysis per MC subtype showed a positive association between current use of NSAIDs (OR 2.28, 95% CI 1.46-3.54) and PPIs (OR 6.15, 95% CI 4.41-8.58) in CC and current use of PPIs (OR 2.40, 95% CI 1.60-3.59) and SSRIs (OR 2.65, 95% CI 1.69-4.15) in LC. Statin use was not associated with MC. A sensitivity analysis with a lag time of 90 days showed conclusions consistent with the primary analysis. Conclusions: Use of NSAIDs, PPIs, and SSRIs is associated with an increased risk of MC. Especially in current users with a continuous exposure duration of 4 to 12 months, drug exposure as cause for MC should be considered.

Greater Than Once Daily Proton Pump Inhibitor Use Increases Risk of Small Intestinal Bacterial Overgrowth

Introduction: The etiology of small intestinal bacterial overgrowth (SIBO) is diverse and frequently multi-factorial. SIBO is thought to result from a disruption of the normal peristalsis of the stomach and small intestine. It is currently unclear if hypochlorhydria secondary to proton pump inhibitors (PPIs) increases risk of SIBO; recent studies have yielded conflicting results regarding this association. To date, no published study has prospectively collected data regarding PPI dose and glucose hydrogen breath test results (GHBT). The goal of this study was to prospectively evaluate the association between small intestinal bacterial overgrowth (SIBO) and PPI use and dose using a GHBT. Methods: A questionnaire pertaining to PPI use was given to 65 consecutive patients prior undergoing GHBT. Breath samples for hydrogen (H2) and methane (CH4) were collected before and every 15 minutes for 180 minutes following ingestion of a 75-g oral glucose load. We used the following criteria to define a positive GHBT: (a) baseline H2 or CH4 over 10 parts per million (ppm), (b) rise in H2 or CH4 of at least 12 ppm after ingestion of the glucose load. All data were analyzed using SAS version 9.2 and R version 3.0.3. Results: The study included 65 patients (74% female; mean age 51 years), 24 of whom had a positive GHBT (37%). Of the patients with positive GHBT, 15 (62.5%) had an elevated baseline H2, 10 (41.6%) had an elevated baseline CH4, 8 (33.3%) had >12 ppm increase in H2 after oral glucose load, and 1 (4.2%) had >12 ppm increase in CH4 after oral glucose load. Current PPI use was not associated with positive GHBT when compared to patients not on PPI (45.4% vs. 32.6%, p=0.31). In the subgroup of patients who were exposed PPIs in the past 2 years, patients with positive GHBT were more likely to use it more than once daily (1.8 ± 0.71 vs. 1.1 ± 0.35; p=0.01). Conclusion: Current PPI use does not significantly increase risk of SIBO; however, use of PPI greater than once daily does increase the risk of SIBO. Further studies are needed to confirm the association between SIBO and PPI dosing.

Proton pump inhibitors and hospitalization with hypomagnesemia: a population-based case-control study.

Some evidence suggests that proton pump inhibitors (PPIs) are an under-appreciated risk factor for hypomagnesemia. Whether hospitalization with hypomagnesemia is associated with use of PPIs is unknown. We conducted a population-based case-control study of multiple health care databases in Ontario, Canada, from April 2002 to March 2012. Patients who were enrolled as cases were Ontarians aged 66 years or older hospitalized with hypomagnesemia. For each individual enrolled as a case, we identified up to four individuals as controls matched on age, sex, kidney disease, and use of various diuretic classes. Exposure to PPIs was categorized according to the most proximate prescription prior to the index date as current (within 90 days), recent (within 91 to 180 days), or remote (within 181 to 365 days). We used conditional logistic regression to estimate the odds ratio for the association of outpatient PPI use and hospitalization with hypomagnesemia. To test the specificity of our findings we examined use of histamine H2 receptor antagonists, drugs with no causal link to hypomagnesemia. We studied 366 patients hospitalized with hypomagnesemia and 1,464 matched controls. Current PPI use was associated with a 43% increased risk of hypomagnesemia (adjusted odds ratio, 1.43; 95% CI 1.06-1.93). In a stratified analysis, the risk was particularly increased among patients receiving diuretics, (adjusted odds ratio, 1.73; 95% CI 1.11-2.70) and not significant among patients not receiving diuretics (adjusted odds ratio, 1.25; 95% CI 0.81-1.91). We estimate that one excess hospitalization with hypomagnesemia will occur among 76,591 outpatients treated with a PPI for 90 days. Hospitalization with hypomagnesemia was not associated with the use of histamine H2 receptor antagonists (adjusted odds ratio 1.06; 95% CI 0.54-2.06). Limitations of this study include a lack of access to serum magnesium levels, uncertainty regarding diagnostic coding of hypomagnesemia, and generalizability of our findings to younger patients. PPIs are associated with a small increased risk of hospitalization with hypomagnesemia among patients also receiving diuretics. Physicians should be aware of this association, particularly for patients with hypomagnesemia. Please see later in the article for the Editors' Summary.

Association between recent use of proton pump inhibitors and nontyphoid salmonellosis: a nested case-control study.

The association between proton pump inhibitors (PPIs) and nontyphoid salmonellosis (NTS) continues to be debated. The current study was designed to determine the association between use of oral PPIs and the diagnosis of NTS. The Taiwan National Health Insurance Research Database from 2000 to 2010 was searched for cases of NTS, defined by the International Classification of Disease, Ninth revision, Clinical Modification. A nested case-control study in hospitalized population was conducted using 4 controls for each case patient (14 736 case patients and 58 944 controls), matched for age, month and year of entry, Charlson comorbidity index score, and well-known predisposing factors for NTS, including autoimmune diseases, acquired immunodeficiency syndrome, diabetes, cirrhosis, transplantation, gastrointestinal operations or diseases, and malignancies. Persons with NTS had a higher rate of using oral PPIs within the prior year (adjusted odds ratio [OR], 2.09; 95% confidence interval [CI], 1.95-2.24; P < .001). The association was greatest for current PPI use (adjusted OR, 5.39; 95% CI, 4.79-6.06; P < .001). Although use of H2-receptor antagonists (adjusted OR, 1.84; 95% CI, 1.71-1.98), antibiotics (5.21; 4.81-5.64), steroids (3.18; 2.99-3.39), and nonsteroidal anti-inflammatory drugs (2.37; 2.26-2.48) within the 30 days were also associated with NTS, the linkage between PPI use and NTS remained significant in the subgroup without these medications. The use of oral PPIs was associated with the occurrence of NTS. The risk waned with time after discontinuation.

Study of the Association Between Hip Fracture and Acid‐Suppressive Drug Use in a UK Primary Care Setting

We aimed to clarify the nature of the association between hip fracture risk and use of proton pump inhibitors (PPIs) or histamine2 -receptor antagonists (H2 RAs). We identified patients 40-89 years of age with a recorded hip fracture diagnosis in 2000-2008 using The Health Improvement Network, a UK primary care research database. Computerized records were reviewed and questionnaires sent to primary care physicians to validate hip fracture cases. A cohort study with a nested case-control analysis was performed to estimate the association between the use of acid-suppressive drugs and hip fracture. Overall incidence of hip fracture per 1000 person-years was 1.31 (95% confidence interval [CI] 1.28-1.33). There was a modest increased risk of hip fracture after adjustment for potential confounders (odds ratios [OR] during current use of PPIs and H2 RAs: 1.09 [95% CI 1.01-1.17] and 1.04 [95% CI 0.90-1.19], respectively). Relative to nonuse, an increased risk of fracture was observed with medium and high doses of PPIs (OR 1.11 [95% CI 1.01-1.22] and OR 1.31 [95% CI 1.06-1.61], respectively) and high doses of H2 RAs (OR 2.77, 95% CI 1.21-6.37). No duration response was observed (ORs for current PPI use less than 1 month and 5 years or longer: 1.16 [95% CI 0.94-1.43] and 1.02 [95% CI 0.87-1.20], respectively). Patients treated with PPIs showed a modest increased risk of hip fracture after adjustment for potential cofounders. Any remaining association between PPI use and hip fracture risk may be attributable to residual confounding.

Risk Factors for Falls with Use of Acid-Suppressive Drugs

Some recent reports suggest an increased risk of fractures with use of proton pump inhibitors (PPIs) and histamine type 2 receptor antagonists (H2RAs), although results are inconsistent and a causal relationship has yet to be proven. As these acid-suppressive drugs may have uncommon adverse effects on the central nervous system (CNS), such as dizziness, we investigated whether their use is associated with falls as a possible mechanism for increasing fracture risk. A cohort study with nested case-control analysis and two validation strategies was performed using data from UK patients (aged 40-89 years) included in The Health Improvement Network database (2000-2008). Due to the large number of falls, a random sample of 20,000 cases was used for the analysis. The overall incidence of falls per 1000 person-years was 13.0 (95% confidence interval [CI] = 12.9-13.1). After adjustment for potential confounders, there was no relationship between falls and current use of single PPIs (odds ratio [OR] = 0.95; 95% CI = 0.89-1.02) or H2RAs (OR = 1.01; 95% CI = 0.90-1.14); there was no relationship with dose or duration of treatment. Falls were associated with CNS disorders and treatment with various pharmacological agents including antiparkinson drugs (OR = 2.7; 95% CI = 2.2-3.3) and antiepileptics (OR = 2.1; 95% CI = 1.8-2.3). There was no association between falls and use of PPIs or H2RAs. Any potential increase in the risk of fractures proposed to be associated with the use of acid-suppressive drugs is not via an increased risk of falls.

Use of clopidogrel and proton pump inhibitors after a serious acute coronary event: Risk of coronary events and peptic ulcer bleeding

Some pharmacokinetic studies have reported that proton pump inhibitors (PPIs) reduce the activity of clopidogrel, but the results of studies assessing clinical outcomes in patients receiving both drugs are inconsistent. We have therefore carried out a population-based cohort study with nested case-control analysis, in order to evaluate changes in the risk of cardiovascular and peptic ulcer bleeding (PUB) events associated with PPI use in patients receiving clopidogrel. A total of 42,542 patients aged 50-84years in 2000-2007 who survived an acute coronary event were identified in two UK-based primary care databases (The Health Improvement Network and the General Practice Research Database). Individuals were followed up to identify incident cases of non-fatal myocardial infarction/coronary death (n=2,546) and PUB (n=194). Controls were frequency matched to cases by age, sex and calendar year. Compared with PPI non-use, current continuous PPI use was not associated with a significant change in risk of non-fatal myocardial infarction/coronary death among current continuous users of clopidogrel monotherapy (relative risk [RR], 1.06; 95% confidence interval [95% CI], 0.47 to 2.36) or dual antiplatelet therapy (DAT; RR, 0.80; 95% CI, 0.47 to 1.37) who initiated their antiplatelet therapy shortly after their coronary event. Among patients prescribed DAT at the start date, the RR of PUB events associated with current PPI use initiated at the start date was 0.66 (95% CI, 0.27 to 1.60).

Helicobacter pylori -Negative Gastritis: Prevalence and Risk Factors

Recent studies using histology alone in select patients have suggested that Helicobacter pylori-negative gastritis may be common. The objective of this study was to investigate the prevalence of H. pylori among individuals with histologic gastritis. Subjects between 40 and 80 years underwent elective esophagogastroduodenoscopy at a VA Medical Center. Gastric biopsies were mapped from seven prespecified sites (two antrum, four corpus, and one cardia) and graded by two gastrointestinal pathologists, using the Updated Sydney System. H. pylori-negative required four criteria: negative triple staining at all seven gastric sites, negative H. pylori culture, negative IgG H. pylori serology, and no previous treatment for H. pylori. Data regarding tobacco smoking, alcohol drinking, nonsteroidal anti-inflammatory drug, and proton pump inhibitor (PPI) use were obtained by questionnaire. Of the 491 individuals enrolled, 40.7% (200) had gastritis of at least grade 2 in at least one biopsy site or grade 1 in at least two sites. Forty-one (20.5%) had H. pylori-negative gastritis; most (30 or 73.2%) had chronic gastritis, five (12.2%) had active gastritis, and six (14.6%) had both. H. pylori-negative gastritis was approximately equally distributed in the antrum, corpus, and both antrum and corpus. Past and current PPI use was more frequent in H. pylori-negative vs. H. pylori-positive gastritis (68.2% and 53.8%; P=0.06). We used multiple methods to define non-H. pylori gastritis and found it in 21% of patients with histologic gastritis. While PPI use is a potential risk factor, the cause or implications of this entity are not known.

PWE-103 A risk stratification score for predicting 30-day mortality in Clostridium difficile associated diarrhoea

IntroductionClostridium difficile associated diarrhoea (CDAD) causes significant morbidity and mortality in susceptible patients. There are no validated risk stratification scores to identify those patients at the greatest risk of death.MethodsData...

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.

Risk of Community-Acquired Pneumonia in Veteran Patients to Whom Proton Pump Inhibitors Were Dispensed

Observational studies linking proton pump inhibitor (PPI) exposure with community-acquired pneumonia (CAP) have reported either modest or no associations. Accordingly, we studied PPI exposure and CAP in veteran patients, using a retrospective, nested case-control design. From linked pharmacy and administrative databases of the New England Veterans Healthcare System, we identified 71985 outpatients newly prescribed PPIs between 1998 and 2007; 1544 patients met criteria for CAP subsequent to PPI initiation; 15440 controls were matched through risk-set sampling by age and time under observation. Crude and adjusted odds ratios comparing current with past PPI exposures, as well as tests for interactions, were conducted for the entire and stratified samples. Current PPI use associated with CAP (adjusted odds ratio [OR], 1.29 [95% confidence interval {CI}, 1.15-1.45]). Risks were not substantially altered by age or year of diagnosis. Dementia (n = 85; P = .062 for interaction) and sedative/tranquilizer use (n = 224; P = .049 for interaction) were likely effect modifiers increasing a PPI-CAP association; conversely, for some chronic medical conditions, PPI-associated CAP risks were reversed. PPI exposures between 1 and 15 days increased CAP risks, compared with longer exposures, but PPI initiation also frequently occurred shortly after CAP diagnoses. Prescribed PPI doses >1 dose/day also increased PPI-associated CAP risks. Among the veterans studied, current compared with past PPI exposures associated modestly with increased risks of CAP. However, our observations that recent treatment initiation and higher PPI doses were associated with greater risks, and the inconsistent PPI-CAP associations between patient subgroups, indicate that further inquiries are needed to separate out coincidental patterns of associations.