Long-term proton pump inhibitor therapy and falls and fractures in elderly women: a prospective cohort study. Appropriate proton pump inhibitor use among older adults: a retrospective chart review. Proton pump inhibitors and vascular function: A prospective cross-over pilot study Risk Factors for Falls with Use of Acid-Suppressive Drugs Inappropriate prescribing of proton pump inhibitors in primary care On-demand PPI therapy in GERD Feasibility of a Patient-Centered Deprescribing Process to Reduce Inappropriate Use of Proton Pump Inhibitors Clinical trial: long‐term use of proton pump inhibitors in primary care patients – a cross sectional analysis of 901 patients Proton pump inhibitors and hospitalization for Clostridium difficile-associated disease: a population-based study. Omeprazole, but not pantoprazole, reduces the antiplatelet effect of clopidogrel: a randomized clinical crossover trial in patients after myocardial infarction evaluating the clopidogrel–PPIs drug interaction Risk of Complications After a Peptic Ulcer Diagnosis: Effectiveness of Proton Pump Inhibitors Discontinuation of long-term proton pump inhibitor therapy in primary care patients: a randomized placebo-controlled trial in patients with symptom relapse Proton-pump inhibitor therapy and the development of dysplasia in patients with Barrett's oesophagus. [Effectiveness of 10 day-sequential therapy for Helicobacter pylori eradication in Korea]. Hip fracture and proton pump inhibitor therapy: position statement. Role of proton pump inhibitors in the management of peptic ulcer bleeding. Impact of proton pump inhibitors on clinical outcomes in patients treated with a 6- or 24-month dual-antiplatelet therapy duration: Insights from the PROlonging Dual-antiplatelet treatment after Grading stent-induced Intimal hyperplasia studY trial. Proton Pump Inhibitors, Platelet Reactivity, and Cardiovascular Outcomes After Drug-Eluting Stents in Clopidogrel-Treated Patients: The ADAPT-DES Study Proton Pump Inhibitors and the Risk of Adverse Cardiac Events Magnitude and economic effect of overuse of antisecretory therapy in the ambulatory care setting. Proton-Pump Inhibitor Use and the Risk for Community-Acquired Pneumonia Laparoscopic magnetic sphincter augmentation versus double-dose proton pump inhibitors for management of moderate-to-severe regurgitation in GERD: a randomized controlled trial. Proton pump inhibitors and clopidogrel - hazardous drug interaction or hazardous interpretation of data?
Proton pump inhibitors ( PPIs ) are widely used in the elderly . Recent studies have suggested that long-term PPI therapy is associated with fractures in the elderly , however the mechanism remains unknown . We investigated the association between long-term PPI therapy ≥1 year and fracture risk factors including bone structure , falls , and balance-related function in a post hoc analysis of a longitudinal population -based prospect i ve cohort of elderly postmenopausal women and replicated the findings in a second prospect i ve study of falling in elderly postmenopausal women .  Long-term PPI therapy was associated with increased risk of falls and fracture-related hospitalizations ; adjusted odds ratio ( AOR ) 2.17 ; 95 % CI , 1.25 - 3.77 ; p = 0.006 and 1.95 ; 95 % CI , 1.20 - 3.16 ; p = 0.007 , respectively . In the replication study , long-term PPI use was associated with an increased risk of self-reported falling ; AOR , 1.51 ; 95 % CI , 1.00 - 2.27 ; p = 0.049 . No association of long-term PPI therapy with bone structure was observed ; however , question naire-assessed falls-associated metrics such as limiting outdoor activity ( p = 0.002 ) and indoor activity ( p = 0.001 ) due to fear of falling , dizziness ( p < 0.001 ) and numbness of feet ( p = 0.017 ) and objective clinical measurement such as Timed Up and Go ( p = 0.002 ) and Romberg eyes closed ( p = 0.025 ) tests were all significantly impaired in long-term PPI users . Long-term PPI users were also more likely to have low vitamin B12 levels than non-users ( 50 % versus 21 % , p = 0.003 ) . In conclusion , similar to previous studies , we identified an increased fracture risk in subjects on long-term PPI therapy . This increase in fracture risk in elderly women , already at high risk of fracture , appears to be mediated via increased falls risk and falling rather than impaired bone structure and should be carefully considered when prescribing long-term PPI therapy BACKGROUND Proton pump inhibitors ( PPIs ) are widely used , but not always with a clear indication . Nonindicated use is of particular concern among older adults , who may have multiple comorbidities and take more medications , increasing their risk for adverse drug reactions . OBJECTIVE This study examined the appropriateness of PPI use at an outpatient geriatric practice and the association between particular patient characteristics and appropriate use of these medications . METHODS This was a retrospective chart review of a group of r and omly identified community-dwelling adults aged > or=65 years with a current prescription for a PPI ( as of August 2006 ) from a geriatric ambulatory care practice within an urban academic medical center . The main outcome was appropriateness of PPI use , categorized as indicated , possibly indicated , or not indicated , based on US Food and Drug Administration-approved indications and national gastroenterology guidelines . RESULTS Out of approximately 2500 patients in the geriatric practice , 702 ( approximately 28 % ) were identified as having a current prescription for a PPI .  From these , 110 charts were r and omly selected for review , of which 10 were excluded based on predefined criteria . The sample was 79 % female and 46 % white , with a mean age of 82.8 years ( range , 66 - 99 years ) .  PPI use was indicated in 64 % of these patients , possibly indicated in 7 % , and not indicated in 29 % . Compared with indicated PPI use , nonindicated use was significantly associated with use for < 1 year ( relative risk = 2.20 ; 95 % CI , 1.00 - 4.86 ; P = 0.05 ) . Nonindicated PPI use was not significantly associated with age , female sex , nonwhite race , or PPI initiation in the inpatient setting . CONCLUSION Almost 30 % of patients receiving a PPI  in this academic geriatric practice had no documented indication for PPI use Proton pump inhibitors ( PPIs ) are commonly used drugs for the treatment of gastric reflux . Recent retrospective cohorts and large data base studies have raised concern that the use of PPIs is associated with increased cardiovascular ( CV ) risk . However , there is no prospect i ve clinical study evaluating whether the use of PPIs directly causes CV harm . We conducted a controlled , open-label , cross-over pilot study among 21 adults aged 18 and older who are healthy ( n=11 ) or have established clinical cardiovascular disease ( n=10 ) . Study subjects were assigned to receive a PPI ( Prevacid ; 30 mg ) or a placebo pill once daily for 4 weeks . After a 2-week washout period , participants were crossed over to receive the alternate treatment for the ensuing 4 weeks . Subjects underwent evaluation of vascular function ( by the EndoPAT technique ) and had plasma levels of asymmetric dimethylarginine ( ADMA , an endogenous inhibitor of endothelial function previously implicated in PPI-mediated risk ) measured prior to and after each treatment interval . We observed a marginal inverse correlation between the EndoPAT score and plasma levels of ADMA ( r = −0.364 ) . Subjects experienced a greater worsening in plasma ADMA levels while on PPI than on placebo , and this trend was more pronounced amongst those subjects with a history of vascular disease . However , these trends did not reach statistical significance , and PPI use was also not associated with an impairment in flow-mediated vasodilation during the course of this study . In conclusion , in this open-label , cross-over pilot study conducted among healthy subjects and coronary disease patients , PPI use did not significantly influence vascular endothelial function . Larger , long-term and blinded trials are needed to mechanistically explain the correlation between PPI use and adverse clinical outcomes , which has recently been reported in retrospective cohort studies Background : 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 . Methods : 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 data base ( 2000–2008 ) . Due to the large number of falls , a r and om sample of 20,000 cases was used for the analysis . Results : 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 ) . Conclusions : 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 Objectives : To determine if an educational intervention initiated in secondary care can influence prescribing of proton pump inhibitors  ( PPIs ) in the community . Methods : A prospect i ve study of  PPI use in patients admitted to medical wards in a university hospital . A simple educational intervention was employed to reduce inappropriate prescribing of PPIs in the community . Results : In the pre-intervention analysis 66/271 ( 24 % ) patients were receiving treatment with a PPI prescribed in the community . In 36/66 ( 54 % ) patients the PPI had been prescribed inappropriately . Six months after the intervention 91/344 ( 26 % ) patients were prescribed a PPI in the community . In only 45 of these 91 ( 49 % ) patients was there a recommended indication . Conclusion : The intervention used in this study had no effect on the proportion of patients taking a PPI  at the time of hospital admission or on the appropriateness of prescribing in the community Opinion statementConsiderable clinical experience with proton pump inhibitors ( PPIs ) attests to their efficacy and safety in short- and long-term therapy for gastroesophageal reflux disease ( GERD ) in erosive esophagitis and endoscopy-negative ( NERD ) patients . One alternative to continuous PPI maintenance is PPI therapy administered noncontinuously ( eg , “ on dem and ” ) . Qualities of good PPI therapy for such a modality should include fast and sustained acid suppression . The newer-generation PPI esomeprazole has provided greater acid inhibition . R and omized controlled clinical trials comparing ondem and PPI versus placebo or versus continuous PPI therapy in GERD patients have shown that on-dem and therapy with currently available PPIs ( esomeprazole in particular ) appears to be effective in the long-term management of patients with NERD or mild esophagitis and uninvestigated forms of GERD , who make up the overwhelming majority of patients with GERD . This is because it is safe and provides adequate symptom control and sustains quality of life . However , it is not indicated in patients with severe erosive esophagitis or with complicated esophagitis ( ie , Barrett ’s esophagus or stricture ) . On-dem and PPI therapy is important for economic reasons , as it may save up to two thirds of daily doses of the drugs , with a considerable containment of drug expenses . For a long-term disease whose treatment is aim ed primarily at symptom control , it is a sensible and cost-effective approach Background : Proton pump inhibitors ( PPIs ) are inappropriately prescribed in up to 50 % of users . Systematic medication review and cessation of inappropriate medications or deprescribing may improve patient outcomes and reduce costs . Objective : The aim of this study was to assess the feasibility of a patient-centered deprescribing process in a population of adults with complex polypharmacy . Methods : This was a prospect i ve feasibility study . Participants were recruited from hospital outpatient clinics . The patient-centered deprescribing process consisted of 5 steps : comprehensive medication history , identification of potentially inappropriate medications , determining if the medication can be ceased , planning the withdrawal regimen ( eg , tapering where necessary ) , and provision of monitoring , support , and documentation . Feasibility was determined by assessing time taken to complete the different steps of the deprescribing process and participant feedback . Results : In all , 57 PPI users were recruited ; participants were 70 ± 14 years old and took 14 ± 6 medications . The indication for PPI use was verified in 43 participants and judged as potentially inappropriate in 19 ( 44 % ) ; 8 were suitable for trial withdrawal , and 6 consented . All 6 successfully ceased ( n = 3 ) or reduced ( n = 3 ) their PPI use , and this was sustained at 6 months postintervention in 4 participants . Conclusions : The patient-centered deprescribing process can safely reduce inappropriate PPI prescribing in a small proportion of people . Although the process was acceptable to participants , difficulties in accessing complete medical histories , time limitations , and minimal evidence to support effectiveness in certain indications were barriers to implementation of the process in clinical practice Background The use of proton pump inhibitors ( PPIs ) is extensive . While the incidence of new treatments remains stable , the prevalence of long‐term treatment is rising . Studies have shown that up to 70 % of patients on chronic acid suppression lack a verified indication for treatment BACKGROUND Previous studies have examined the association between proton pump inhibitor ( PPI ) use and the risk of Clostridium difficile-associated disease ( CDAD ) , with conflicting results . Whether outpatient PPI use influences the risk of hospital admission for CDAD  among older patients who have recently been treated with antibiotics is unknown . METHODS We conducted a population -based , nested case-control study of linked health care data bases in Ontario , Canada , from 1 April 2002 through 31 March 2005 . We identified patients aged > or = 66 years who were hospitalized for CDAD within 60 days of receiving outpatient antibiotic therapy .  Each case patient with CDAD was matched with 10 control subjects on the basis of age , sex , and details of antibiotic use ( antibiotic class , timing , and number of antibiotics used ) . PPI use by case patients and control subjects was categorized as current ( within 90 days ) , recent ( 91 - 180 days ) , or remote ( 181 - 365 days ) . We used conditional logistic regression to estimate the odds ratio for the association between outpatient  PPI  use and risk of hospitalization for CDAD . RESULTS We identified 1389 case patients and 12,303 matched control subjects . Case patients were no more likely than control subjects to have received a PPI  in the preceding 90 days ( adjusted odds ratio , 0.9 ; 95 % confidence interval , 0.8 - 1.1 ) . Similarly , we found no association between hospitalization for CDAD and more remote use of PPIs . CONCLUSIONS Among community-dwelling older patients , PPI use is not a risk factor for hospitalization with CDAD Background Proton pump inhibitors ( PPIs ) are usually prescribed to patients undergoing dual antiplatelet therapy  to decrease the risk of gastrointestinal bleeding . Recent studies have raised concerns that PPIs could reduce clopidogrel 's efficacy by competitive inhibition of cytochrome P450 2C19 isoenzyme . All PPIs are metabolized by cytochrome P450 2C19 , although to varying degrees , and according to in-vitro studies , pantoprazole is the weakest inhibitor of this isoenzyme . We hypothesized that this drug interaction might not be a class effect . Methods One month after an acute myocardial infa rct ion 34 consecutive patients undergoing dual antiplatelet therapy were prospect ively analyzed .  Platelet function was measured ( VerifyNow system ) , in each patient , in three consecutive clinical scenarios : ( i ) first , after a 1-month washout period , without any PPI , ( ii ) after a 4-week period taking omeprazole 40 mg , and ( iii ) after another 1-month washout period , followed by 4-weeks taking pantoprazole 40 mg . In this crossover trial , patients were first r and omized to receive either omeprazole or pantoprazole . Results We observed a significant reduction in clopidogrel 's effect when patients were initiated with omeprazole ;  the mean P2Y12 reaction units ( PRU ) increased from 202±52 to 235±58 with omeprazole ( P<0.001 ) . With pantoprazole , clopidogrel efficacy was preserved ( PRU 215±54 , P=0.16 ) . Without any PPI , 26 % of patients were ‘ nonresponders ’ to clopidogrel ( PRU > 240 ) but when patients started omeprazole , this proportion increased to 45 versus 23 % with pantoprazole . Conclusion In this r and omized crossover study analyzing patients after acute myocardial infa rct ion , omeprazole coadministration showed a significant pharmacodynamic interaction with clopidogrel , whereas pantoprazole did not . These data suggest that the clopidogrel – PPIs drug interaction may not be a class effect Background Few studies have evaluated the prevention of upper gastrointestinal complications ( UGIC ; bleeding or perforation ) in patients with uncomplicated peptic ulcer ( PU ) . We assessed the effect of proton pump inhibitors ( PPI ) in a non-r and omized setting . To maximize exchangeability of exposed and unexposed groups we restricted the study to patients with a new diagnosis of PU , i.e. , a clear indication . To minimize selection bias we mimicked an intention to treat approach by assessing the effect of PPI prescription after PU diagnosis . Methods Within a population of subjects aged 40–84 years from The Health Improvement Network data base , 1997–2006 , we identified 3,850 patients with incident PU . Among them , we confirmed 74 first UGIC episodes during a mean follow-up of 4 years . Exposure was prescription coverage during the month following PU diagnosis . We performed a nested case – control analysis and compared UGIC cases with 400 controls matched for age , sex , year and duration of follow-up . Relative risks ( RR ) and 95 % confidence intervals ( CI ) were estimated . Results The overall incidence of UGIC was 4.6 cases/1,000 person-years ; it was highest during the months after PU diagnosis , increased with age , and it was higher in men and subjects with Helicobacter pylori infection , anemia , and alcohol use at PU diagnosis . The RR for UGIC associated with PPI prescriptions during the month after PU diagnosis was 0.56 ( 95 % CI 0.31–1.0 ) . The RR for NSAIDs with and without a PPI was 1.72 ( 0.68–4.45 ) and 3.27 ( 0.85–12.67 ) , respectively . Conclusions Findings suggest that prescription of PPIs after a PU diagnosis is associated with a reduced risk of UGIC Background A significant proportion of patients treated empirically with a proton pump inhibitor ( PPI ) present with symptoms of functional dyspepsia with a high placebo-response to therapy . It is possible that a subgroup of empirically treated patients redeem repeated prescriptions because of a positive response to therapy despite symptoms that are not acid related . Objectives To study whether discontinuation of long-term PPI therapy is possible in symptomatically treated patients . To investigate the effect of a PPI in patients with symptom relapse without abnormal endoscopic findings . Methods Seventy-eight long-term primary care PPI users without verified indication for therapy discontinued treatment . In case of symptom recurrence , an endoscopy was performed . Patients without abnormal endoscopic findings were r and omized to 7 days oesomeprazole 40 mg once daily or placebo . Results A total of 11 of 78 ( 14 % ) patients discontinued the therapy successfully . Fifty-three of 78 patients ( 68 % ) experienced symptom recurrence . Thirty-one of 53 patients ( 59 % ) had a normal endoscopy . Successful effect of therapy after 7 days was observed in 12 of 15 patients ( 80 % ) in the oesomeprazole group versus two of 16 ( 13 % ) in the placebo group ( P<0.001 ) . Conclusion Discontinuation of long-term PPI therapy is possible in a minority of primary care patients . Short-term oesomeprazole was superior to placebo in patients with symptom recurrence and a normal endoscopy OBJECTIVE To examine whether proton-pump inhibitor ( PPI ) therapy influences the incidence and progression of dysplasia in patients with Barrett 's oesophagus . DESIGN AND SETTING Review of prospect i ve data on patients undergoing surveillance with regular endoscopy and biopsy at a private endoscopy centre in Canberra , ACT , between 1981 and 2001 . PATIENTS 350 patients diagnosed with Barrett 's oesophagus . INTERVENTIONS PPI therapy was progressively introduced into clinical practice from late 1989 . Once begun , PPI therapy was ongoing , with no attempt to reduce the dose . MAIN OUTCOME MEASURES Relationship between development of dysplasia or adenocarcinoma and delay between diagnosis with Barrett 's oesophagus and starting PPI therapy was determined by Cox regression analyses , stratified by year of enrollment . Age , sex , presence of macroscopic markers ( severe oesophagitis , nodularity , Barrett 's ulcer , stricture ) and use of aspirin or non-steroidal anti-inflammatory drugs were considered as confounding factors in the regression analyses . RESULTS The 350 patients had 1422 surveillance endoscopies , with a median follow-up of 4.7 years . Patients who delayed using a PPI  for 2 years or more after diagnosis with Barrett 's oesophagus had 5.6 times ( 95 % CI , 2.0 - 15.7 ) the risk of developing low- grade dysplasia at any given time as those who used a PPI in the first year . Similar results were found for the risk of developing high- grade dysplasia or adenocarcinoma ( hazard ratio , 20.9 ; 95 % CI , 2.8 - 158 ) . CONCLUSIONS Use of ongoing PPI therapy appeared beneficial in the prevention of dysplasia and adenocarcinoma in patients with Barrett 's oesophagus . We suggest that all patients with this condition , even those with no oesophagitis or symptoms , should be encouraged to continue long term PPI therapy BACKGROUND / AIMS Antibiotic resistance and poor compliance are the main causes of Helicobacter pylori ( H. pylori ) eradication failure . Proton pump inhibitor (PPI)-based triple therapy is the most preferred regimen in clinical practice . However , a critical fall in the H. pylori eradication rate has been observed in the recent years . A novel 10 day-sequential therapy consists of five days of dual therapy followed by five days of triple therapy regimen has recently been described . We aim ed to evaluate whether 10 day-sequential therapy eradicated H. pylori infection better than the PPI-based triple therapy in Korea . METHODS 158 patients with proven H. pylori infection were r and omized to receive either 10 day-sequential therapy ( 20 mg of omeprazole , 1.0 g of amoxicillin , each administered twice daily for the first 5 days , followed by 20 mg of omeprazole , 500 mg of clarithromycin , 500 mg of metronidazole , each administered twice daily for the remaining 5 days ) or PPI-based triple therapy ( 20 mg of omeprazole , 1.0 g of amoxicillin , 500 mg of clarithromycin , each administered twice daily for 1 week ) . Outcome of eradication therapy was assessed 8 weeks after the cessation of treatment . RESULTS Eradication rates of 10 day-sequential therapy and PPI-based triple therapy were 77.9 % ( 60/77 ) and 71.6 % ( 58/81 ) by intention to treat analysis , respectively ( p=0.361 ) . By per protocol analysis , eradication rates of 10 day-sequential therapy and triple therapy were 85.7 % ( 60/70 ) and 76.6 % ( 58/76 ) , respectively ( p=0.150 ) . There were no significant differences in adverse event rates and treatment compliance between two groups . CONCLUSIONS The 10 day-sequential therapy regimen failed to achieve significantly higher eradication rates than PPI-based triple therapy There has been recent media attention to the possibility that long-term proton pump inhibitor ( PPI ) prescribing may be linked to an increased risk of hip fracture  according to data from the United Kingdom ( UK ) ( 1 ) and Canada ( 2 ) . The Canadian Association of Gastroenterology has prepared the following position statement on the association between PPI therapy and hip fracture in light of this evidence . The present position statement is outlined in greater detail elsewhere ( 3 ) . Yang et al ( 1 ) reported a nested case-control study using the UK General Practice Research Data base that selected patients older than 50 years of age with an incident hip fracture , and age and sex-matched controls . There were 13,556 hip fracture cases and 135,386 controls ;  PPI therapy for more than one year was associated with an increased risk of hip fracture ( adjusted OR 1.44 ; 95 % CI 1.30 to 1.59 ) . Targownik et al ( 2 ) reported a further nested case-control study using the Manitoba Population Health Research Data Repository , in which 15,792 patients with osteoporosis-related fractures were compared with 47,289 controls . There was no overall association between  PPI use and fracture until after five or more years of exposure , when the risk of osteoporotic fracture became significant ( adjusted OR 1.62 ; 95 % CI 1.02 to 2.58 ) . Similarly , the risk of hip fracture became significant after seven years of PPI exposure ( adjusted OR 4.55 ; 95 % CI 1.68 to 12.29 ) . The clinical significance of this is uncertain because extrapolation of these figures ( assuming 1.8 per 1000 patients develop a hip fracture [ 1 ] ) suggests that 1263 patients need to be treated with a PPI for more than one year to develop one excess hip fracture , although the number needed to harm may be much lower after seven years according to the Canadian study . These studies use reputable data bases and are rigorously conducted and analyzed appropriately . The discussion s in both of these articles suggest quite strongly that the association they have found is likely to be causal . Large data bases provide a wonderful opportunity to evaluate benefits and harms of medical interventions , but caution must be exercised before assuming the latest finding represents a risk to patients . The ready availability of data bases means that literally millions of associations can be tested ; even within a particular hypothesis there are a variety of approaches to splitting the data ( eg , duration of therapy , therapy dose , length of follow-up , patient age , male versus female ) . Research ers and journals are prone to emphasize positive findings and tend to underplay the role of chance or confounding factors . These issues are less likely to be important if a consistent association is found . An accompanying editorial ( 4 ) to the Canadian study also cites a third Danish data base study ( 5 ) that supports an association between PPI therapy and fracture . It is interesting to note that the Danish study had a much greater number of cases ( 124,655 ) than the other two studies , and yet had much more muted conclusions and was published in a lower impact factor journal . The Danish study was circumspect in their conclusions because there were inconsistencies in the data and there was no dose response information . For example , there seemed to be an increased risk with taking less than 25 doses of a PPI in one year with a lower ( but still statistically significant ) risk in those taking one dose per day for a year . There seemed to be no biologically plausible hypothesis why such infrequent use of PPI therapy would be associated with an increased risk of fracture . There were also inconsistencies with the UK and Canadian studies . The UK study reported an increased risk of hip fracture after one year of PPI therapy ; there seemed to be little increase in risk over the next four years , whereas the Canadian study only found a significant association after seven years . Targownik et al ( 2 ) suggest that perhaps the UK data base included patients that had in fact been taking PPIs for much longer ; however , this is speculation . Furthermore , a Canadian cohort study ( 6 ) followed-up on elderly patients in Ontario on  warfarin ( n=52,701 ) , thyroid replacement  ( n=40,555 ) , oral corticosteroid ( n=43,915 ) and PPI therapy  ( n=60,383 ) for five years . There was no increased risk of hip fracture in those taking warfarin compared with those on PPI therapy ( adjusted OR 0.94 ; 95 % CI 0.81 to 1.09 ) , but there was an increased risk with  corticosteroid therapy compared with PPI therapy ( adjusted OR 1.44 ; 95 % CI 1.21 to 1.70 ) . It could be that warfarin is also associated with an increased risk of hip fracture ; however , it is interesting that Targownik et al ( 2 ) found little increase in fracture risk in those taking anticoagulants ( 14.5 % of fracture cases taking anticoagulants compared with 13.4 % of controls ) . The CAG is proud to acknowledge its Benefactor Corporate Sponsors : Abbott Canada AstraZeneca Canada Inc Axcan Pharma Inc Olympus Canada Inc Pentax Canada Inc. Procter & Gamble Pharmaceuticals Schering-Plough Canada Inc. UCB Pharma Inc. Finally , there is the issue of biological plausibility . It has been proposed that acid suppression may reduce calcium absorption and increase the risk of fracture ( 1 ) . The role of pH in calcium absorption is , however , controversial . The dissolution of calcium carbonate is pH-dependent in vitro , although the clinical significance of this is uncertain given that calcium is absorbed in the small intestine where the pH is nonacidic regardless of stomach pH. A review of the literature ( 7 ) identified seven r and omized trials that evaluated calcium absorption with acid suppression in healthy subjects or those with ulcer disease . There were major method ological issues with many of the studies and they were all small . Four studies found no impact on calcium absorption while three reported decreased absorption . Further work is needed in this area , but there are no conclusive data that would make the association between fracture and PPI biologically plausible . Furthermore , some research suggests that PPI therapy may inhibit bone resorption ( 8) , which may protect against fracture risk . PPIs are one of the most well-tolerated classes of drugs on the market . They have also improved the quality of life of countless patients with acid-related disease . There are risks in prescribing any drug and this should be borne in mind by all prescribing clinicians . PPI therapy should only be prescribed for indications where there is a proven or likely benefit and the need for these drugs should be review ed on a regular basis . This applies particularly to frail and elderly patients with multiple comorbidities and those taking a number of different medications where the possibility for drug interactions increases . This message applies to all the drugs clinicians prescribe including PPI therapy . Current data would not support particular care in prescribing PPI therapy due to concerns about the risk of hip fracture . There is no persuasive evidence that the association is causal , although this can never be excluded as a possibility . The Canadian Association of Gastroenterology encourages health professionals to keep continually up date d on the medical literature and will endeavour to disseminate further guidance if more information on the possible harms of PPI therapy becomes available Peptic ulcer bleeding is a serious medical problem with significant morbidity and mortality . Endoscopic therapy significantly reduces further bleeding , surgery and mortality in patients with bleeding peptic ulcers and is now recommended as the first hemostatic modality for these patients . The efficacy of large-dose proton pump inhibitor ( PPI ) therapy in reducing re-bleeding after endoscopic therapy has been supported by evidence derived from r and omized controlled trials . It may be premature to recommend small-dose intravenous injection PPI after endoscopic hemostasis in patients with bleeding ulcers . An up date d systematic review shows that PPI therapy before endoscopy significantly reduces the proportion with major stigmata and requirement for endoscopic therapy at index endoscopy . Some studies show that there is no significant difference between oral and intravenous PPIs in raising intragastric pH. However , clinical data is lacking in patients with peptic ulcer bleeding to date BACKGROUND Proton pump inhibitors ( PPIs ) are frequently prescribed in combination with clopidogrel , but conflicting data exist as to whether PPIs diminish the efficacy of clopidogrel . We assessed the association between PPI use and clinical outcomes for patients treated with percutaneous coronary intervention ( PCI ) and dual-antiplatelet therapy ( DAPT ) with clopidogrel plus aspirin .  METHODS AND RESULTS In the PRODIGY trial , 1,970 patients were r and omized to 6- or 24-month DAPT at 30 days from index procedure . Among them , 738 patients ( 37.5 % ) received PPI  ( mainly lansoprazole ; 90.1 % ) at the time of r and omization . Proton pump inhibitor users were older , were most likely to be woman , had a lower creatinine clearance , presented more frequently with acute coronary syndrome , and had a higher CRUSADE bleeding score . After adjustment , the primary efficacy end point ( composite of all-cause death , myocardial infa rct ion , and cerebrovascular accident ) was similar between no PPI and PPI users ( 9.2 % vs 11.5 % , adjusted hazard ratio [ HR ] 1.051 , 95 % CI 0.788 - 1.400 , P = .736 ) . Bleeding rates did not differ between the 2 groups ( Bleeding Academic Research Consortium type 2 , 3 , or 5 : adjusted HR 0.996 , 95 % CI 0.672 - 1.474 , P = .980 ) . Net clinical adverse events were also similar in no PPI and PPI patients ( 12.9 % vs 14.9 % , adjusted HR 0.99 , 95 % CI 0.772 - 1.268 , P = .93 ) . Results remained consistent at sensitivity analysis when focusing on the 548 patients who remained on PPI for the whole study duration . CONCLUSIONS The current findings suggest that the concomitant use of PPIs , when clinical ly indicated , in patients receiving clopidogrel is not associated with adverse clinical outcome Background —Certain proton pump inhibitors ( PPIs ) interfere with clopidogrel metabolism , potentially attenuating P2Y12 receptor inhibition . Previous observational and r and omized trials report conflicting results regarding the clinical significance of this pharmacological interaction . We examined the interaction between concomitant administration of PPI and clopidogrel on platelet reactivity and clinical outcomes in the large-scale , prospect i ve Assessment of Dual AntiPlatelet Therapy With Drug-Eluting Stents study . Methods and Results —On-treatment P2Y12 platelet reactivity testing was performed using the VerifyNow assay after clopidogrel loading and successful drug-eluting stent implantation at 11 sites in the United States and Germany .  PPIs were prescribed at the discretion of treating physicians ; patients were followed for 2 years . High platelet reactivity was defined as P2Y12 reactivity units > 208 . Of 8582 enrolled patients , 2697 ( 31.4 % ) were taking a PPI at the time of coronary intervention . After adjustment for differences in baseline characteristics , PPI use was independently associated with high platelet reactivity ( odds ratio , 1.38 : 95 % confidence interval , 1.25–1.52 , P=0.0001 ) . A total of 2162 ( 25.2 % ) patients were prescribed a  PPI at hospital discharge . In a propensity-adjusted multivariable analysis , discharge PPI use was independently associated with increased risk for postdischarge major adverse cardiac events ( cardiac death , myocardial infa rct ion , or ischemia-driven target lesion revascularization ) at 2-year follow-up ( hazard ratio , 1.21 ; 95 % confidence interval , 1.04–1.42 , P=0.02 ) . Conclusions —In patients treated with clopidogrel after successful drug-eluting stents implantation , the concomitant administration of PPI was associated with high platelet reactivity and a greater rate of adverse outcomes during long-term follow-up . Additional studies are warranted to determine the risk – benefit ratio of PPIs in patients with drug-eluting stents treated with clopidogrel . Clinical Trial Registration —URL : http://www . clinical trials.gov . Unique identifier : NCT00433966 Background Recent evidence suggests that proton pump inhibitors ( PPIs ) might be linked with adverse cardiac events , but a causal relationship is unproven . Methods We applied the self-matched case series method to two studies using population -based health care data from Ontario , Canada between 1996 and 2008 . The first included subjects aged 66 years or older hospitalized for acute myocardial infa rct ion within 12 weeks following initiation of PPI , while the second included subjects hospitalized for heart failure . In both studies we design ated the primary risk interval as the initial 4 weeks of therapy and the control interval as the final 4 weeks . To test the specificity of our findings we examined use of histamine H2 receptor antagonists and benzodiazepines , drugs with no plausible causal link to adverse cardiac events . Results During the 13-year study period , we identified 5550 hospital admissions for acute myocardial infa rct ion and 6003 admissions for heart failure within 12 weeks of commencing PPI therapy . In the main analyses , we found that initiation of a PPI was associated with a higher risk of acute myocardial infa rct ion ( odds ratio 1.8 ; 95 % confidence interval 1.7 to 1.9 ) and heart failure ( odds ratio 1.8 ; 95 % confidence interval 1.7 to 1.9 ) . However , secondary analyses revealed similar risk estimates histamine H2 receptor antagonists and benzodiazepines , drugs with no known or suspected association with adverse cardiac events . Conclusion PPIs are associated with a short-term risk of adverse cardiac events , but similar associations are seen with other drugs exhibiting no known cardiac toxicity . Collectively these observations suggest that the association between PPIs and adverse cardiac events does not represent reflect cause- and -effect OBJECTIVES To determine the prevalence and economic effect of inappropriate proton pump inhibitor ( PPI ) use in an ambulatory care setting . STUDY DESIGN Retrospective medical record review of r and om sample with subgroup analysis . METHODS Patients were categorized according to appropriateness of pharmacotherapy  based on documented upper gastrointestinal tract diagnoses , gastrointestinal or extraesophageal symptoms , or gastroprotection . Adverse events potentially associated with PPI use were identified . RESULTS Of 946 patients in an ambulatory care setting , 35.4 % were given PPI therapy for an appropriately documented upper gastrointestinal tract diagnosis , 10.1 % received PPIs empirically for symptomatic treatment based on extraesophageal symptoms , 18.4 % received PPIs for gastroprotection , and 36.1 % had no documented appropriate indication for PPI therapy . In a subgroup analysis , 48.6 % of patients across all 4 categories received PPIs without documentation of reevaluation of upper gastrointestinal tract symptoms , accounting for 1034 patient-years of PPI use . The total cost of inappropriate PPI use was $ 233,994 based on over-the-counter PPI costs and $ 1,566,252 based on average wholesale price costs . Potentially related adverse events in this cohort included Clostridium difficile – associated diarrhea ( 6 cases ) and community-acquired pneumonia ( 1 case ) , but no cases of hip fracture or vitamin B12 deficiency were identified . CONCLUSIONS Proton pump inhibitors are often overused in the ambulatory care setting without documented valid indications . Inappropriate use of PPIs is associated with substantial cost expenditure and with the potential for adverse events Context Some studies suggest that proton-pump inhibitors ( PPIs ) may increase risk for community-acquired pneumonia ( CAP ) .  Contribution This large , nested casecontrol study involving adults in general practice s in the United Kingdom found that current , long-term PPI use was not associated with increased risk for CAP . Recently started PPI therapy was associated with increased risk : Adjusted odds ratios for PPI use started within 2 , 7 , and 14 days of CAP diagnosis were 6.5 , 3.8 , and 3.2 , respectively . Implication Long-term PPI use is not associated with increased risk for CAP . The association between recently started PPIs and CAP risk is not clear but is not necessarily causal . The Editors Proton-pump inhibitors ( PPIs ) are potent gastric acid suppressants . With its excellent efficacy for acid-related diseases and increasing availability of both over-the-counter and generic formulations , PPI use continues to escalate ( 1 ) . Antiulcer drugs , primarily PPIs , ranked second in overall U.S. retail sales at $ 10.8 billion in 2001 ( 2 ) . Two studies recently suggested that PPI use may increase the risk for community-acquired pneumonia ( CAP ) ( 3 , 4 ) . A proposed mechanism is increased bacterial colonization in the upper gastrointestinal tract due to gastric acid suppression ( 3 , 4 ) . However , other noncausal mechanisms may also be responsible for the association between PPIs and CAP . Residual confounding may have contributed to the relatively modest increased risk seen in these studies . Furthermore , both studies found that the association was weakest among current recipients who had been taking PPIs for the longest duration , which is contrary to what one would expect if PPIs increase the risk for CAP . Community-acquired pneumonia leads to significant morbidity and mortality and dramatic costs to the health care system . In the United States , more than 1.1 million persons are hospitalized each year because of CAP ( 5 ) . In the Medicare program alone , more than $ 3.5 billion are spent on pneumonia-related admissions annually ( 5 ) . Given the widespread use of PPIs , clarifying the potential association between PPI therapy and risk for CAP is of great importance to public health . A recent systematic review on management strategies for gastroesophageal reflux disease , commissioned by the U.S. Agency for Healthcare Research and Quality , called for further studies to eluci date the role of acid suppression on the development of CAP ( 6 ) . Thus , we sought to more definitively examine the effect of current PPI exposure on CAP development in a large , population -based cohort . Methods Data Source We conducted a nested casecontrol study by using the General Practice Research Data base ( GPRD ) . The GPRD comprises prospect ively collected , computerized medical records from a sample of general practice s throughout the United Kingdom that represents the U.K. population in terms of age , sex , and geographic distribution ( 7 ) . Under the National Health Service , a general practitioner coordinates the health care of 98 % of U.K. residents . The GPRD differs fundamentally from cl aims data bases because it comprises the actual medical record , which contains complete and comprehensive clinical data . The information collected in the data base includes demographic characteristics , prescription use , clinical diagnoses , subspecialty consultation notes , and hospital discharge diagnoses . Prescriptions for most medications are written for 1 month in U.K. general practice s. Details of every prescription issued include date , dosage , quantity dispensed , duration of therapy , and indication . The Read clinical classification and the Oxford Medical Information System codes are used to classify medical diagnoses ( 8 , 9 ) . The Read clinical classification was adopted in the United Kingdom in 1990 as an electronic medical coding system . These codes incorporate information on medical history , physical examination , procedures , symptoms , medication use , and social history . These codes are cross-referenced with other major systems of medical coding , including but not limited to the International Classification of Diseases , Ninth and Tenth Revisions ( ICD-9 and ICD-10 ) , and Current Procedural Terminology-4 . The Oxford Medical Information System codes are related to the ICD-9 codes , with the first 3 numbers typically corresponding to the first 3 digits of the ICD-9 codes . The GPRD uses a practice -based quality marker known as up-to-st and ard to indicate when data recording by the practice adhered to specific quality measures according to GPRD Recording Guidelines , with respect to completeness , continuity , and plausibility ( 7 ) . We used only data that were collected after the up-to-st and ard date in each practice to maximize the validity of the study . Previous validation studies have shown that the GPRD captures 90 % to 95 % of the diagnoses from specialty referral visits and greater than 90 % of the principal hospital discharge diagnoses ( 1012 ) . The institutional review board at the University of Pennsylvania and the GPRD Independent Scientific Advisory Committee approved this study . The University of Pennsylvania 's institutional review board granted a waiver of informed consent because we used existing data that contained no patient identifiers . Study Cohort Study participants were drawn from a cohort of approximately 9 million patients who started follow-up in the GPRD from May 1987 to April 2002 . The Figure shows the cohort selection process and the exclusion criteria . A substantial proportion of patients met several exclusion criteria . We excluded patients who received a diagnosis of CAP within the initial 6 months of GPRD follow-up to avoid misclassification of prevalent CAP cases as incident cases ( 13 ) . We excluded patients receiving Helicobacter pylori eradication therapy  because their antibiotics concurrent with PPI therapy  could potentially mask the effect of PPI use on the risk for CAP . We excluded patients who received a diagnosis of aspiration pneumonia because it differs from CAP in terms of pathophysiology and risk factors . Only 1 % of case patients were excluded solely on the basis of this criterion . Figure . Study flow diagram . GPRD = General Practice Research Data base . * Some patients met multiple exclusion criteria . Case Patients Case patients consisted of all individuals in the eligible study cohort who received a diagnosis with their first episode of CAP within the GPRD follow-up period . The CAP diagnosis was determined on the basis of a list of relevant Read clinical classification or Oxford Medical Information System codes . The date of the first CAP diagnosis was design ated as the index date for each case . To improve the specificity of our CAP case patient definition , we did a secondary analysis in which we restricted our case-patient group to those who had a first episode of CAP in the GPRD that result ed in a hospital admission . A case of CAP was considered to have required hospitalization if the recorded diagnosis was linked with a hospitalization outcome code . Control Participants By using incidence density sampling , we r and omly selected up to 10 control participants for each case patient from the eligible study cohort . Incidence density sampling of control participants yields odds ratios ( ORs ) that are unbiased estimates of the incidence rate ratios ( 14 ) . Control participants were selected 1 case at a time with replacement ( that is , a patient can be a control participant for several cases ) . For each CAP case , we first identified all patients in the study cohort who remained at risk for CAP on the index date of the case . We then selected , among patients at risk , those who were followed at the same general practice site as the case . From those at-risk patients in the same practice site , we then selected patients who started GPRD follow-up on a date that is within 1 month before or after the GPRD start date of the case . Patients who fulfilled all criteria were eligible matched control participants and were assigned an index date that was the same as the case index date . By definition , all eligible control participants were matched to their respective case patients on index date , general practice site , and both calendar period and duration ( 1 month ) of follow-up before the index date . In the event that 10 or fewer eligible matched control participants were available for a particular case , all control participants were included . If more than 10 eligible matched control participants were available for a case , we r and omly selected 10 for our analysis . We then repeated the process for all case patients . We were able to identify 10 control participants for greater than 99 % of the cases and at least 1 eligible matched control participant for all cases . The reason for choosing 10 control participants was based on considerations for statistical power and efficiency of analysis . Generally , significant statistical power can be gained by going from a 1-to-1 to a 1-to-10 casecontrol ratio . There would be little further gain in statistical power , yet the computational time would increase significantly by increasing the controlcase ratio above 10 . Measure of Exposure The primary exposure of interest was current PPI therapy : use of any PPI ( esomeprazole , omeprazole , rabeprazole , pantoprazole , or lansoprazole ) within 30 days before the index date . Patients were considered to be exposed if they had a PPI prescription that would have lasted beyond 30 days before the index date . Among current PPI recipients , we examined the effect of daily dose ( 1.5 defined daily dose/d vs. > 1.5 defined daily dose/d ) ( 15 ) and duration of use before index date ( that is , < 30 days , 30 to 180 days , or > 180 days ) as a secondary analysis . We also did a sensitivity analysis by varying the current exposure window to 15 , 60 , 90 , and 120 days . Past recipients were those who were exposed to PPI therapy that ended more than 30 days before the index date in the primary analysis . Statistical Analysis We used conditional logistic BACKGROUND AND AIMS GERD patients frequently complain of regurgitation of gastric contents . Medical therapy with proton-pump inhibitors ( PPIs ) is frequently ineffective in alleviating regurgitation symptoms , because PPIs do nothing to restore a weak lower esophageal sphincter . Our aim was to compare effectiveness of increased PPI dosing with laparoscopic magnetic sphincter augmentation ( MSA ) in patients with moderate-to-severe regurgitation despite once-daily PPI therapy . METHODS One hundred fifty-two patients with GERD , aged ≥21 years with moderate-to-severe regurgitation despite 8 weeks of once-daily PPI therapy , were prospect ively enrolled at 21 U.S. sites . Participants were r and omized 2:1 to treatment with twice-daily ( BID ) PPIs ( N = 102 ) or to laparoscopic MSA ( N = 50 ) . St and ardized foregut symptom question naires and ambulatory esophageal reflux monitoring were performed at baseline and at 6 months . Relief of regurgitation , improvement in foregut question naire scores , decrease in esophageal acid exposure and reflux events , discontinuation of PPIs , and adverse events were the measures of efficacy . RESULTS Per protocol , 89 % ( 42/47 ) of treated patients with MSA reported relief of regurgitation compared with 10 % ( 10/101 ) of the BID PPI group ( P < .001 ) at the 6-month primary endpoint . By intention-to-treat analysis , 84 % ( 42/50 ) of patients in the MSA group and 10 % ( 10/102 ) in the BID PPI group met this primary endpoint ( P < .001 ) . Eighty-one percent ( 38/47 ) of patients with MSA versus 8 % ( 7/87 ) of patients with BID PPI had ≥50 % improvement in GERD-health-related quality of life scores ( P < .001 ) , and 91 % ( 43/47 ) remained off of PPI therapy . A normal number of reflux episodes and acid exposures was observed in 91 % ( 40/44 ) and 89 % ( 39/44 ) of MSA patients , respectively , compared with 58 % ( 46/79 ) ( P < .001 ) and 75 % ( 59/79 ) ( P = .065 ) of BID PPI patients at 6 months . No significant safety issues were observed . In MSA patients , 28 % reported transient dysphagia ; 4 % reported ongoing dysphagia . CONCLUSION Patients with GERD with moderate-to-severe regurgitation , especially despite once-daily PPI treatment , should be considered for minimally invasive treatment with MSA rather than increased PPI therapy . ( Clinical trial registration number : NCT02505945 . ) Gastroenterologists frequently prescribe proton pump inhibitors ( PPIs ) for the prevention of nonsteroidal anti-inflammatory drug-induced upper gastrointestinal ( GI ) bleeding . There is good scientific evidence to support this treatment strategy ( 1 ) . It is increasingly recognized that antiplatelet agents such as clopidogrel are also associated with increased rates of GI bleeding , similar to those reported with cardioprotective doses of acetylsalicylic acid ( ASA ) ( 2 ) . Indeed , a r and omized controlled trial ( 3 ) has demonstrated that the risk of GI bleeding is higher in patients taking clopidogrel compared with those taking ASA plus a PPI .  When administered in combination with ASA , clopidogrel is particularly potent in increasing the risk for upper GI bleeding ( RR of bleeding 15.2 ; 95 % CI 4.1 to 56.5 ) ( 4 ) . Because of this , PPIs are prescribed with clopidogrel in this situation in the belief that their administration will reduce bleeding . Until recently , the safety of this therapeutic manoeuvre has not been question ed . It is well known in the cardiovascular community that the antiplatelet effect of clopidogrel varies from patient to patient , and that reduced platelet inhibition by clopidogrel is associated with an increased risk for cardiac events ( 5 ) . The mechanisms underlying clopidogrel resistance are controversial and may relate to heterogeneity in clopidogrel metabolism . Clopidogrel is a prodrug that requires metabolism by cytochrome P450 to an active form . One isoenzyme potentially critical in this step is cytochrome P450 2C19 ( CYP2C19 ) . It has been demonstrated that this critical enzyme can be inhibited by PPIs and that reduced patient responsiveness to clopidogrel may be associated with PPI use . An example of this drug-drug interaction is seen in the Omeprazole CLopidogrel Aspirin ( OCLA ) study ( 6 ) . One hundred twenty-four consecutive patients undergoing coronary artery stent implantation were r and omly assigned to clopidogrel plus omeprazole ( 20 mg/day ) or clopidogrel plus placebo . The effect of  clopidogrel on platelet function was assessed by using the platelet phosphorylated vasodilator-stimulated phosphoprotein assay at day 7 . The study found that the omeprazole group had a significantly decreased clopidogrel inhibitory effect on platelet function . This report has prompted the United States Food and Drug Administration to request additional studies from the manufacturers of clopidogrel ( sanofi-aventis , Bristol-Myers Squibb ) to further characterize this potential interaction . In addition to the OCLA trial , two large observational studies ( 7,8 ) presented in abstract form have suggested that PPIs may attenuate the beneficial effects of clopidogrel . However , these studies have several shortcomings and a joint comment by the American College of Cardiology ( ACC ) , the American Heart Association ( AHA ) and the American College of Gastroenterology ( ACG ) stated that “ In the interest of patient safety , the AHA/ACC and the ACG advise that patients who are currently taking these medications should not change their medication regimen unless advised by their health care provider ” ( 9,10 ) . A new Canadian study by Juurlink et al ( 10 ) examined hospital discharge data after treatment for myocardial infa rct ion . The investigators found that readmission rates for cardiovascular events within 90 days were statistically higher in patients taking PPIs and clopidogrel .  This interaction was not demonstrated with pantoprazole . Similar observations were made in a recently published American study ( 11 ) that was previously available only in abstract form . Should these new data change the recommendation by ACC/AHA and ACG ? Should we avoid using PPI therapy in patients taking clopidogrel or at least switch them to pantoprazole ? The Canadian ( 10 ) and American ( 11 ) studies are difficult to interpret because the increase in the RR of cardiovascular events for patients taking PPIs was very modest . Because these studies relied on provincial or Veterans Affairs ’ retrospective data bases , the authors were unable to control for important confounding factors . Studies ( 12 ) have shown that patients at high risk for upper GI bleeding ( and therefore more likely to be prescribed PPI therapy ) are also at higher risk of mortality from cardiovascular events . The results seen in these observational studies may simply be due to a greater tendency to prescribe prophylactic PPIs to patients at higher risk of cardiovascular events . Therefore , it would be important to control for predictors of recurrent myocardial infa rct ion such as left ventricular function , smoking status , ASA use and blood pressure . In both studies , the control and case groups had marked differences in important comorbid health factors , with those taking PPIs  having a higher prevalence of renal disease , cancer , chronic obstructive pulmonary disease , congestive heart failure , low left ventricular ejection fraction , previous myocardial infa rct ion , previous coronary artery bypass surgery and diabetes mellitus . The authors performed the appropriate analyses to control for these imbalances but statistics can not control for unknown or unmeasured confounders that may also exist between the two groups . Given the differences both studies found between cases and controls , it is likely that further imbalances exist and the results could simply be due to residual confounding . To demonstrate the effect of these confounders , a r and omized controlled trial ( 13 ) of clopidogrel versus placebo stratified for PPI use found that patients given PPIs were more likely to have a cardiovascular event at one year compared with subjects not taking PPIs . Clopidogrel , however , reduced the incidence of cardiovascular events at one year compared with placebo , regardless of whether patients were taking a PPI . Are there other factors at play that may provide an alternative explanation to the PPI-clopidogrel interaction theory ? Recently , the existence of reduced-function CYP2C19 alleles has been characterized ( 14 ) . It was shown that carriers of a CYP2C19 reduced-function allele have significantly lower levels of the active metabolite of clopidogrel  , diminished platelet inhibition and a higher rate of major adverse cardiovascular events , including stent thrombosis , than do noncarriers . To date , there are no published reports of the interaction between these alleles and PPIs . The distribution of these reduced-function alleles in the general population is unknown but preliminary evidence suggests that they may be present in 30 % of Caucasians and in up to 55 % of East Asians ( 15 ) . Is there a difference between PPIs in their ability to inhibit CYP2C19 ? Juurlink et al ( 10 ) suggest that pantoprazole does not significantly inhibit CYP2C19 . However , a systematic review ( 16 ) evaluating the impact of PPIs on cytochrome P450 suggests that the data are heterogeneous and the picture is far from clear . As well , a recent Austrian study ( 17 ) of 300 patients undergoing coronary stent insertion found no effect of either pantoprazole or esomeprazole on platelet inhibition by clopidogrel . Esomeprazole was not evaluated by Juurlink et al ( 10 ) because this drug was not captured by the Ontario Health Insurance Plan data base . Furthermore , from an epidemiological perspective , the data regarding pantoprazole are not as statistically signficant as Juurlink et al ( 10 ) cl aim . When conducting subgroup analyses , it is important not to find just one subgroup that is ( or is not ) statistically significant for the outcome of interest . The conservative statistical approach is to determine whether one subgroup is significantly different from the other ( ie , if there is significant heterogeneity between groups ) . When this analysis was conducted , there was no significant difference between pantoprazole and the other PPIs ( χ2=2.99 , degrees of freedom = 1 ; P=0.08 ) . In light of the above , should PPI prophylaxis of GI bleeding for patients taking ASA and clopidogrel be curtailed ? Given the ambiguity in the current level of evidence , we believe that the conclusion reached by the ACC/AHA and ACG remains valid . The United States Food and Drug Administration have also maintained that there is insufficient evidence regarding the interaction between clopidogrel and PPIs , and have highlighted the need for further studies ( 18 ) . The data are far from clear and multiple confounders require a careful re appraisal of the literature . In particular , some of the previous investigations , such as the OCLA study , will need to be repeated with a subgroup analysis based on reduced-function CYP2C19 allele status . GI bleeding in the setting of ASA and clopidogrel is often severe and is frequently associated with adverse outcomes in groups with pre-existing cardiovascular disease . Discontinuation of PPI prophylaxis for these patients , given the current shaky level of evidence , is premature at best and hazardous at worst
Conclusions We demonstrate a significant association between the use of PPIs and increased risk of fall .
In addition , there is potentially higher risk of fall among PPIs users over time
Background Fall prevention among older adults is a worldwide public health advocacy because of negative consequences of fall .
Recent studies have shown that proton pump inhibitors ( PPIs ) increase the risk of fall .
PPIs are among the widely prescribed medications oftentimes without clear indications .
Concerns for safety of long-term use of PPIs have been raised by numerous studies .