previous observational studies and their meta - analysis have found that proton pump inhibitors are associated with an increased risk of community - acquired pneumonia . potential confounding by gastroesophageal reflux disease and protopathic bias limit the conclusions that can be drawn from these studies . proton pump inhibitors are also prescribed prophylactically with non - steroidal anti - inflammatory drugs , and the study of this population may overcome the limitations of previous studies examining this association . proton pump inhibitors are not associated with an increased risk of hospitalisation for community - acquired pneumonia ( hcap ) ( adjusted or=1.05 ; 95% ci 0.89 to 1.25 ) . there is also no association between histamine-2 receptor antagonists and the risk of hcap ( adjusted or=0.95 , 95% ci 0.75 to 1.21 ) , suggesting a lack of dose - response relationship between potency of gastric acid suppression and the risk of hcap . our results suggest that concerns regarding this association should not influence prescribing of gastric acid - suppressing medications . overutilisation of proton pump inhibitors ( ppis ) and their potential health risks are attracting increasing attention.1 
 2 one of the suspected health concerns associated with their use is a possible increase in the risk of pneumonia.3 the proposed mechanism behind this potential effect is bacterial overgrowth of the stomach and oesophagus increasing the risk of bacterial aspiration . although evidence from previous observational studies support the existence of an association between the use of ppis and the risk of community - acquired pneumonia,3 these studies had important limitations . these limitations include confounding due to gastroesophageal reflux disease ( gerd ) , a potentially independent risk factor for pneumonia,4 
 5 and with a sharp increase in risk observed shortly after ppi initiation,3 
 6 
 7 the likely presence of protopathic bias . although ppis are most commonly prescribed for the treatment of symptoms of gerd , they may also be prescribed concomitantly with non - steroidal anti - inflammatory drugs ( nsaids ) to prevent ulcer formation and dyspepsia.810 as patients who are prescribed ppis for this indication are less likely to have gerd , an analysis restricted to this specific cohort may help isolate the independent contribution of ppi exposure to the risk of hospitalisation for community - acquired pneumonia ( hcap ) by minimising bias from unmeasured confounders . we therefore examined the risk of hcap with ppis prescribed prophylactically in a cohort of new users of nsaids who were not previously exposed to gastric acid - suppressing medications . we also examined the association between hcap and histamine-2 receptor antagonists ( h2ras ) , a less potent class of gastroprotective agents , to investigate the effect of gastric acid suppression potency on the risk of incident hcap . our a priori hypothesis was that use of ppis and h2ras would result in an increased risk of incident hcap relative to non - use . we applied a common protocol to databases from eight jurisdictions ( alberta , saskatchewan , manitoba , ontario , quebec , nova scotia , us marketscan , and the uk 's general practice research database ( gprd ) ) as part of the canadian network for observational drug effect studies ( cnodes).11 within each jurisdiction , we conducted a retrospective cohort study of all individuals aged > 40  years who were prescribed an oral nsaid ( who anatomical therapeutic chemical ( atc ) code m01a ) for the first time between 1 january 1997 and 31 march 2010 . patients were permitted to enter the study multiple times provided that all inclusion criteria were met.12 the six canadian databases encompass > 90% of the entire population of their respective provinces , with excluded individuals being those whose drug plan coverage is funded federally ( eg , members of the armed forces , inmates of federal penitentiaries ) . the gprd includes a representative sample of the uk 's population , and marketscan contains data for those covered by large us employer health insurance plans . analyses in alberta , nova scotia , ontario and quebec were limited to those aged > 66  years as prescription drug data were not available for younger patients . analyses conducted using marketscan were limited to those aged 4065  years , as complete data capture was not possible in older patients due to their eligibility for medicare . due to data availability , analyses conducted using quebec data were restricted to a 10% random sample of patients covered by the provincial drug plan . in all analyses , the study population was restricted to those receiving an nsaid prescription of > 28  days duration as patients receiving short - duration prescriptions are unlikely to be prescribed a ppi for prophylactic reasons . for prescriptions missing duration , duration was estimated by multiplying the dosage by the quantity dispensed , and dividing by who - defined daily dosage . we excluded all patients who met any of the following criteria : ( 1 ) aged < 40  years at cohort entry due to the low incidence of hcap in this population ; ( 2 ) received a prescription for a ppi , a h2ra , or a nsaid ( any route of administration ) in the 6  months prior to cohort entry ; ( 3 ) had an hcap ( icd-9-cm code ( in any field ) : 480.x-487.x ; icd-10-ca code : j10.0  j18.9 ) or an extended emergency room visit for community - acquired pneumonia ( defined as the presence of emergency room billing codes for pneumonia on two consecutive days ) in the year prior to cohort entry in databases in which emergency room data were available ; ( 4 ) hospitalised at the time of cohort entry ; ( 5 ) received a prescription for medications used for the treatment of tuberculosis ( atc code j04a ) in databases where these data were available ; ( 6 ) had a history of cancer ( other than non - melanoma skin cancer ) in the year prior to cohort entry as cancer and its treatments may increase the risk of pneumonia ; ( 7 ) hospitalised > 3  days within the 30  days before cohort entry to ensure that all events were community - acquired and ( 8) had < 1  year of continuous observation time in the database prior to cohort entry to ensure complete assessment of relevant medical history . patients meeting the study inclusion criteria were followed until a first - ever hcap ( defined below ) , death from any cause , admission for a hospitalisation with a length of stay > 3  days , departure from the database , end of follow - up ( 180  days ) , or end of the study period ( 30 september 2011 ) , whichever came first . we obtained all information for medications dispensed by pharmacies for all patients , except for the gprd , which collects prescriptions entered electronically . patients receiving a prescription for any of the following oral ppis ( alone or in combination therapy ) on the same day as their nsaid prescription ( cohort entry ) were considered exposed to ppis : esomeprazole , omeprazole , pantoprazole , lansoprazole and rabeprazole . the second category included patients prescribed any of the following oral h2ras on the same day as their nsaid prescription ( cohort entry ) : cimetidine , ranitidine , famotidine , nisatidine , niperotidine , roxatidine , ranitidine bismuth citrate , lafutidine , cimetidine combinations and famotidine combinations . the third category , which served as the reference category , consisted of those not prescribed a ppi or h2ra on the same day as the nsaid prescription defining cohort entry . patients prescribed both an h2ra and ppi on the day of cohort entry were excluded . in our primary analysis , exposure was defined using an intention - to - treat approach . in sensitivity analyses , we examined the effect of misclassification of exposure by excluding initially unexposed patients prescribed a ppi or h2ra during follow - up . the primary outcome was incident hcap during the 6  months following initiation of nsaid therapy . hcap was defined using a validated algorithm based on icd-10 discharge codes.13 in a previous validation study conducted using data from alberta , this definition was associated with positive and negative predictive values of 96% and 98% compared with data extracted from patients charts and 71% and 84% compared with chest x - ray reports . the definition was restricted to codes identified as the most responsible diagnosis that did not also appear as a code indicating that the condition arose during hospitalisation . we used multiple logistic regression to estimate adjusted ors ( aor ) and corresponding 95% cis . as the proportion of patients with hcap during the 6-month follow - up period is small , the estimated ors approximate the cumulative incidence ratios.14 to further minimise bias from confounding by indication and other factors , we constructed high - dimensional propensity scores.15 the following variables were forced into the propensity score model : index year , income category , hospitalisation in the previous year , use of > 4 medications in the previous year , > 4 physician visits in the previous year , asthma , chronic obstructive pulmonary disease , bronchiectasis , diabetes and use of immunosuppressive agents , inhaled bronchodilators , inhaled corticosteroids , non - topical antibiotics , non - topical corticosteroids and , where data were available , use of influenza or pneumococcal vaccines . excessive alcohol use , body mass index ( bmi ) and smoking were also forced into the propensity score model fit in the gprd . in addition to these prespecified potential confounders , up to 500 additional confounders were empirically selected for inclusion in the propensity score models . comorbidities were assessed using discharge diagnoses in the year before cohort entry , and medications were assessed using prescriptions in the year before cohort entry . following the estimation of the high - dimensional propensity score for each patient using a logistic model , patients were categorised into propensity score deciles , which were included as a categorical variable in our final logistic model to estimate the independent effect of ppis on the risk of hcap . we also adjusted for age , sex , previous non - hospitalised pneumonia , and prescription of ppis , h2ras and nsaids in the 712  months before cohort entry ( prescriptions in the 6  months before cohort entry resulted in exclusion ) in our outcome model . in order to account for the possibility of multiple cohort entry dates for each patient , generalised estimating equations were used . analyses were then repeated to estimate the effect of h2ras on the risk of hcap . ppis and h2ras were examined separately to allow for the calculation of separate high - dimensional propensity scores for each exposure . first , analyses were restricted to one randomly selected observation per patient to reduce the influence of intrasubject correlation . second , we excluded patients who received a prescription for a ppi , h2ra , or nsaid in the previous 12  months rather than in the prior 6  months to further increase the probability that patients with gerd were excluded . finally , we repeated analyses excluding  crossovers : unexposed patients who received a ppi or h2ra during follow - up , ppi users also exposed to h2ras during follow - up , and h2ra users also exposed to ppis during follow - up . all site - specific analyses were conducted using sas v.9.2 ( the sas institute , cary , north carolina , usa ) . site - specific estimates were then pooled using fixed - effect meta - analytic models with inverse variance weighting.16 the amount of between - site heterogeneity was estimated by the i statistic.17 in sensitivity analyses , data were pooled using random - effects models . in additional sensitivity analyses , data from nova scotia were excluded as the nova scotia seniors pharmacare program required specific criteria to be followed prior to ppi reimbursement until 11 january 2008.18 all meta - analyses were conducted using stata v.11.2 ( statacorp lp , college station , texas , usa ) . we applied a common protocol to databases from eight jurisdictions ( alberta , saskatchewan , manitoba , ontario , quebec , nova scotia , us marketscan , and the uk 's general practice research database ( gprd ) ) as part of the canadian network for observational drug effect studies ( cnodes).11 within each jurisdiction , we conducted a retrospective cohort study of all individuals aged > 40  years who were prescribed an oral nsaid ( who anatomical therapeutic chemical ( atc ) code m01a ) for the first time between 1 january 1997 and 31 march 2010 . patients were permitted to enter the study multiple times provided that all inclusion criteria were met.12 the six canadian databases encompass > 90% of the entire population of their respective provinces , with excluded individuals being those whose drug plan coverage is funded federally ( eg , members of the armed forces , inmates of federal penitentiaries ) . the gprd includes a representative sample of the uk 's population , and marketscan contains data for those covered by large us employer health insurance plans . analyses in alberta , nova scotia , ontario and quebec were limited to those aged > 66  years as prescription drug data were not available for younger patients . analyses conducted using marketscan were limited to those aged 4065  years , as complete data capture was not possible in older patients due to their eligibility for medicare . due to data availability , analyses conducted using quebec data were restricted to a 10% random sample of patients covered by the provincial drug plan . in all analyses , the study population was restricted to those receiving an nsaid prescription of > 28  days duration as patients receiving short - duration prescriptions are unlikely to be prescribed a ppi for prophylactic reasons . for prescriptions missing duration , duration was estimated by multiplying the dosage by the quantity dispensed , and dividing by who - defined daily dosage . we excluded all patients who met any of the following criteria : ( 1 ) aged < 40  years at cohort entry due to the low incidence of hcap in this population ; ( 2 ) received a prescription for a ppi , a h2ra , or a nsaid ( any route of administration ) in the 6  months prior to cohort entry ; ( 3 ) had an hcap ( icd-9-cm code ( in any field ) : 480.x-487.x ; icd-10-ca code : j10.0  j18.9 ) or an extended emergency room visit for community - acquired pneumonia ( defined as the presence of emergency room billing codes for pneumonia on two consecutive days ) in the year prior to cohort entry in databases in which emergency room data were available ; ( 4 ) hospitalised at the time of cohort entry ; ( 5 ) received a prescription for medications used for the treatment of tuberculosis ( atc code j04a ) in databases where these data were available ; ( 6 ) had a history of cancer ( other than non - melanoma skin cancer ) in the year prior to cohort entry as cancer and its treatments may increase the risk of pneumonia ; ( 7 ) hospitalised > 3  days within the 30  days before cohort entry to ensure that all events were community - acquired and ( 8) had < 1  year of continuous observation time in the database prior to cohort entry to ensure complete assessment of relevant medical history . patients meeting the study inclusion criteria were followed until a first - ever hcap ( defined below ) , death from any cause , admission for a hospitalisation with a length of stay > 3  days , departure from the database , end of follow - up ( 180  days ) , or end of the study period ( 30 september 2011 ) , whichever came first . we obtained all information for medications dispensed by pharmacies for all patients , except for the gprd , which collects prescriptions entered electronically . patients receiving a prescription for any of the following oral ppis ( alone or in combination therapy ) on the same day as their nsaid prescription ( cohort entry ) were considered exposed to ppis : esomeprazole , omeprazole , pantoprazole , lansoprazole and rabeprazole . the second category included patients prescribed any of the following oral h2ras on the same day as their nsaid prescription ( cohort entry ) : cimetidine , ranitidine , famotidine , nisatidine , niperotidine , roxatidine , ranitidine bismuth citrate , lafutidine , cimetidine combinations and famotidine combinations . the third category , which served as the reference category , consisted of those not prescribed a ppi or h2ra on the same day as the nsaid prescription defining cohort entry . patients prescribed both an h2ra and ppi on the day of cohort entry were excluded . in our primary analysis , exposure was defined using an intention - to - treat approach . in sensitivity analyses , we examined the effect of misclassification of exposure by excluding initially unexposed patients prescribed a ppi or h2ra during follow - up . the primary outcome was incident hcap during the 6  months following initiation of nsaid therapy . hcap was defined using a validated algorithm based on icd-10 discharge codes.13 in a previous validation study conducted using data from alberta , this definition was associated with positive and negative predictive values of 96% and 98% compared with data extracted from patients charts and 71% and 84% compared with chest x - ray reports . the definition was restricted to codes identified as the most responsible diagnosis that did not also appear as a code indicating that the condition arose during hospitalisation . in quebec , we used multiple logistic regression to estimate adjusted ors ( aor ) and corresponding 95% cis . as the proportion of patients with hcap during the 6-month follow - up period is small , the estimated ors approximate the cumulative incidence ratios.14 to further minimise bias from confounding by indication and other factors , we constructed high - dimensional propensity scores.15 the following variables were forced into the propensity score model : index year , income category , hospitalisation in the previous year , use of > 4 medications in the previous year , > 4 physician visits in the previous year , asthma , chronic obstructive pulmonary disease , bronchiectasis , diabetes and use of immunosuppressive agents , inhaled bronchodilators , inhaled corticosteroids , non - topical antibiotics , non - topical corticosteroids and , where data were available , use of influenza or pneumococcal vaccines . excessive alcohol use , body mass index ( bmi ) and smoking were also forced into the propensity score model fit in the gprd . in addition to these prespecified potential confounders , up to 500 additional confounders were empirically selected for inclusion in the propensity score models . comorbidities were assessed using discharge diagnoses in the year before cohort entry , and medications were assessed using prescriptions in the year before cohort entry . following the estimation of the high - dimensional propensity score for each patient using a logistic model , patients were categorised into propensity score deciles , which were included as a categorical variable in our final logistic model to estimate the independent effect of ppis on the risk of hcap . we also adjusted for age , sex , previous non - hospitalised pneumonia , and prescription of ppis , h2ras and nsaids in the 712  months before cohort entry ( prescriptions in the 6  months before cohort entry resulted in exclusion ) in our outcome model . in order to account for the possibility of multiple cohort entry dates for each patient , generalised analyses were then repeated to estimate the effect of h2ras on the risk of hcap . ppis and h2ras were examined separately to allow for the calculation of separate high - dimensional propensity scores for each exposure . first , analyses were restricted to one randomly selected observation per patient to reduce the influence of intrasubject correlation . second , we excluded patients who received a prescription for a ppi , h2ra , or nsaid in the previous 12  months rather than in the prior 6  months to further increase the probability that patients with gerd were excluded . finally , we repeated analyses excluding  crossovers : unexposed patients who received a ppi or h2ra during follow - up , ppi users also exposed to h2ras during follow - up , and h2ra users also exposed to ppis during follow - up . all site - specific analyses were conducted using sas v.9.2 ( the sas institute , cary , north carolina , usa ) . site - specific estimates were then pooled using fixed - effect meta - analytic models with inverse variance weighting.16 the amount of between - site heterogeneity was estimated by the i statistic.17 in sensitivity analyses , data were pooled using random - effects models . in additional sensitivity analyses , data from nova scotia were excluded as the nova scotia seniors pharmacare program required specific criteria to be followed prior to ppi reimbursement until 11 january 2008.18 all meta - analyses were conducted using stata v.11.2 ( statacorp lp , college station , texas , usa ) . when data were pooled across all sites , our ppi analyses included 96  870 exposed and 4  141  634 unexposed patients , and our h2ra analyses included 47  344 exposed and 4  342  733 unexposed patients . all sites contributed data to the ppi analysis except saskatchewan , where ppi data were incomplete because ppis are listed in the formulary with restricted coverage and , therefore , require approval under the exception drug status program in order to be captured in the database . compared with unexposed patients , those prescribed ppis were more likely to be older , female and had a higher burden of comorbidities ( table 1 ) . in the gprd , where additional information was available , patients prescribed ppis were also more likely to have a history of excessive alcohol use ( 4.1% vs 2.8% ) and a history of smoking ( 53.4% vs 49.8% among those with smoking data ) but a similar proportion of patients with a bmi > 30  kg / m ( both 29.7% among those with bmi data ) . not surprisingly , in all databases , exposed patients were more likely to have been prescribed a ppi in the 712  months before cohort entry . patients prescribed ppis were also more likely to have been prescribed vaccinations for influenza and pneumonia . similar patterns in baseline characteristics were observed when comparing patients prescribed h2ras to unexposed patients ( see online supplementary appendix 1 ) . additionally , similar distributions were observed when inclusion was restricted to one , randomly selected observation per patient ( see online supplementary appendix 2 ) . demographic and clinical characteristics by exposure status at cohort entry in a restricted cohort of new users of nsaids * saskatchewan did not contribute to the ppi analysis . in addition , small differences in the unexposed groups exist in the ppi and h2ra analyses because of trimming during the estimation of high - dimensional propensity scores . alberta , ontario , quebec and nova scotia only contributed data for those > 66  years of age whereas marketscan only contributed data for those aged 4065  years . the proportion of study participants living in nursing homes was only reported by manitoba and ontario . data regarding urban / rural location were only available in alberta , manitoba , nova scotia and ontario . comorbidities and medication use are defined using data in the year prior to and including the date of cohort entry . * vaccination data were only available for the gprd , manitoba , marketscan and nova scotia . copd , chronic obstructive pulmonary disease ; gprd , general practice research database ; h2ra , histamine-2 receptor antagonist ; nsaids , non - steroidal anti - inflammatory drugs ; ppi , proton pump inhibitor . the cumulative 6-month incidence of hcap was 0.17% among patients prescribed ppis and 0.12% in unexposed patients . when data were pooled across all databases , ppis were not associated with the incidence of hcap ( aor=1.05 ; 95% ci 0.89 to 1.25 ; i=0% ) ( figure 1 ) . all site - specific aors were between 0.93 and 1.21 except for that of nova scotia ( aor=3.73 ; 95% ci 1.12 to 12.4 ) . when analyses were repeated excluding nova scotia , results were consistent with those of our primary analysis ( aor=1.03 , 95% ci 0.87 to 1.22 i=0% ) . forest plot of the association between the use of proton pump inhibitors ( ppis ) and the 6-month cumulative incidence of hospitalisation for community - acquired pneumonia in a restricted cohort of new users of non - steroidal anti - inflammatory drugs ( nsaids ) . analyses were adjusted for age , sex , previous non - hospitalised pneumonia , prescription of  ppis , histamine-2 receptor antagonists and nsaids  in the 712  months prior to cohort entry , and high - dimensional propensity score decile . analyses of the association between h2ras and hcap yielded similar results ( 6-month cumulative incidence=0.16% in the h2ra group vs 0.12% in the unexposed group ; aor=0.95 , 95% ci to 0.75 to 1.21 ; i=0% ) ( figure 2 ) . quebec did not contribute to this analysis as there were no hcaps that occurred in h2ra users in their 10% data sample . forest plot of the association between the use of histamine-2 receptor antagonists and the 6-month cumulative incidence of hospitalisation for community - acquired pneumonia in a restricted cohort of new users of non - steroidal anti - inflammatory drugs ( nsaids ) . analyses were adjusted for age , sex , previous non - hospitalised pneumonia , prescription of proton pump inhibitors , histamine-2 receptor antagonists and nsaids in the 712  months prior to cohort entry , and high - dimensional propensity score decile . we conducted multiple sensitivity analyses , including analyses restricted to a single , random , observation per patient analyses , that excluded those who received a prescription for a ppi , h2ra , or nsaid in the 12  months before cohort entry , and analyses that excluded crossovers . these sensitivity analyses produced results that were consistent with those of our primary analyses ( table 2 , see online supplementary appendices 38 ) . additionally , similar results were obtained in sensitivity analyses involving the use of random - effects meta - analyses ( data not shown ) . summary of analyses examining association between the use of gastric acid suppressing medications and the 6-month cumulative incidence of hospitalisation for community - acquired pneumonia in a restricted cohort of nsaids * patients prescribed a ppi , h2ra , or nsaid in the 6  months before cohort entry were excluded from all analyses . h2ra , histamine-2 receptor antagonist ; nsaids , non - steroidal anti - inflammatory drugs ;  ppi , proton pump inhibitor . when data were pooled across all sites , our ppi analyses included 96  870 exposed and 4  141  634 unexposed patients , and our h2ra analyses included 47  344 exposed and 4  342  733 unexposed patients . all sites contributed data to the ppi analysis except saskatchewan , where ppi data were incomplete because ppis are listed in the formulary with restricted coverage and , therefore , require approval under the exception drug status program in order to be captured in the database . compared with unexposed patients , those prescribed ppis were more likely to be older , female and had a higher burden of comorbidities ( table 1 ) . in the gprd , where additional information was available , patients prescribed ppis were also more likely to have a history of excessive alcohol use ( 4.1% vs 2.8% ) and a history of smoking ( 53.4% vs 49.8% among those with smoking data ) but a similar proportion of patients with a bmi > 30  kg / m ( both 29.7% among those with bmi data ) . not surprisingly , in all databases , exposed patients were more likely to have been prescribed a ppi in the 712  months before cohort entry . patients prescribed ppis were also more likely to have been prescribed vaccinations for influenza and pneumonia . similar patterns in baseline characteristics were observed when comparing patients prescribed h2ras to unexposed patients ( see online supplementary appendix 1 ) . additionally , similar distributions were observed when inclusion was restricted to one , randomly selected observation per patient ( see online supplementary appendix 2 ) . demographic and clinical characteristics by exposure status at cohort entry in a restricted cohort of new users of nsaids * saskatchewan did not contribute to the ppi analysis . in addition , small differences in the unexposed groups exist in the ppi and h2ra analyses because of trimming during the estimation of high - dimensional propensity scores . alberta , ontario , quebec and nova scotia only contributed data for those > 66  years of age whereas marketscan only contributed data for those aged 4065  years . the proportion of study participants living in nursing homes was only reported by manitoba and ontario . data regarding urban / rural location were only available in alberta , manitoba , nova scotia and ontario . comorbidities and medication use are defined using data in the year prior to and including the date of cohort entry . * vaccination data were only available for the gprd , manitoba , marketscan and nova scotia . copd , chronic obstructive pulmonary disease ; gprd , general practice research database ; h2ra , histamine-2 receptor antagonist ; nsaids , non - steroidal anti - inflammatory drugs ; ppi , proton pump inhibitor . the cumulative 6-month incidence of hcap was 0.17% among patients prescribed ppis and 0.12% in unexposed patients . when data were pooled across all databases , ppis were not associated with the incidence of hcap ( aor=1.05 ; 95% ci 0.89 to 1.25 ; i=0% ) ( figure 1 ) . all site - specific aors were between 0.93 and 1.21 except for that of nova scotia ( aor=3.73 ; 95% ci 1.12 to 12.4 ) . when analyses were repeated excluding nova scotia , results were consistent with those of our primary analysis ( aor=1.03 , 95% ci 0.87 to 1.22 i=0% ) . forest plot of the association between the use of proton pump inhibitors ( ppis ) and the 6-month cumulative incidence of hospitalisation for community - acquired pneumonia in a restricted cohort of new users of non - steroidal anti - inflammatory drugs ( nsaids ) . analyses were adjusted for age , sex , previous non - hospitalised pneumonia , prescription of  ppis , histamine-2 receptor antagonists and nsaids  in the 712  months prior to cohort entry , and high - dimensional propensity score decile . analyses of the association between h2ras and hcap yielded similar results ( 6-month cumulative incidence=0.16% in the h2ra group vs 0.12% in the unexposed group ; aor=0.95 , 95% ci to 0.75 to 1.21 ; i=0% ) ( figure 2 ) . quebec did not contribute to this analysis as there were no hcaps that occurred in h2ra users in their 10% data sample . forest plot of the association between the use of histamine-2 receptor antagonists and the 6-month cumulative incidence of hospitalisation for community - acquired pneumonia in a restricted cohort of new users of non - steroidal anti - inflammatory drugs ( nsaids ) . analyses were adjusted for age , sex , previous non - hospitalised pneumonia , prescription of proton pump inhibitors , histamine-2 receptor antagonists and nsaids in the 712  months prior to cohort entry , and high - dimensional propensity score decile . we conducted multiple sensitivity analyses , including analyses restricted to a single , random , observation per patient analyses , that excluded those who received a prescription for a ppi , h2ra , or nsaid in the 12  months before cohort entry , and analyses that excluded crossovers . these sensitivity analyses produced results that were consistent with those of our primary analyses ( table 2 , see online supplementary appendices 38 ) . additionally , similar results were obtained in sensitivity analyses involving the use of random - effects meta - analyses ( data not shown ) . summary of analyses examining association between the use of gastric acid suppressing medications and the 6-month cumulative incidence of hospitalisation for community - acquired pneumonia in a restricted cohort of nsaids * patients prescribed a ppi , h2ra , or nsaid in the 6  months before cohort entry were excluded from all analyses . h2ra , histamine-2 receptor antagonist ; nsaids , non - steroidal anti - inflammatory drugs ;  ppi , proton pump inhibitor . among new users of nsaids , we found that ppis were not associated with the risk of hcap . similar results were obtained across all sites except nova scotia , where formulary restrictions introduced strong confounding by indication . the potential association between use of gastric acid - suppressing medications and pneumonia has been examined extensively.3 
 6 
 7 
 1925 eom and colleagues3 meta - analysed data across eight observational studies and found that ppi use was associated with a 27% increased risk of either hospital - acquired or community - acquired pneumonia ( aor=1.27 , 95% ci 1.11 to 1.46 ) . this increased risk was predominantly due to an increased risk of community - acquired pneumonia ( five studies : aor=1.34 , 95% ci 1.14 to 1.57 ) . importantly , a strong temporal relationship was observed , with a duration of exposure < 7  days being associated with a three - fold increase in the risk of pneumonia ( aor=3.95 , 95% ci 2.86 to 5.45 ) . these apparent short - term effects are further illustrated in the nested case - control study by sarkar and colleagues,20 who found a null association overall but a substantially increased risk of community - acquired pneumonia in those who initiated ppi therapy in the 2  days before the index date ( aor=6.5 , 95% ci 3.95 to 10.80 ) . such a temporally close increased risk , before ppis achieve full effect , is suggestive of protopathic bias due to early signs of pneumonia , including non - specific chest symptoms and discomfort , being misdiagnosed as gerd . these studies were also likely affected by confounding by gerd , which has been associated with an increased risk of respiratory symptoms , and may promote the translocation of gastric contents into the respiratory tract.26 
 27 the role of confounding in the purported ppi - pneumonia association has recently been examined by jena and colleagues , who found that ppi users also had increased risk of other medical conditions thought to be unrelated to ppi use.28 our null results , both from our primary analyses and in sensitivity analyses that excluded all patients who received a prescription for a ppi , h2ra , or nsaid in the year before cohort entry , suggest that the ppi - pneumonia association found in previous observational studies6 
 7 
 1923 and published meta - analyses3 
 24 was likely due to the presence of confounding and/or protopathic bias ; these limitations were minimised in the present study by our use of a restricted cohort and an intention - to - treat approach . in addition to these previous observational studies , the association between ppis and community - acquired pneumonia was examined in a retrospective analysis of 31 trials of esomeprazole.29 the rate of pneumonia was similar in those receiving this ppi and those treated with placebo or non - ppi comparator ( or=0.94 , 99% ci 0.29 to 3.07 ) . however , the generalisability of these trial data to a real - world setting is unclear . furthermore , despite the large sample size ( n=16  000 ) , the wide 99% ci suggests that the analysis was underpowered to identify clinically important effects . first , although the use of ppis specifically to prevent nsaid - related gastrointestinal complications is relatively uncommon , analysis of data from seven sites resulted in a sufficiently large source population to examine this association using a restricted cohort of new nsaid users , chosen to avoid confounding by indication and protopathic bias . second , protection against confounding was also provided by our use of high - dimensional propensity scores . third , our use of a distributed - protocol approach decreased the heterogeneity typically present in meta - analyses of observational studies while respecting legal and ethical privacy requirements.30 
 31 fourth , while respiratory illnesses , such as pneumonia , chronic obstructive pulmonary disorder and acute asthma exacerbations may be misdiagnosed as one or the other , we used a validated hcap definition,13 minimising potential misclassification . this study involved databases that have been used extensively for pharmacoepidemiologic investigations , and previous studies indicate that these data are valid.3234 finally , our use of a new user design avoided the underestimation of effects that frequently occurs with the study of prevalent users.12 our study also has some potential limitations . first , at least two forms of h2ras are available without a prescription in canada ( ranitidine 75  mg/150  mg and famotidine 10  mg/20  mg ) , and some ppis are available over the counter in the usa and the uk . unfortunately , if there is a true increased risk of hcap due to the use of  gastroprotective agents , the exclusion of over - the - counter gastric acid - suppressing medications may bias the results towards the null . second , we used an intention - to - treat approach , which mirrors that of a randomised controlled trial . this analytical approach may result in some exposure misclassification as some unexposed patients may have initiated therapy during follow - up and some exposed patients did not receive additional prescriptions during follow - up , resulting in a potential bias towards the null . however , sensitivity analyses that excluded unexposed patients who initiated ppi therapy during follow - up produced results that were consistent with those of our primary analysis . with exposure defined using written prescriptions ( in the gprd ) and medication dispensations ( the other seven sites ) , third , with the use of a restricted cohort , the generalisability of our results is unclear . for example , it is possible that the anti - inflammatory properties of nsaids interfere with the harmful side effects of ppis found in other studies . fourth , data regarding the indication for acid suppression ( ie , treatment of gerd , gastroprotection ) were not available . nonetheless , with inclusion restricted to those receiving an nsaid prescription with no prescriptions for ppis or h2ras in the prior 6  months ( 12  months in sensitivity analyses ) , the vast majority of ppi and h2ra prescriptions were likely for gastroprotection . finally , while there is some evidence that coding practices for hcap may have changed over time,35 it is unlikely that these changes were differential across exposure groups . our common protocol analysis does not support the hypothesis of an independent association between gastric acid - suppressing medications and the risk of hcap . the positive results of previous studies examining this association are likely due to confounding and protopathic bias , which have been minimised in the present study through the use of a restricted cohort approach . our results call a causal ppi - hcap association into question and suggest that concerns regarding this association should not influence prescribing of gastric acid - suppressing medications .
objectiveprevious observational studies suggest that the use of proton pump inhibitors ( ppis ) may increase the risk of hospitalisation for community - acquired pneumonia ( hcap ) . 
 however , the potential presence of confounding and protopathic biases limits the conclusions that can be drawn from these studies . 
 our objective was , therefore , to examine the risk of hcap with ppis prescribed prophylactically in new users of non - steroidal anti - inflammatory drugs ( nsaids).designwe formed eight restricted cohorts of new users of nsaids , aged 40  years , using a common protocol in eight databases ( alberta , saskatchewan , manitoba , ontario , quebec , nova scotia , us marketscan and the uk 's general practice research database ( gprd ) ) . 
 this specific patient population was studied to minimise bias due to unmeasured confounders . 
 high - dimensional propensity scores were used to estimate site - specific adjusted ors ( aors ) for hcap at 6  months in ppi patients compared with unexposed patients . 
 fixed - effects meta - analytic models were used to estimate overall effects across databases.resultsof the 4  238  504 new users of nsaids , 2.3% also started a ppi . 
 the cumulative 6-month incidence of hcap was 0.17% among patients prescribed ppis and 0.12% in unexposed patients . 
 after adjustment , ppis were not associated with an increased risk of hcap ( aor=1.05 ; 95% ci 0.89 to 1.25 ) . 
 histamine-2 receptor antagonists yielded similar results ( aor=0.95 , 95% ci  0.75 to 1.21).conclusionsour study does not support the proposition of a pharmacological effect of gastric acid suppressors on the risk of hcap .