Marshall Miller, MD

Proton pump inhibitors (PPIs) are the third most commonly prescribed class of medication in the United States, with $13.6 billion in yearly sales.1 Despite their effectiveness in treating acid reflux2 and their mortality benefit in the treatment of patients with gastrointestinal bleeding,3 recent literature has identified a number of risks associated with PPIs, including an increased incidence of Clostridium difficile infection,4 decreased effectiveness of clopidogrel in patients with acute coronary syndrome,5 increased risk of community‐ and hospital‐acquired pneumonia, and an increased risk of hip fracture.69 Additionally, in March of 2011, the US Food and Drug Administration (FDA) issued a warning regarding the potential for PPIs to cause low magnesium levels which can, in turn, cause muscle spasms, an irregular heartbeat, and convulsions.10

Inappropriate PPI prescription practice has been demonstrated in the primary care setting,11 as well as in small studies conducted in the hospital setting.1216 We hypothesized that many hospitalized patients receive these medications without having an accepted indication, and examined 2 populations of hospitalized patients, including administrative data from 6.5 million discharges from US university hospitals, to look for appropriate diagnoses justifying their use.

METHODS

We performed a retrospective review of administrative data collected between January 1, 2008 and December 31, 2009 from 2 patient populations: (a) those discharged from Denver Health (DH), a university‐affiliated public safety net hospital in Denver, CO; and (b) patients discharged from 112 academic health centers and 256 of their affiliated hospitals that participate in the University HealthSystem Consortium (UHC). The Colorado Multiple Institution Review Board reviewed and approved the conduct of this study.

Inclusion criteria for both populations were age >18 or <90 years, and hospitalization on a Medicine service. Prisoners and women known to be pregnant were excluded. In both cohorts, if patients had more than 1 admission during the 2‐year study period, only data from the first admission were used.

We recorded demographics, admitting diagnosis, and discharge diagnoses together with information pertaining to the name, route, and duration of administration of all PPIs (ie, omeprazole, lansoprazole, esomeprazole, pantoprazole, rabeprazole). We created a broadly inclusive set of valid indications for PPIs by incorporating diagnoses that could be identified by International Classification of Diseases, Ninth Revision.

(ICD‐9) codes from a number of previously published sources including the National Institute of Clinical Excellence (NICE) guidelines issued by the National Health Service (NHS) of the United Kingdom in 200012, 1721 (Table 1).

To assess the accuracy of the administrative data from DH, we also reviewed the Emergency Department histories, admission histories, progress notes, electronic pharmacy records, endoscopy reports, and discharge summaries of 123 patients randomly selected (ie, a 5% sample) from the group of patients identified by administrative data to have received a PPI without a valid indication, looking for any accepted indication that might have been missed in the administrative data.

All analyses were performed using SAS Enterprise Guide 4.1 (SAS Institute, Cary, NC). A Student t test was used to compare continuous variables and a chi‐square test was used to compare categorical variables. Bonferroni corrections were used for multiple comparisons, such that P values less than 0.01 were considered to be significant for categorical variables.

RESULTS

Inclusion criteria were met by 9875 patients in the Denver Health database and 6,592,100 patients in the UHC database. The demographics and primary discharge diagnoses for these patients are summarized in Table 2.

Only 39% and 27% of the patients in the DH and UHC databases, respectively, had a valid indication for PPIs on the basis of discharge diagnoses (Table 3). In the DH data, if admission ICD‐9 codes were also inspected for valid PPI indications, 1579 (40%) of patients receiving PPIs had a valid indication (admission ICD‐9 codes were not available for patients in the UHC database). Thirty‐one percent of Denver Health patients spent time in the intensive care unit (ICU) during their hospital stay and 65% of those patients received a PPI without a valid indication, as compared to 59% of patients who remained on the General Medicine ward (Table 3).

Higher rates of concurrent C. difficile infections were observed in patients receiving PPIs in both databases; a higher rate of concurrent diagnosis of pneumonia was seen in patients receiving PPIs in the UHC population, with a nonsignificant trend towards the same finding in DH patients (Table 4).

Chart review in the DH population found valid indications for PPIs in 19% of patients who were thought not have a valid indication on the basis of the administrative data (Table 5). For 56% of those in whom no valid indication was confirmed, physicians identified prophylaxis as the justification.

DISCUSSION

The important finding of this study was that the majority of patients in 2 large groups of Medicine patients hospitalized in university‐affiliated hospitals received PPIs without having a valid indication. To our knowledge, the more than 900,000 UHC patients who received a PPI during their hospitalization represent the largest inpatient population evaluated for appropriateness of PPI prescriptions.

Our finding that 41% of the patients admitted to the DH Medicine service received a PPI during their hospital stay is similar to what has been observed by others.9, 14, 22 The rate of PPI prescription was lower in the UHC population (14%) for unclear reasons. By our definition, 61% lacked an adequate diagnosis to justify the prescription of the PPI. After performing a chart review on a randomly selected 5% of these records, we found that the DH administrative database had failed to identify 19% of patients who had a valid indication for receiving a PPI. Adjusting the administrative data accordingly still resulted in 50% of DH patients not having a valid indication for receiving a PPI. This is consistent with the 54% recorded by Batuwitage and colleagues11 in the outpatient setting by direct chart review, as well as a range of 60%‐75% for hospitalized patients in other studies.12, 13, 15, 23, 24

Stomach acidity is believed to provide an important host defense against lower gastrointestinal tract infections including Salmonella, Campylobacter, and Clostridium difficile.25 A recent study by Howell et al26 showed a doseresponse effect between PPI use and C. difficile infection, supporting a causal connection between loss of stomach acidity and development of Clostridium difficile‐associated diarrhea (CDAD). We found that C. difficile infection was more common in both populations of patients receiving PPIs (although the relative risk was much higher in the UHC database) (Table 5). The rate of CDAD in DH patients who received PPIs was 2.6 times higher than in patients who did not receive these acid suppressive agents.

The role of acid suppression in increasing risk for community‐acquired pneumonia is not entirely clear. Theories regarding the loss of an important host defense and bacterial proliferation head the list.6, 8, 27 Gastric and duodenal bacterial overgrowth is significantly more common in patients receiving PPIs than in patients receiving histamine type‐2 (H2) blockers.28 Previous studies have identified an increased rate of hospital‐acquired pneumonia and recurrent community‐acquired pneumonia27 in patients receiving any form of acid suppression therapy, but the risk appears to be greater in patients receiving PPIs than in those receiving H2 receptor antagonists (H2RAs).9 Significantly more patients in the UHC population who were taking PPIs had a concurrent diagnosis of pneumonia, consistent with previous studies alerting to this association6, 8, 9, 27 and consistent with the nonsignificant trend observed in the DH population.

Our study has a number of limitations. Our database comes from a single university‐affiliated public hospital with residents and hospitalists writing orders for all medications. The hospitals in the UHC are also teaching hospitals. Accordingly, our results might not generalize to other settings or reflect prescribing patterns in private, nonteaching hospital environments. Because our study was retrospective, we could not confirm the decision‐making process supporting the prescription of PPIs. Similarly, we could not temporarily relate the existence of the indication with the time the PPI was prescribed. Our list of appropriate indications for prescribing PPIs was developed by reviewing a number of references, and other studies have used slightly different lists (albeit the more commonly recognized indications are the same), but it may be argued that the list either includes or misses diagnoses in error.

While there is considerable debate about the use of PPIs for stress ulcer prophylaxis,29 we specifically chose not to include this as one of our valid indications for PPIs for 4 reasons. First, the American Society of Health‐System Pharmacists (ASHP) Report does not recommend prophylaxis for non‐ICU patients, and only recommends prophylaxis for those ICU patients with a coagulopathy, those requiring mechanical ventilation for more than 48 hours, those with a history of gastrointestinal ulceration or bleeding in the year prior to admission, and those with 2 or more of the following indications: sepsis, ICU stay >1 week, occult bleeding lasting 6 or more days, receiving high‐dose corticosteroids, and selected surgical situations.30 At the time the guideline was written, the authors note that there was insufficient data on PPIs to make any recommendations on their use, but no subsequent guidelines have been issued.30 Second, a review by Mohebbi and Hesch published in 2009, and a meta‐analysis by Lin and colleagues published in 2010, summarize subsequent randomized trials that suggest that PPIs and H2 blockers are, at best, similarly effective at preventing upper gastrointestinal (GI) bleeding among critically ill patients.31, 32 Third, the NICE guidelines do not include stress ulcer prophylaxis as an appropriate indication for PPIs except in the prevention and treatment of NSAID [non‐steroidal anti‐inflammatory drug]‐associated ulcers.19 Finally, H2RAs are currently the only medications with an FDA‐approved indication for stress ulcer prophylaxis. We acknowledge that PPIs may be a reasonable and acceptable choice for stress ulcer prophylaxis in patients who meet indications, but we were unable to identify such patients in either of our administrative databases.

In our Denver Health population, only 31% of our patients spent any time in the intensive care unit, and only a fraction of these would have both an accepted indication for stress ulcer prophylaxis by the ASHP guidelines and an intolerance or contraindication to an H2RA or sulcralfate. While our administrative database lacked the detail necessary to identify this small group of patients, the number of patients who might have been misclassified as not having a valid PPI indication was likely very small. Similar to the findings of previous studies,15, 18, 23, 29 prophylaxis against gastrointestinal bleeding was the stated justification for prescribing the PPI in 56% of the DH patient charts reviewed. It is impossible for us to estimate the number of patients in our administrative database for whom stress ulcer prophylaxis was justified by existing guidelines, as it would be necessary to gather a number of specific clinical details for each patient including: 1) ICU stay; 2) presence of coagulopathy; 3) duration of mechanical ventilation; 4) presence of sepsis; 5) duration of ICU stay; 6) presence of occult bleeding for >6 days; and 7) use of high‐dose corticosteroids. This level of clinical detail would likely only be available through a prospective study design, as has been suggested by other authors.33 Further research into the use, safety, and effectiveness of PPIs specifically for stress ulcer prophylaxis is warranted.

In conclusion, we found that 73% of nearly 1 million Medicine patients discharged from academic medical centers received a PPI without a valid indication during their hospitalization. The implications of our findings are broad. PPIs are more expensive31 than H2RAs and there is increasing evidence that they have significant side effects. In both databases we examined, the rate of C. difficile infection was higher in patients receiving PPIs than others. The prescribing habits of physicians in these university hospital settings appear to be far out of line with published guidelines and evidence‐based practice. Reducing inappropriate prescribing of PPIs would be an important educational and quality assurance project in most institutions.

Proton pump inhibitors (PPIs) are the third most commonly prescribed class of medication in the United States, with $13.6 billion in yearly sales.1 Despite their effectiveness in treating acid reflux2 and their mortality benefit in the treatment of patients with gastrointestinal bleeding,3 recent literature has identified a number of risks associated with PPIs, including an increased incidence of Clostridium difficile infection,4 decreased effectiveness of clopidogrel in patients with acute coronary syndrome,5 increased risk of community‐ and hospital‐acquired pneumonia, and an increased risk of hip fracture.69 Additionally, in March of 2011, the US Food and Drug Administration (FDA) issued a warning regarding the potential for PPIs to cause low magnesium levels which can, in turn, cause muscle spasms, an irregular heartbeat, and convulsions.10

Inappropriate PPI prescription practice has been demonstrated in the primary care setting,11 as well as in small studies conducted in the hospital setting.1216 We hypothesized that many hospitalized patients receive these medications without having an accepted indication, and examined 2 populations of hospitalized patients, including administrative data from 6.5 million discharges from US university hospitals, to look for appropriate diagnoses justifying their use.

METHODS

We performed a retrospective review of administrative data collected between January 1, 2008 and December 31, 2009 from 2 patient populations: (a) those discharged from Denver Health (DH), a university‐affiliated public safety net hospital in Denver, CO; and (b) patients discharged from 112 academic health centers and 256 of their affiliated hospitals that participate in the University HealthSystem Consortium (UHC). The Colorado Multiple Institution Review Board reviewed and approved the conduct of this study.

Inclusion criteria for both populations were age >18 or <90 years, and hospitalization on a Medicine service. Prisoners and women known to be pregnant were excluded. In both cohorts, if patients had more than 1 admission during the 2‐year study period, only data from the first admission were used.

We recorded demographics, admitting diagnosis, and discharge diagnoses together with information pertaining to the name, route, and duration of administration of all PPIs (ie, omeprazole, lansoprazole, esomeprazole, pantoprazole, rabeprazole). We created a broadly inclusive set of valid indications for PPIs by incorporating diagnoses that could be identified by International Classification of Diseases, Ninth Revision.

(ICD‐9) codes from a number of previously published sources including the National Institute of Clinical Excellence (NICE) guidelines issued by the National Health Service (NHS) of the United Kingdom in 200012, 1721 (Table 1).

To assess the accuracy of the administrative data from DH, we also reviewed the Emergency Department histories, admission histories, progress notes, electronic pharmacy records, endoscopy reports, and discharge summaries of 123 patients randomly selected (ie, a 5% sample) from the group of patients identified by administrative data to have received a PPI without a valid indication, looking for any accepted indication that might have been missed in the administrative data.

All analyses were performed using SAS Enterprise Guide 4.1 (SAS Institute, Cary, NC). A Student t test was used to compare continuous variables and a chi‐square test was used to compare categorical variables. Bonferroni corrections were used for multiple comparisons, such that P values less than 0.01 were considered to be significant for categorical variables.

RESULTS

Inclusion criteria were met by 9875 patients in the Denver Health database and 6,592,100 patients in the UHC database. The demographics and primary discharge diagnoses for these patients are summarized in Table 2.

Only 39% and 27% of the patients in the DH and UHC databases, respectively, had a valid indication for PPIs on the basis of discharge diagnoses (Table 3). In the DH data, if admission ICD‐9 codes were also inspected for valid PPI indications, 1579 (40%) of patients receiving PPIs had a valid indication (admission ICD‐9 codes were not available for patients in the UHC database). Thirty‐one percent of Denver Health patients spent time in the intensive care unit (ICU) during their hospital stay and 65% of those patients received a PPI without a valid indication, as compared to 59% of patients who remained on the General Medicine ward (Table 3).

Higher rates of concurrent C. difficile infections were observed in patients receiving PPIs in both databases; a higher rate of concurrent diagnosis of pneumonia was seen in patients receiving PPIs in the UHC population, with a nonsignificant trend towards the same finding in DH patients (Table 4).

Chart review in the DH population found valid indications for PPIs in 19% of patients who were thought not have a valid indication on the basis of the administrative data (Table 5). For 56% of those in whom no valid indication was confirmed, physicians identified prophylaxis as the justification.

DISCUSSION

The important finding of this study was that the majority of patients in 2 large groups of Medicine patients hospitalized in university‐affiliated hospitals received PPIs without having a valid indication. To our knowledge, the more than 900,000 UHC patients who received a PPI during their hospitalization represent the largest inpatient population evaluated for appropriateness of PPI prescriptions.

Our finding that 41% of the patients admitted to the DH Medicine service received a PPI during their hospital stay is similar to what has been observed by others.9, 14, 22 The rate of PPI prescription was lower in the UHC population (14%) for unclear reasons. By our definition, 61% lacked an adequate diagnosis to justify the prescription of the PPI. After performing a chart review on a randomly selected 5% of these records, we found that the DH administrative database had failed to identify 19% of patients who had a valid indication for receiving a PPI. Adjusting the administrative data accordingly still resulted in 50% of DH patients not having a valid indication for receiving a PPI. This is consistent with the 54% recorded by Batuwitage and colleagues11 in the outpatient setting by direct chart review, as well as a range of 60%‐75% for hospitalized patients in other studies.12, 13, 15, 23, 24

Stomach acidity is believed to provide an important host defense against lower gastrointestinal tract infections including Salmonella, Campylobacter, and Clostridium difficile.25 A recent study by Howell et al26 showed a doseresponse effect between PPI use and C. difficile infection, supporting a causal connection between loss of stomach acidity and development of Clostridium difficile‐associated diarrhea (CDAD). We found that C. difficile infection was more common in both populations of patients receiving PPIs (although the relative risk was much higher in the UHC database) (Table 5). The rate of CDAD in DH patients who received PPIs was 2.6 times higher than in patients who did not receive these acid suppressive agents.

The role of acid suppression in increasing risk for community‐acquired pneumonia is not entirely clear. Theories regarding the loss of an important host defense and bacterial proliferation head the list.6, 8, 27 Gastric and duodenal bacterial overgrowth is significantly more common in patients receiving PPIs than in patients receiving histamine type‐2 (H2) blockers.28 Previous studies have identified an increased rate of hospital‐acquired pneumonia and recurrent community‐acquired pneumonia27 in patients receiving any form of acid suppression therapy, but the risk appears to be greater in patients receiving PPIs than in those receiving H2 receptor antagonists (H2RAs).9 Significantly more patients in the UHC population who were taking PPIs had a concurrent diagnosis of pneumonia, consistent with previous studies alerting to this association6, 8, 9, 27 and consistent with the nonsignificant trend observed in the DH population.

Our study has a number of limitations. Our database comes from a single university‐affiliated public hospital with residents and hospitalists writing orders for all medications. The hospitals in the UHC are also teaching hospitals. Accordingly, our results might not generalize to other settings or reflect prescribing patterns in private, nonteaching hospital environments. Because our study was retrospective, we could not confirm the decision‐making process supporting the prescription of PPIs. Similarly, we could not temporarily relate the existence of the indication with the time the PPI was prescribed. Our list of appropriate indications for prescribing PPIs was developed by reviewing a number of references, and other studies have used slightly different lists (albeit the more commonly recognized indications are the same), but it may be argued that the list either includes or misses diagnoses in error.

While there is considerable debate about the use of PPIs for stress ulcer prophylaxis,29 we specifically chose not to include this as one of our valid indications for PPIs for 4 reasons. First, the American Society of Health‐System Pharmacists (ASHP) Report does not recommend prophylaxis for non‐ICU patients, and only recommends prophylaxis for those ICU patients with a coagulopathy, those requiring mechanical ventilation for more than 48 hours, those with a history of gastrointestinal ulceration or bleeding in the year prior to admission, and those with 2 or more of the following indications: sepsis, ICU stay >1 week, occult bleeding lasting 6 or more days, receiving high‐dose corticosteroids, and selected surgical situations.30 At the time the guideline was written, the authors note that there was insufficient data on PPIs to make any recommendations on their use, but no subsequent guidelines have been issued.30 Second, a review by Mohebbi and Hesch published in 2009, and a meta‐analysis by Lin and colleagues published in 2010, summarize subsequent randomized trials that suggest that PPIs and H2 blockers are, at best, similarly effective at preventing upper gastrointestinal (GI) bleeding among critically ill patients.31, 32 Third, the NICE guidelines do not include stress ulcer prophylaxis as an appropriate indication for PPIs except in the prevention and treatment of NSAID [non‐steroidal anti‐inflammatory drug]‐associated ulcers.19 Finally, H2RAs are currently the only medications with an FDA‐approved indication for stress ulcer prophylaxis. We acknowledge that PPIs may be a reasonable and acceptable choice for stress ulcer prophylaxis in patients who meet indications, but we were unable to identify such patients in either of our administrative databases.

In our Denver Health population, only 31% of our patients spent any time in the intensive care unit, and only a fraction of these would have both an accepted indication for stress ulcer prophylaxis by the ASHP guidelines and an intolerance or contraindication to an H2RA or sulcralfate. While our administrative database lacked the detail necessary to identify this small group of patients, the number of patients who might have been misclassified as not having a valid PPI indication was likely very small. Similar to the findings of previous studies,15, 18, 23, 29 prophylaxis against gastrointestinal bleeding was the stated justification for prescribing the PPI in 56% of the DH patient charts reviewed. It is impossible for us to estimate the number of patients in our administrative database for whom stress ulcer prophylaxis was justified by existing guidelines, as it would be necessary to gather a number of specific clinical details for each patient including: 1) ICU stay; 2) presence of coagulopathy; 3) duration of mechanical ventilation; 4) presence of sepsis; 5) duration of ICU stay; 6) presence of occult bleeding for >6 days; and 7) use of high‐dose corticosteroids. This level of clinical detail would likely only be available through a prospective study design, as has been suggested by other authors.33 Further research into the use, safety, and effectiveness of PPIs specifically for stress ulcer prophylaxis is warranted.

In conclusion, we found that 73% of nearly 1 million Medicine patients discharged from academic medical centers received a PPI without a valid indication during their hospitalization. The implications of our findings are broad. PPIs are more expensive31 than H2RAs and there is increasing evidence that they have significant side effects. In both databases we examined, the rate of C. difficile infection was higher in patients receiving PPIs than others. The prescribing habits of physicians in these university hospital settings appear to be far out of line with published guidelines and evidence‐based practice. Reducing inappropriate prescribing of PPIs would be an important educational and quality assurance project in most institutions.

Proton pump inhibitors (PPIs) are the third most commonly prescribed class of medication in the United States, with $13.6 billion in yearly sales.1 Despite their effectiveness in treating acid reflux2 and their mortality benefit in the treatment of patients with gastrointestinal bleeding,3 recent literature has identified a number of risks associated with PPIs, including an increased incidence of Clostridium difficile infection,4 decreased effectiveness of clopidogrel in patients with acute coronary syndrome,5 increased risk of community‐ and hospital‐acquired pneumonia, and an increased risk of hip fracture.69 Additionally, in March of 2011, the US Food and Drug Administration (FDA) issued a warning regarding the potential for PPIs to cause low magnesium levels which can, in turn, cause muscle spasms, an irregular heartbeat, and convulsions.10

Inappropriate PPI prescription practice has been demonstrated in the primary care setting,11 as well as in small studies conducted in the hospital setting.1216 We hypothesized that many hospitalized patients receive these medications without having an accepted indication, and examined 2 populations of hospitalized patients, including administrative data from 6.5 million discharges from US university hospitals, to look for appropriate diagnoses justifying their use.

METHODS

We performed a retrospective review of administrative data collected between January 1, 2008 and December 31, 2009 from 2 patient populations: (a) those discharged from Denver Health (DH), a university‐affiliated public safety net hospital in Denver, CO; and (b) patients discharged from 112 academic health centers and 256 of their affiliated hospitals that participate in the University HealthSystem Consortium (UHC). The Colorado Multiple Institution Review Board reviewed and approved the conduct of this study.

Inclusion criteria for both populations were age >18 or <90 years, and hospitalization on a Medicine service. Prisoners and women known to be pregnant were excluded. In both cohorts, if patients had more than 1 admission during the 2‐year study period, only data from the first admission were used.

We recorded demographics, admitting diagnosis, and discharge diagnoses together with information pertaining to the name, route, and duration of administration of all PPIs (ie, omeprazole, lansoprazole, esomeprazole, pantoprazole, rabeprazole). We created a broadly inclusive set of valid indications for PPIs by incorporating diagnoses that could be identified by International Classification of Diseases, Ninth Revision.

(ICD‐9) codes from a number of previously published sources including the National Institute of Clinical Excellence (NICE) guidelines issued by the National Health Service (NHS) of the United Kingdom in 200012, 1721 (Table 1).

To assess the accuracy of the administrative data from DH, we also reviewed the Emergency Department histories, admission histories, progress notes, electronic pharmacy records, endoscopy reports, and discharge summaries of 123 patients randomly selected (ie, a 5% sample) from the group of patients identified by administrative data to have received a PPI without a valid indication, looking for any accepted indication that might have been missed in the administrative data.

All analyses were performed using SAS Enterprise Guide 4.1 (SAS Institute, Cary, NC). A Student t test was used to compare continuous variables and a chi‐square test was used to compare categorical variables. Bonferroni corrections were used for multiple comparisons, such that P values less than 0.01 were considered to be significant for categorical variables.

RESULTS

Inclusion criteria were met by 9875 patients in the Denver Health database and 6,592,100 patients in the UHC database. The demographics and primary discharge diagnoses for these patients are summarized in Table 2.

Only 39% and 27% of the patients in the DH and UHC databases, respectively, had a valid indication for PPIs on the basis of discharge diagnoses (Table 3). In the DH data, if admission ICD‐9 codes were also inspected for valid PPI indications, 1579 (40%) of patients receiving PPIs had a valid indication (admission ICD‐9 codes were not available for patients in the UHC database). Thirty‐one percent of Denver Health patients spent time in the intensive care unit (ICU) during their hospital stay and 65% of those patients received a PPI without a valid indication, as compared to 59% of patients who remained on the General Medicine ward (Table 3).

Higher rates of concurrent C. difficile infections were observed in patients receiving PPIs in both databases; a higher rate of concurrent diagnosis of pneumonia was seen in patients receiving PPIs in the UHC population, with a nonsignificant trend towards the same finding in DH patients (Table 4).

Chart review in the DH population found valid indications for PPIs in 19% of patients who were thought not have a valid indication on the basis of the administrative data (Table 5). For 56% of those in whom no valid indication was confirmed, physicians identified prophylaxis as the justification.

DISCUSSION

The important finding of this study was that the majority of patients in 2 large groups of Medicine patients hospitalized in university‐affiliated hospitals received PPIs without having a valid indication. To our knowledge, the more than 900,000 UHC patients who received a PPI during their hospitalization represent the largest inpatient population evaluated for appropriateness of PPI prescriptions.

Our finding that 41% of the patients admitted to the DH Medicine service received a PPI during their hospital stay is similar to what has been observed by others.9, 14, 22 The rate of PPI prescription was lower in the UHC population (14%) for unclear reasons. By our definition, 61% lacked an adequate diagnosis to justify the prescription of the PPI. After performing a chart review on a randomly selected 5% of these records, we found that the DH administrative database had failed to identify 19% of patients who had a valid indication for receiving a PPI. Adjusting the administrative data accordingly still resulted in 50% of DH patients not having a valid indication for receiving a PPI. This is consistent with the 54% recorded by Batuwitage and colleagues11 in the outpatient setting by direct chart review, as well as a range of 60%‐75% for hospitalized patients in other studies.12, 13, 15, 23, 24

Stomach acidity is believed to provide an important host defense against lower gastrointestinal tract infections including Salmonella, Campylobacter, and Clostridium difficile.25 A recent study by Howell et al26 showed a doseresponse effect between PPI use and C. difficile infection, supporting a causal connection between loss of stomach acidity and development of Clostridium difficile‐associated diarrhea (CDAD). We found that C. difficile infection was more common in both populations of patients receiving PPIs (although the relative risk was much higher in the UHC database) (Table 5). The rate of CDAD in DH patients who received PPIs was 2.6 times higher than in patients who did not receive these acid suppressive agents.

The role of acid suppression in increasing risk for community‐acquired pneumonia is not entirely clear. Theories regarding the loss of an important host defense and bacterial proliferation head the list.6, 8, 27 Gastric and duodenal bacterial overgrowth is significantly more common in patients receiving PPIs than in patients receiving histamine type‐2 (H2) blockers.28 Previous studies have identified an increased rate of hospital‐acquired pneumonia and recurrent community‐acquired pneumonia27 in patients receiving any form of acid suppression therapy, but the risk appears to be greater in patients receiving PPIs than in those receiving H2 receptor antagonists (H2RAs).9 Significantly more patients in the UHC population who were taking PPIs had a concurrent diagnosis of pneumonia, consistent with previous studies alerting to this association6, 8, 9, 27 and consistent with the nonsignificant trend observed in the DH population.

Our study has a number of limitations. Our database comes from a single university‐affiliated public hospital with residents and hospitalists writing orders for all medications. The hospitals in the UHC are also teaching hospitals. Accordingly, our results might not generalize to other settings or reflect prescribing patterns in private, nonteaching hospital environments. Because our study was retrospective, we could not confirm the decision‐making process supporting the prescription of PPIs. Similarly, we could not temporarily relate the existence of the indication with the time the PPI was prescribed. Our list of appropriate indications for prescribing PPIs was developed by reviewing a number of references, and other studies have used slightly different lists (albeit the more commonly recognized indications are the same), but it may be argued that the list either includes or misses diagnoses in error.

While there is considerable debate about the use of PPIs for stress ulcer prophylaxis,29 we specifically chose not to include this as one of our valid indications for PPIs for 4 reasons. First, the American Society of Health‐System Pharmacists (ASHP) Report does not recommend prophylaxis for non‐ICU patients, and only recommends prophylaxis for those ICU patients with a coagulopathy, those requiring mechanical ventilation for more than 48 hours, those with a history of gastrointestinal ulceration or bleeding in the year prior to admission, and those with 2 or more of the following indications: sepsis, ICU stay >1 week, occult bleeding lasting 6 or more days, receiving high‐dose corticosteroids, and selected surgical situations.30 At the time the guideline was written, the authors note that there was insufficient data on PPIs to make any recommendations on their use, but no subsequent guidelines have been issued.30 Second, a review by Mohebbi and Hesch published in 2009, and a meta‐analysis by Lin and colleagues published in 2010, summarize subsequent randomized trials that suggest that PPIs and H2 blockers are, at best, similarly effective at preventing upper gastrointestinal (GI) bleeding among critically ill patients.31, 32 Third, the NICE guidelines do not include stress ulcer prophylaxis as an appropriate indication for PPIs except in the prevention and treatment of NSAID [non‐steroidal anti‐inflammatory drug]‐associated ulcers.19 Finally, H2RAs are currently the only medications with an FDA‐approved indication for stress ulcer prophylaxis. We acknowledge that PPIs may be a reasonable and acceptable choice for stress ulcer prophylaxis in patients who meet indications, but we were unable to identify such patients in either of our administrative databases.

In our Denver Health population, only 31% of our patients spent any time in the intensive care unit, and only a fraction of these would have both an accepted indication for stress ulcer prophylaxis by the ASHP guidelines and an intolerance or contraindication to an H2RA or sulcralfate. While our administrative database lacked the detail necessary to identify this small group of patients, the number of patients who might have been misclassified as not having a valid PPI indication was likely very small. Similar to the findings of previous studies,15, 18, 23, 29 prophylaxis against gastrointestinal bleeding was the stated justification for prescribing the PPI in 56% of the DH patient charts reviewed. It is impossible for us to estimate the number of patients in our administrative database for whom stress ulcer prophylaxis was justified by existing guidelines, as it would be necessary to gather a number of specific clinical details for each patient including: 1) ICU stay; 2) presence of coagulopathy; 3) duration of mechanical ventilation; 4) presence of sepsis; 5) duration of ICU stay; 6) presence of occult bleeding for >6 days; and 7) use of high‐dose corticosteroids. This level of clinical detail would likely only be available through a prospective study design, as has been suggested by other authors.33 Further research into the use, safety, and effectiveness of PPIs specifically for stress ulcer prophylaxis is warranted.

In conclusion, we found that 73% of nearly 1 million Medicine patients discharged from academic medical centers received a PPI without a valid indication during their hospitalization. The implications of our findings are broad. PPIs are more expensive31 than H2RAs and there is increasing evidence that they have significant side effects. In both databases we examined, the rate of C. difficile infection was higher in patients receiving PPIs than others. The prescribing habits of physicians in these university hospital settings appear to be far out of line with published guidelines and evidence‐based practice. Reducing inappropriate prescribing of PPIs would be an important educational and quality assurance project in most institutions.