Sofia Medvedev, PhD

Pulmonary embolism (PE) and deep venous thrombosis (DVT), historically referred to together as venous thromboembolism (VTE), are common, treatable, sometimes fatal, and potentially preventable medical problems.[1] Such thromboses can both precipitate a hospitalization as well as complicate it (either during or soon after discharge). Preventing such thrombosis as a complication of medical care has become a national imperative. Landmark studies such as Prophylaxis in Medical Patients With Enoxaparin (MEDENOX)[2] and Prospective Evaluation of Dalteparin Efficacy for Prevention of VTE in Immobilized Patients Trial (PREVENT)[3] demonstrated both a high incidence of thrombosis in a hospitalized high‐risk medical population (15% and 5% in the 2 trials' placebo arms, respectively) as well as significant relative risk reduction through venous thromboembolism pharmacoprophylaxis (VTEP)63% and 45%, respectively. The Joint Commission,[4] the Society of Hospital Medicine,[5] and the American College of Chest Physicians[6, 7] have thus all strived to ensure the appropriate provision of VTEP in order to reduce the morbidity and mortality associated with thrombosis in hospitalized patients, including those on medical services.

Ideally, the global success of these efforts would be assessed by measuring the rate of hospital‐associated VTE (potentially including superficial venous thrombosis [SVT], which, like upper‐extremity deep venous thrombosis [UE‐DVT], is commonly a central venous catheter [CVC]‐associated, or peripherally inserted central catheter [PICC]‐associated, complication)thrombosis acquired and diagnosed during either the index hospitalization (hospital‐acquired, or HA‐VTE/SVT) or up to 30 days postdischarge. Unfortunately, postdischarge VTE/SVT is difficult to measure because patients developing it may not present to the original hospital, or at all (eg, if they do not seek care, are treated as outpatients, or, in the most extreme case, die at home). In this context, despite being far less comprehensive, HA‐VTE/SVT is a useful subset of hospital‐associated VTE/SVT, for several reasons. First, the Centers for Medicare & Medicaid Services (CMS) have mandated hospitals to qualify all medical diagnoses as present‐on‐admission (POA = Y) or not (POA = N) since 2008, such that all medical diagnoses coded POA = N can be considered hospital acquired.[8] Second, refinements made to the International Classification of Diseases, 9th Revision (ICD‐9) codes now allow differentiation of UE‐DVT and SVT from lower‐extremity (LE) DVT/PE, whereas the former were sometimes obscured by nonspecific coding.[9] Third, recent studies have shown that medical diagnoses administratively coded as HA‐VTE/SVT correlated well with HA‐VTE/SVT ascertained through chart review.[9, 10] Finally, previous work has estimated that approximately half of all hospital‐associated VTE are HA‐VTE and the other half are postdischarge VTE.[11] Thus, HA‐VTE, though comprising only approximately half of all hospital‐associated VTE, is often used as a surrogate for measuring the success of ongoing VTE prevention programs.[12]

Our study aimed to assess the incidence of HA‐VTE plus HA‐SVT in the era of mandatory POA coding and newer ICD‐9 codes for VTE.

METHODS

RESULTS

For the 18‐month period between October 1, 2009, and March 31, 2011, across 83 UHC hospitals, there were 2,525,068 cases. Among these, 12,847 (0.51%) had 1 HA‐VTE/SVT coded. As per the clinical importance hierarchy described above, 2449 (19.1%) cases had at least a PE coded; 3848 (30%) had at least a LE‐DVT (but not a PE) coded; 2893 (22.5%) had at least an UE‐DVT coded; 3248 (25.3%) had at least an SVT coded; 30 had at least a chronic VTE coded; and 379 had at least a VTE coded with no specified location. Of those with SVT, 192 (5.8%) were LE‐SVT codes, whereas the rest were SVT/thrombophlebitis of the upper extremities or not otherwise specified. There were 11,882 (92.5%) hospitalizations with a single HA‐VTE/SVT code and an additional 965 (7.5%) with multiple codes, for a total of 13,749 HA‐VTE/SVT events (see Supporting Information, Table S1, in the online version of this article for more specific data for the individual ICD‐9 codes used to specify HA‐VTE events).

Compared with those who did not develop any HA‐VTE/SVT, patients with HA‐PE/LE‐DVT were more likely to be Caucasian (65% vs 58%, P < 0.001) and were older (age 62 vs 48 years, P < 0.001) and sicker (79.9% vs 44.9% with a severe or extreme SOI, P < 0.001). They also were more likely to have cancer, have longer lengths of stay, be more likely to stay in the ICU, and die in the hospital (P < 0.001 for all comparisons; Table 1).

Among cases with a code for UE‐DVT (22.5% of all patients with HA‐VTE), 74% were noted to also have a code for a CVC, as did 60% of cases with a HA‐SVT of the antecubital, basilic, or cephalic veins (71% of SVT events; see Supporting Information, Table S1, in the online version of this article).

Of those with HA‐PE/LE‐DVT, 54.9% received pharmacologic prophylaxis on hospital day 1 or 2 (mostly with low‐molecular‐weight heparin or unfractionated heparin).

DISCUSSION

In this study of medical patients admitted to academic medical centers throughout the United States, we found that HA‐VTE/SVT was coded in approximately 0.51% of discharges, and the incidence of HA‐PE/LE‐DVT was 0.25%. Patients with a HA‐PE/LE‐DVT code were, in general, older and sicker than those who did not develop VTE. We further found that close to half of all HA‐VTE/SVT occurred in the upper extremity, with the majority of these occurring in patients who had CVCs. Finally, the majority of patients diagnosed with HA‐PE/LE‐DVT were started on VTEP on the first or second hospital day.

The overall incidence of HA‐VTE/SVT we discovered corresponds well to other studies, even those with disparate populations. A single‐institution study found a HA‐VTE/SVT incidence of approximately 0.6% among hospitalized patients on medical and nonmedical services.[12] The study by Barba found a rate of 0.93%,[18] whereas the study by Lederle found a rate of approximately 1%.[19] Spyropolous found an HA‐VTE incidence of 0.55%.[11] Rothberg found a lower rate of 0.25% in his risk‐stratification study, though in the pre‐POA and preupdated code era.[20] Our findings extend and provide context for, in a much larger population, the results of these prior studies, and represent the first national examination of HA‐VTE/SVT in the setting of numerous quality‐improvement and other efforts to reduce hospital‐associated VTE.

The incidence of HA‐VTE/SVT codes we observed likely underestimates the incidence of hospital‐associated VTE/SVT by a factor of approximately 4, for 2 reasons. First, although VTE/SVT codes with a POA flag set to No are truly hospital‐acquired events on chart review approximately 75% of the time, and thus overestimate HA‐VTE/SVT, 25% of POA = Yes codes are actually HA‐VTE/SVT events on chart review, and therefore lead to underestimation of HA‐VTE/SVT.[9] Because VTE/SVT codes with a POA flag set to Yes outnumber those flagged No by 3 or 4 to 1, events mis‐flagged Yes contribute a much greater number of undercounted HA‐VTE/SVT, elevating the actual HA‐VTE/SVT event rate by a factor of approximately 2. Second, HA‐VTE events do not include hospital‐associated VTE events that are diagnosed after the index hospitalization. In the Spyropolous study, 45% of hospital‐associated VTE events occurred after discharge, so translating HA‐VTE/SVT events to hospital‐associated VTE/SVT events would again involve multiplying by a factor of 2.[11] Thus, the overall incidence of hospital‐associated VTE/SVT events in our sample may have been approximately 2% (0.51% 4), and the overall incidence of hospital‐associated PE or LE‐DVT events may have been approximately 1%, though there may be significant variation around these estimates given that individual institutions were themselves quite variable in their POA flag accuracy in our study.[9] There is additionally the possibility that hospitals may have deliberately left some VTE/SVT uncoded, but in the absence of financial incentives to do so for anything other than postsurgical VTE, and in the presence of penalties from CMS for undercoding, we believe this to be unlikely, at least at present.

Despite these upward extrapolations, the estimated incidence of hospital‐associated VTE/SVT in our study may seem low compared with that reported in the MEDENOX[2] and PREVENT studies.[3] Much of this discrepancy vanishes on closer examination. In the large randomized trials, patients were uniformly and routinely assessed for LE‐DVT using vascular ultrasound; in contrast, in our population of hospitalizations patients may have only had diagnostic studies done for signs or symptoms. Clinically apparent hospital‐associated VTE is less common than all hospital‐associated VTE, as it was even in PREVENT,[3] and increased surveillance may even be partially driving increased hospital‐associated VTE/SVT at some hospitals.[21] Our findings suggest that success or failure in preventing administratively coded, clinically apparent HA LE‐VTE/PE should be judged, broadly, against numbers in the range established in our study (eg, 0.25%), not the 5% or 15% of chart‐abstracted, aggressively ascertained (and sometimes clinically silent) hospital‐associated VTE in the large randomized controlled trials. That is, 0.25% is not an achievement, but rather the average, expected value.

Almost 25% of the observed HA‐VTE/SVTs coded were UE‐DVT, with roughly 75% of these being likely related to central venous catheterization (including those peripherally inserted). An additional 1/5 were upper‐extremity SVT of the antecubital, cephalic, and basilic veins, with the majority of these (60%) also listed as catheter‐related. Such thrombosis is best prevented by decreased use of central catheters or perhaps by using smaller‐caliber catheters.[22] It is unclear if VTEP can prevent such clots, though in cancer patients at least one recent trial seems promising.[23]

We found that patients with a coded HA‐PE/LE‐DVT were remarkably different from those not developing HA‐VTE/SVT. Patients with HA‐PE or HA‐LE‐DVT were older, sicker, more likely to have cancer, significantly more likely to spend time in the ICU, and much more likely to die in the hospital; risk factors for HA‐VTE overlap significantly with risk factors for death in the hospital. A small majority (55%) of patients in the HA‐PE/LE‐DVT group had actually received VTEP on at least day 1 or 2 of hospitalization. It may be the case that the dose of VTEP was insufficient to suppress clot formation in these patients, or that HA‐PE/LE‐DVT in patients with this degree of comorbidity is difficult to prevent.

There are a number of limitations to our study. We analyzed administrative codes, which underestimate hospital‐associated VTE/SVT events as noted above. This was a descriptive study, cross‐sectional across each hospitalization, and we were unable to draw any causal inference for differences in HA‐VTE/SVT incidence that might exist between subpopulations. We estimated VTEP from medication usage in just the first 2 days of hospitalization; we could not assess mechanical prophylaxis in this dataset; and we did not have any VTEP data for the first 2 days of hospitalization on the patients who did not develop a HA‐VTE/SVT, which made it impossible to compare the 2 populations on this measure. For those who did not receive VTEP, we were unable to obtain data regarding possible contraindications to VTEP, such as ongoing gastrointestinal or intracerebral hemorrhage. Additionally, our data are based on academic hospitals only and may not generalize to nonacademic settings. Extrapolating from HA‐VTE/SVT to hospital‐associated VTE/SVT may not be possible due to heterogeneity of clotting events and perhaps variability in whether patients would return to the hospital for all of them (eg, superficial or UE VTE may not result in readmission). Finally, it is unclear whether a switch to ICD Tenth Revision (ICD‐10) codes will impact our measured baseline in the coming year. The strengths of our analysis included stratification by type of HA‐VTE/SVT and our ability to assess the incidence of HA‐VTE/SVT in a large national population, and the provision of a baseline for VTE incidenceeasily usable by any individual hospital, network, or researcher with access to administrative datagoing forward.

In conclusion, among patients hospitalized in academic medical centers, HA‐VTE/SVT was coded in approximately 0.51% of patients with a medical illness staying >2 days, with approximately half of the events due to HA‐PE/LE‐DVT. Patients who developed HA‐PE/LE‐DVT were more acutely ill than those who did not, and VTE developed despite 55% of these patients receiving VTEP on day 1 or 2. Hospitals can reasonably treat the 0.25% figure as the baseline around which to assess their own performance in preventing HA‐PE/LE‐DVT, and can measure their own performance using administrative data. Further research is needed to determine how best to achieve further reductions in HA‐VTE/SVT through risk stratification and/or through other interventions.

Pulmonary embolism (PE) and deep venous thrombosis (DVT), historically referred to together as venous thromboembolism (VTE), are common, treatable, sometimes fatal, and potentially preventable medical problems.[1] Such thromboses can both precipitate a hospitalization as well as complicate it (either during or soon after discharge). Preventing such thrombosis as a complication of medical care has become a national imperative. Landmark studies such as Prophylaxis in Medical Patients With Enoxaparin (MEDENOX)[2] and Prospective Evaluation of Dalteparin Efficacy for Prevention of VTE in Immobilized Patients Trial (PREVENT)[3] demonstrated both a high incidence of thrombosis in a hospitalized high‐risk medical population (15% and 5% in the 2 trials' placebo arms, respectively) as well as significant relative risk reduction through venous thromboembolism pharmacoprophylaxis (VTEP)63% and 45%, respectively. The Joint Commission,[4] the Society of Hospital Medicine,[5] and the American College of Chest Physicians[6, 7] have thus all strived to ensure the appropriate provision of VTEP in order to reduce the morbidity and mortality associated with thrombosis in hospitalized patients, including those on medical services.

Ideally, the global success of these efforts would be assessed by measuring the rate of hospital‐associated VTE (potentially including superficial venous thrombosis [SVT], which, like upper‐extremity deep venous thrombosis [UE‐DVT], is commonly a central venous catheter [CVC]‐associated, or peripherally inserted central catheter [PICC]‐associated, complication)thrombosis acquired and diagnosed during either the index hospitalization (hospital‐acquired, or HA‐VTE/SVT) or up to 30 days postdischarge. Unfortunately, postdischarge VTE/SVT is difficult to measure because patients developing it may not present to the original hospital, or at all (eg, if they do not seek care, are treated as outpatients, or, in the most extreme case, die at home). In this context, despite being far less comprehensive, HA‐VTE/SVT is a useful subset of hospital‐associated VTE/SVT, for several reasons. First, the Centers for Medicare & Medicaid Services (CMS) have mandated hospitals to qualify all medical diagnoses as present‐on‐admission (POA = Y) or not (POA = N) since 2008, such that all medical diagnoses coded POA = N can be considered hospital acquired.[8] Second, refinements made to the International Classification of Diseases, 9th Revision (ICD‐9) codes now allow differentiation of UE‐DVT and SVT from lower‐extremity (LE) DVT/PE, whereas the former were sometimes obscured by nonspecific coding.[9] Third, recent studies have shown that medical diagnoses administratively coded as HA‐VTE/SVT correlated well with HA‐VTE/SVT ascertained through chart review.[9, 10] Finally, previous work has estimated that approximately half of all hospital‐associated VTE are HA‐VTE and the other half are postdischarge VTE.[11] Thus, HA‐VTE, though comprising only approximately half of all hospital‐associated VTE, is often used as a surrogate for measuring the success of ongoing VTE prevention programs.[12]

Our study aimed to assess the incidence of HA‐VTE plus HA‐SVT in the era of mandatory POA coding and newer ICD‐9 codes for VTE.

METHODS

RESULTS

For the 18‐month period between October 1, 2009, and March 31, 2011, across 83 UHC hospitals, there were 2,525,068 cases. Among these, 12,847 (0.51%) had 1 HA‐VTE/SVT coded. As per the clinical importance hierarchy described above, 2449 (19.1%) cases had at least a PE coded; 3848 (30%) had at least a LE‐DVT (but not a PE) coded; 2893 (22.5%) had at least an UE‐DVT coded; 3248 (25.3%) had at least an SVT coded; 30 had at least a chronic VTE coded; and 379 had at least a VTE coded with no specified location. Of those with SVT, 192 (5.8%) were LE‐SVT codes, whereas the rest were SVT/thrombophlebitis of the upper extremities or not otherwise specified. There were 11,882 (92.5%) hospitalizations with a single HA‐VTE/SVT code and an additional 965 (7.5%) with multiple codes, for a total of 13,749 HA‐VTE/SVT events (see Supporting Information, Table S1, in the online version of this article for more specific data for the individual ICD‐9 codes used to specify HA‐VTE events).

Compared with those who did not develop any HA‐VTE/SVT, patients with HA‐PE/LE‐DVT were more likely to be Caucasian (65% vs 58%, P < 0.001) and were older (age 62 vs 48 years, P < 0.001) and sicker (79.9% vs 44.9% with a severe or extreme SOI, P < 0.001). They also were more likely to have cancer, have longer lengths of stay, be more likely to stay in the ICU, and die in the hospital (P < 0.001 for all comparisons; Table 1).

Among cases with a code for UE‐DVT (22.5% of all patients with HA‐VTE), 74% were noted to also have a code for a CVC, as did 60% of cases with a HA‐SVT of the antecubital, basilic, or cephalic veins (71% of SVT events; see Supporting Information, Table S1, in the online version of this article).

Of those with HA‐PE/LE‐DVT, 54.9% received pharmacologic prophylaxis on hospital day 1 or 2 (mostly with low‐molecular‐weight heparin or unfractionated heparin).

DISCUSSION

In this study of medical patients admitted to academic medical centers throughout the United States, we found that HA‐VTE/SVT was coded in approximately 0.51% of discharges, and the incidence of HA‐PE/LE‐DVT was 0.25%. Patients with a HA‐PE/LE‐DVT code were, in general, older and sicker than those who did not develop VTE. We further found that close to half of all HA‐VTE/SVT occurred in the upper extremity, with the majority of these occurring in patients who had CVCs. Finally, the majority of patients diagnosed with HA‐PE/LE‐DVT were started on VTEP on the first or second hospital day.

The overall incidence of HA‐VTE/SVT we discovered corresponds well to other studies, even those with disparate populations. A single‐institution study found a HA‐VTE/SVT incidence of approximately 0.6% among hospitalized patients on medical and nonmedical services.[12] The study by Barba found a rate of 0.93%,[18] whereas the study by Lederle found a rate of approximately 1%.[19] Spyropolous found an HA‐VTE incidence of 0.55%.[11] Rothberg found a lower rate of 0.25% in his risk‐stratification study, though in the pre‐POA and preupdated code era.[20] Our findings extend and provide context for, in a much larger population, the results of these prior studies, and represent the first national examination of HA‐VTE/SVT in the setting of numerous quality‐improvement and other efforts to reduce hospital‐associated VTE.

The incidence of HA‐VTE/SVT codes we observed likely underestimates the incidence of hospital‐associated VTE/SVT by a factor of approximately 4, for 2 reasons. First, although VTE/SVT codes with a POA flag set to No are truly hospital‐acquired events on chart review approximately 75% of the time, and thus overestimate HA‐VTE/SVT, 25% of POA = Yes codes are actually HA‐VTE/SVT events on chart review, and therefore lead to underestimation of HA‐VTE/SVT.[9] Because VTE/SVT codes with a POA flag set to Yes outnumber those flagged No by 3 or 4 to 1, events mis‐flagged Yes contribute a much greater number of undercounted HA‐VTE/SVT, elevating the actual HA‐VTE/SVT event rate by a factor of approximately 2. Second, HA‐VTE events do not include hospital‐associated VTE events that are diagnosed after the index hospitalization. In the Spyropolous study, 45% of hospital‐associated VTE events occurred after discharge, so translating HA‐VTE/SVT events to hospital‐associated VTE/SVT events would again involve multiplying by a factor of 2.[11] Thus, the overall incidence of hospital‐associated VTE/SVT events in our sample may have been approximately 2% (0.51% 4), and the overall incidence of hospital‐associated PE or LE‐DVT events may have been approximately 1%, though there may be significant variation around these estimates given that individual institutions were themselves quite variable in their POA flag accuracy in our study.[9] There is additionally the possibility that hospitals may have deliberately left some VTE/SVT uncoded, but in the absence of financial incentives to do so for anything other than postsurgical VTE, and in the presence of penalties from CMS for undercoding, we believe this to be unlikely, at least at present.

Despite these upward extrapolations, the estimated incidence of hospital‐associated VTE/SVT in our study may seem low compared with that reported in the MEDENOX[2] and PREVENT studies.[3] Much of this discrepancy vanishes on closer examination. In the large randomized trials, patients were uniformly and routinely assessed for LE‐DVT using vascular ultrasound; in contrast, in our population of hospitalizations patients may have only had diagnostic studies done for signs or symptoms. Clinically apparent hospital‐associated VTE is less common than all hospital‐associated VTE, as it was even in PREVENT,[3] and increased surveillance may even be partially driving increased hospital‐associated VTE/SVT at some hospitals.[21] Our findings suggest that success or failure in preventing administratively coded, clinically apparent HA LE‐VTE/PE should be judged, broadly, against numbers in the range established in our study (eg, 0.25%), not the 5% or 15% of chart‐abstracted, aggressively ascertained (and sometimes clinically silent) hospital‐associated VTE in the large randomized controlled trials. That is, 0.25% is not an achievement, but rather the average, expected value.

Almost 25% of the observed HA‐VTE/SVTs coded were UE‐DVT, with roughly 75% of these being likely related to central venous catheterization (including those peripherally inserted). An additional 1/5 were upper‐extremity SVT of the antecubital, cephalic, and basilic veins, with the majority of these (60%) also listed as catheter‐related. Such thrombosis is best prevented by decreased use of central catheters or perhaps by using smaller‐caliber catheters.[22] It is unclear if VTEP can prevent such clots, though in cancer patients at least one recent trial seems promising.[23]

We found that patients with a coded HA‐PE/LE‐DVT were remarkably different from those not developing HA‐VTE/SVT. Patients with HA‐PE or HA‐LE‐DVT were older, sicker, more likely to have cancer, significantly more likely to spend time in the ICU, and much more likely to die in the hospital; risk factors for HA‐VTE overlap significantly with risk factors for death in the hospital. A small majority (55%) of patients in the HA‐PE/LE‐DVT group had actually received VTEP on at least day 1 or 2 of hospitalization. It may be the case that the dose of VTEP was insufficient to suppress clot formation in these patients, or that HA‐PE/LE‐DVT in patients with this degree of comorbidity is difficult to prevent.

There are a number of limitations to our study. We analyzed administrative codes, which underestimate hospital‐associated VTE/SVT events as noted above. This was a descriptive study, cross‐sectional across each hospitalization, and we were unable to draw any causal inference for differences in HA‐VTE/SVT incidence that might exist between subpopulations. We estimated VTEP from medication usage in just the first 2 days of hospitalization; we could not assess mechanical prophylaxis in this dataset; and we did not have any VTEP data for the first 2 days of hospitalization on the patients who did not develop a HA‐VTE/SVT, which made it impossible to compare the 2 populations on this measure. For those who did not receive VTEP, we were unable to obtain data regarding possible contraindications to VTEP, such as ongoing gastrointestinal or intracerebral hemorrhage. Additionally, our data are based on academic hospitals only and may not generalize to nonacademic settings. Extrapolating from HA‐VTE/SVT to hospital‐associated VTE/SVT may not be possible due to heterogeneity of clotting events and perhaps variability in whether patients would return to the hospital for all of them (eg, superficial or UE VTE may not result in readmission). Finally, it is unclear whether a switch to ICD Tenth Revision (ICD‐10) codes will impact our measured baseline in the coming year. The strengths of our analysis included stratification by type of HA‐VTE/SVT and our ability to assess the incidence of HA‐VTE/SVT in a large national population, and the provision of a baseline for VTE incidenceeasily usable by any individual hospital, network, or researcher with access to administrative datagoing forward.

In conclusion, among patients hospitalized in academic medical centers, HA‐VTE/SVT was coded in approximately 0.51% of patients with a medical illness staying >2 days, with approximately half of the events due to HA‐PE/LE‐DVT. Patients who developed HA‐PE/LE‐DVT were more acutely ill than those who did not, and VTE developed despite 55% of these patients receiving VTEP on day 1 or 2. Hospitals can reasonably treat the 0.25% figure as the baseline around which to assess their own performance in preventing HA‐PE/LE‐DVT, and can measure their own performance using administrative data. Further research is needed to determine how best to achieve further reductions in HA‐VTE/SVT through risk stratification and/or through other interventions.

Pulmonary embolism (PE) and deep venous thrombosis (DVT), historically referred to together as venous thromboembolism (VTE), are common, treatable, sometimes fatal, and potentially preventable medical problems.[1] Such thromboses can both precipitate a hospitalization as well as complicate it (either during or soon after discharge). Preventing such thrombosis as a complication of medical care has become a national imperative. Landmark studies such as Prophylaxis in Medical Patients With Enoxaparin (MEDENOX)[2] and Prospective Evaluation of Dalteparin Efficacy for Prevention of VTE in Immobilized Patients Trial (PREVENT)[3] demonstrated both a high incidence of thrombosis in a hospitalized high‐risk medical population (15% and 5% in the 2 trials' placebo arms, respectively) as well as significant relative risk reduction through venous thromboembolism pharmacoprophylaxis (VTEP)63% and 45%, respectively. The Joint Commission,[4] the Society of Hospital Medicine,[5] and the American College of Chest Physicians[6, 7] have thus all strived to ensure the appropriate provision of VTEP in order to reduce the morbidity and mortality associated with thrombosis in hospitalized patients, including those on medical services.

Ideally, the global success of these efforts would be assessed by measuring the rate of hospital‐associated VTE (potentially including superficial venous thrombosis [SVT], which, like upper‐extremity deep venous thrombosis [UE‐DVT], is commonly a central venous catheter [CVC]‐associated, or peripherally inserted central catheter [PICC]‐associated, complication)thrombosis acquired and diagnosed during either the index hospitalization (hospital‐acquired, or HA‐VTE/SVT) or up to 30 days postdischarge. Unfortunately, postdischarge VTE/SVT is difficult to measure because patients developing it may not present to the original hospital, or at all (eg, if they do not seek care, are treated as outpatients, or, in the most extreme case, die at home). In this context, despite being far less comprehensive, HA‐VTE/SVT is a useful subset of hospital‐associated VTE/SVT, for several reasons. First, the Centers for Medicare & Medicaid Services (CMS) have mandated hospitals to qualify all medical diagnoses as present‐on‐admission (POA = Y) or not (POA = N) since 2008, such that all medical diagnoses coded POA = N can be considered hospital acquired.[8] Second, refinements made to the International Classification of Diseases, 9th Revision (ICD‐9) codes now allow differentiation of UE‐DVT and SVT from lower‐extremity (LE) DVT/PE, whereas the former were sometimes obscured by nonspecific coding.[9] Third, recent studies have shown that medical diagnoses administratively coded as HA‐VTE/SVT correlated well with HA‐VTE/SVT ascertained through chart review.[9, 10] Finally, previous work has estimated that approximately half of all hospital‐associated VTE are HA‐VTE and the other half are postdischarge VTE.[11] Thus, HA‐VTE, though comprising only approximately half of all hospital‐associated VTE, is often used as a surrogate for measuring the success of ongoing VTE prevention programs.[12]

Our study aimed to assess the incidence of HA‐VTE plus HA‐SVT in the era of mandatory POA coding and newer ICD‐9 codes for VTE.

METHODS

RESULTS

For the 18‐month period between October 1, 2009, and March 31, 2011, across 83 UHC hospitals, there were 2,525,068 cases. Among these, 12,847 (0.51%) had 1 HA‐VTE/SVT coded. As per the clinical importance hierarchy described above, 2449 (19.1%) cases had at least a PE coded; 3848 (30%) had at least a LE‐DVT (but not a PE) coded; 2893 (22.5%) had at least an UE‐DVT coded; 3248 (25.3%) had at least an SVT coded; 30 had at least a chronic VTE coded; and 379 had at least a VTE coded with no specified location. Of those with SVT, 192 (5.8%) were LE‐SVT codes, whereas the rest were SVT/thrombophlebitis of the upper extremities or not otherwise specified. There were 11,882 (92.5%) hospitalizations with a single HA‐VTE/SVT code and an additional 965 (7.5%) with multiple codes, for a total of 13,749 HA‐VTE/SVT events (see Supporting Information, Table S1, in the online version of this article for more specific data for the individual ICD‐9 codes used to specify HA‐VTE events).

Compared with those who did not develop any HA‐VTE/SVT, patients with HA‐PE/LE‐DVT were more likely to be Caucasian (65% vs 58%, P < 0.001) and were older (age 62 vs 48 years, P < 0.001) and sicker (79.9% vs 44.9% with a severe or extreme SOI, P < 0.001). They also were more likely to have cancer, have longer lengths of stay, be more likely to stay in the ICU, and die in the hospital (P < 0.001 for all comparisons; Table 1).

Among cases with a code for UE‐DVT (22.5% of all patients with HA‐VTE), 74% were noted to also have a code for a CVC, as did 60% of cases with a HA‐SVT of the antecubital, basilic, or cephalic veins (71% of SVT events; see Supporting Information, Table S1, in the online version of this article).

Of those with HA‐PE/LE‐DVT, 54.9% received pharmacologic prophylaxis on hospital day 1 or 2 (mostly with low‐molecular‐weight heparin or unfractionated heparin).

DISCUSSION

In this study of medical patients admitted to academic medical centers throughout the United States, we found that HA‐VTE/SVT was coded in approximately 0.51% of discharges, and the incidence of HA‐PE/LE‐DVT was 0.25%. Patients with a HA‐PE/LE‐DVT code were, in general, older and sicker than those who did not develop VTE. We further found that close to half of all HA‐VTE/SVT occurred in the upper extremity, with the majority of these occurring in patients who had CVCs. Finally, the majority of patients diagnosed with HA‐PE/LE‐DVT were started on VTEP on the first or second hospital day.

The overall incidence of HA‐VTE/SVT we discovered corresponds well to other studies, even those with disparate populations. A single‐institution study found a HA‐VTE/SVT incidence of approximately 0.6% among hospitalized patients on medical and nonmedical services.[12] The study by Barba found a rate of 0.93%,[18] whereas the study by Lederle found a rate of approximately 1%.[19] Spyropolous found an HA‐VTE incidence of 0.55%.[11] Rothberg found a lower rate of 0.25% in his risk‐stratification study, though in the pre‐POA and preupdated code era.[20] Our findings extend and provide context for, in a much larger population, the results of these prior studies, and represent the first national examination of HA‐VTE/SVT in the setting of numerous quality‐improvement and other efforts to reduce hospital‐associated VTE.

The incidence of HA‐VTE/SVT codes we observed likely underestimates the incidence of hospital‐associated VTE/SVT by a factor of approximately 4, for 2 reasons. First, although VTE/SVT codes with a POA flag set to No are truly hospital‐acquired events on chart review approximately 75% of the time, and thus overestimate HA‐VTE/SVT, 25% of POA = Yes codes are actually HA‐VTE/SVT events on chart review, and therefore lead to underestimation of HA‐VTE/SVT.[9] Because VTE/SVT codes with a POA flag set to Yes outnumber those flagged No by 3 or 4 to 1, events mis‐flagged Yes contribute a much greater number of undercounted HA‐VTE/SVT, elevating the actual HA‐VTE/SVT event rate by a factor of approximately 2. Second, HA‐VTE events do not include hospital‐associated VTE events that are diagnosed after the index hospitalization. In the Spyropolous study, 45% of hospital‐associated VTE events occurred after discharge, so translating HA‐VTE/SVT events to hospital‐associated VTE/SVT events would again involve multiplying by a factor of 2.[11] Thus, the overall incidence of hospital‐associated VTE/SVT events in our sample may have been approximately 2% (0.51% 4), and the overall incidence of hospital‐associated PE or LE‐DVT events may have been approximately 1%, though there may be significant variation around these estimates given that individual institutions were themselves quite variable in their POA flag accuracy in our study.[9] There is additionally the possibility that hospitals may have deliberately left some VTE/SVT uncoded, but in the absence of financial incentives to do so for anything other than postsurgical VTE, and in the presence of penalties from CMS for undercoding, we believe this to be unlikely, at least at present.

Despite these upward extrapolations, the estimated incidence of hospital‐associated VTE/SVT in our study may seem low compared with that reported in the MEDENOX[2] and PREVENT studies.[3] Much of this discrepancy vanishes on closer examination. In the large randomized trials, patients were uniformly and routinely assessed for LE‐DVT using vascular ultrasound; in contrast, in our population of hospitalizations patients may have only had diagnostic studies done for signs or symptoms. Clinically apparent hospital‐associated VTE is less common than all hospital‐associated VTE, as it was even in PREVENT,[3] and increased surveillance may even be partially driving increased hospital‐associated VTE/SVT at some hospitals.[21] Our findings suggest that success or failure in preventing administratively coded, clinically apparent HA LE‐VTE/PE should be judged, broadly, against numbers in the range established in our study (eg, 0.25%), not the 5% or 15% of chart‐abstracted, aggressively ascertained (and sometimes clinically silent) hospital‐associated VTE in the large randomized controlled trials. That is, 0.25% is not an achievement, but rather the average, expected value.

Almost 25% of the observed HA‐VTE/SVTs coded were UE‐DVT, with roughly 75% of these being likely related to central venous catheterization (including those peripherally inserted). An additional 1/5 were upper‐extremity SVT of the antecubital, cephalic, and basilic veins, with the majority of these (60%) also listed as catheter‐related. Such thrombosis is best prevented by decreased use of central catheters or perhaps by using smaller‐caliber catheters.[22] It is unclear if VTEP can prevent such clots, though in cancer patients at least one recent trial seems promising.[23]

We found that patients with a coded HA‐PE/LE‐DVT were remarkably different from those not developing HA‐VTE/SVT. Patients with HA‐PE or HA‐LE‐DVT were older, sicker, more likely to have cancer, significantly more likely to spend time in the ICU, and much more likely to die in the hospital; risk factors for HA‐VTE overlap significantly with risk factors for death in the hospital. A small majority (55%) of patients in the HA‐PE/LE‐DVT group had actually received VTEP on at least day 1 or 2 of hospitalization. It may be the case that the dose of VTEP was insufficient to suppress clot formation in these patients, or that HA‐PE/LE‐DVT in patients with this degree of comorbidity is difficult to prevent.

There are a number of limitations to our study. We analyzed administrative codes, which underestimate hospital‐associated VTE/SVT events as noted above. This was a descriptive study, cross‐sectional across each hospitalization, and we were unable to draw any causal inference for differences in HA‐VTE/SVT incidence that might exist between subpopulations. We estimated VTEP from medication usage in just the first 2 days of hospitalization; we could not assess mechanical prophylaxis in this dataset; and we did not have any VTEP data for the first 2 days of hospitalization on the patients who did not develop a HA‐VTE/SVT, which made it impossible to compare the 2 populations on this measure. For those who did not receive VTEP, we were unable to obtain data regarding possible contraindications to VTEP, such as ongoing gastrointestinal or intracerebral hemorrhage. Additionally, our data are based on academic hospitals only and may not generalize to nonacademic settings. Extrapolating from HA‐VTE/SVT to hospital‐associated VTE/SVT may not be possible due to heterogeneity of clotting events and perhaps variability in whether patients would return to the hospital for all of them (eg, superficial or UE VTE may not result in readmission). Finally, it is unclear whether a switch to ICD Tenth Revision (ICD‐10) codes will impact our measured baseline in the coming year. The strengths of our analysis included stratification by type of HA‐VTE/SVT and our ability to assess the incidence of HA‐VTE/SVT in a large national population, and the provision of a baseline for VTE incidenceeasily usable by any individual hospital, network, or researcher with access to administrative datagoing forward.

In conclusion, among patients hospitalized in academic medical centers, HA‐VTE/SVT was coded in approximately 0.51% of patients with a medical illness staying >2 days, with approximately half of the events due to HA‐PE/LE‐DVT. Patients who developed HA‐PE/LE‐DVT were more acutely ill than those who did not, and VTE developed despite 55% of these patients receiving VTEP on day 1 or 2. Hospitals can reasonably treat the 0.25% figure as the baseline around which to assess their own performance in preventing HA‐PE/LE‐DVT, and can measure their own performance using administrative data. Further research is needed to determine how best to achieve further reductions in HA‐VTE/SVT through risk stratification and/or through other interventions.

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.