Banafsheh Sadeghi, MD, 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.

Symptomatic venous thromboembolism (VTE) is a common complication following total knee arthroplasty (TKA).17 In fact, the high incidence of thrombosis after TKA has made this operation the principal condition used to study the efficacy of new anticoagulants, and it is a principal target of quality improvement oversight and measurement.8 The Agency for Healthcare Research and Quality (AHRQ) has developed a Patient Safety Indicator (PSI‐12) to assist hospitals, payers, and other stakeholders identify patients who experienced VTE after major surgery. The Centers for Medicare * Medicaid Services has deemed that because a VTE that develops after TKA is potentially preventable, it withholds the additional payment for this complication.9

Prior the introduction of new oral anticoagulants, most guidelines from North America recommended the use of postoperative low‐molecular‐weight heparin (LMWH), fondaparinux, or warfarin for at least 10 days after TKA.2, 10 However, there is some ongoing controversy about whether pharmacological prophylaxis is necessary after total joint replacement surgery, and whether it is effective in preventing pulmonary embolism.1114 In addition, there is controversy regarding the effectiveness of mechanical prophylaxis alone as a means of preventing VTE.2, 4, 14, 15

Pharmacological thromboprophylaxis using LMWH or fondaparinux calls for using a fixed‐dose that does not depend on the patient's weight or body mass index (BMI). This stands in sharp contrast to the consistent recommendation to use weight‐based dosing of LMWH/fondaparinux in patients who have acute VTE.16 The absence of any adjustment in the dose of thromboprophylaxis based on weight may be particularly important after TKA because the majority of these patients are obese or extremely obese,1719 making the dose of LMWH/fondaparinux potentially insufficient. It is noteworthy that surgeons who perform bariatric surgery currently recommend a higher dose of LMWH, usually 40 mg of enoxaparin every 12 hours.20, 21

We conducted this case‐control study to address 3 hypotheses. First, we hypothesized that use of standard pharmacologic thromboprophylaxis drugs is associated with a lower risk of acute VTE compared with mechanical prophylaxis alone. Second, we hypothesized that among patients given LMWH/fondaparinux, excessive obesity (BMI >35) is associated with a higher risk of developing VTE. Third, based on prior studies that identified immobilization as a risk factor for VTE, we hypothesized that delayed ambulation after TKA is associated with higher risk for VTE.

METHODS

RESULTS

A total of 593 TKA records were abstracted by the 15 participating hospitals. All patients underwent TKA on the day of admission or the day after admission. A total of 16 cases (12 PE and 4 DVT) were diagnosed with VTE on the day of surgery, or the day after surgery, and were deemed nonpreventable in the multivariable analysis. There were 114 additional cases with VTE (44 PE, 68 DVT, 2 both) diagnosed 2 or more days after surgery, and 463 controls that had no VTE diagnosed by the index hospital within 90 days after surgery.

In bivariate analyses (Table 1), the mean age of cases was significantly greater for controls (65.5 10.4 vs 63.5 10.4, P < 0.05). More cases underwent bilateral simultaneous TKA compared with controls (23% vs 7%, P < 0.001). The mean BMI was marginally higher among VTE cases than among controls (34.6 8.0 vs 33.3 7.1, P = 0.07). Among cases with PE, a significantly greater percentage were morbidly obese than among controls (30% vs 16%, P value = 0.01), whereas there was not a difference for the DVT cases.

Fewer VTE cases began ambulation on or before the second postoperative day compared with controls (47% vs 73%, P < 0.001). There was no difference in the number or types of comorbidities between cases and controls. All patients received at least 1 type of pharmacologic or mechanical prophylaxis within the first 24 hours after TKA. Although the difference was not statistically significant, controls had marginally higher odds of receiving FDA‐approved pharmacologic prophylaxis than cases (P = 0.07; Table 2). Table 3 presents the criterion that led to 242 cases not meeting the definition of FDA‐approved pharmacologic prophylaxis definition. Administering a suboptimal dose was the most common reason. Also, about half of the patients received only mechanical prophylaxis.

In the primary multivariable analysis (Table 4), neither age, gender, nor obesity (defined as BMI >30, BMI >35, or BMI >40) was a significant predictor of VTE. Undergoing bilateral simultaneous TKA versus unilateral TKA was associated with higher risk of VTE (OR = 4.2; 95% CI: 1.909.10), whereas early ambulation on or before the second postoperative day versus later (OR = 0.30; 95% CI: 0.100.90). Receiving FDA‐approved pharmacologic prophylaxis (right dose and time described in Table 4) versus any other prophylaxis regimen was adversely associated with VTE (OR = 0.50; 95% CI: 0.300.80, P = 0.01). There was no significant effect of receipt of FDA‐approved pharmacologic prophylaxis on being diagnosed with VTE among the cases that were severely or morbidly obese (P for interaction = 0.92). In a secondary analysis, the adjusted odds of being diagnosed with VTE were not significantly different for severely (OR = 0.9; CI 0.531.5) or morbidly obese (OR = 1.5; CI 0.802.80) patients.

In a sensitivity analysis, we did not find any significant changes in the results when the 12 cases that developed VTE on the day of, or day after, TKA were included.

DISCUSSION

Venous thromboembolism is a frequent and potentially serious complication following TKA. In population‐based studies that report the number of patients who develop symptomatic acute VTE, the incidence is approximately 2.0%2.5%.3, 2224 Thromboprophylaxis reduces the risk of developing asymptomatic VTE by more than 60%, and pharmacologic prophylaxis using LMWH, fondaparinux, or warfarin alone is recommended by the ACCP and other organizations, with use of mechanical pneumatic compression, low‐dose unfractionated heparin, or aspirin as alternative options.25 Nevertheless, because extremely obese patients are not commonly enrolled in clinical trials and because current guidelines do not recommend any adjustment in the dose of LMWH or fondaparinux based on weight, we hypothesized that LMWH/fondaparinux would be significantly less effective in severely or morbidly obese patients. We also hypothesized that pharmacologic prophylaxis would be superior to mechanical prophylaxis alone,26 and that delayed ambulation after TKA would be associated with a higher risk of developing VTE.

Two widely cited clinical guidelines that pertain to prophylaxis of venous thromboembolism after total knee arthroplasty are the ACCP guidelines2 and the American Academy of Orthopedic Surgeons (AAOS) guidelines.27 Although we acknowledge that there are differences in these and other guidelines, recommendations and quality measures,13, 28, 29 the aim of the current study was not to evaluate or compare specific guidelines. We simply classified the thromboprophylaxis regimens into logical groups, the 2 most frequent being use of LMWH/fondaparinux (mechanical) and mechanical prophylaxis alone, and then performed the case‐control analysis. We followed FDA‐approved labeling to assess whether pharmacologic therapy was provided at the proper dose in the proper time period.

A principal finding of this study was that FDA‐approved pharmacologic prophylaxis using LMWH, fondaparinux, or warfarin, was associated with significantly lower odds of developing VTE compared to all other prophylaxis regimens.

When the effect of FDA‐approved pharmacologic prophylaxis was analyzed in severely or morbidly obese patients versus less obese patients, there was no significant difference in the risk of VTE across the BMI levels that were compared. Further, among the patients whose pharmacologic prophylaxis was LMWH or fondaparinux, severe or morbid obesity was not associated with significantly higher odds of developing VTE. Although it is logical to think that heavier patients require a larger dose of LMWH or fondaparinux, the findings of this study suggest that current FDA‐approved doses of these drugs are adequate even in morbidly obese patients.

Two other findings were noteworthy. First, early mobilization with active ambulation in the first 2 days after TKA was strongly associated with lower odds of developing VTE. This finding is similar to the report by Chandrasekaran et al that sitting out of bed or walking for at least 1530 minutes twice a day on the first postoperative day after TKA significantly reduced the incidence of thromboembolic complications (OR = 0.35; 95% CI: 0.11, 1.03, P = 0.03) compared those confined to bed.22, 30 In our study, the beneficial effect of mobilization disappeared if ambulation commenced on day 3 or later after surgery. This finding emphasizes the importance of early mobilization in prevention of VTE, as has been reported after total hip arthroplasty.31

The other important finding was that bilateral simultaneous TKA was strongly associated with VTE, with over 4‐fold greater odds of developing VTE compared with unilateral TKA. This effect did not disappear when we adjusted for obesity or the time to mobilization. This finding was not unexpected and is consistent with other reports in the literature showing a higher incidence of VTE after bilateral TKA compared with unilateral TKA.3235

This study has several limitations. We were unable to ascertain postdischarge VTE unless a patient was readmitted to the same hospital. It has been reported that between 35% to 45% of postoperative VTEs occur after hospital discharge,22, 23 and some of these complications are treated at other institutions or in the outpatient arena.36 Second, it has been shown that hospital volume and hospital specialization are associated with the incidence of VTE after TKA procedures.37, 38 To minimize the risk of confounding by hospital characteristics, we conditioned our analysis on hospital and adjusted for the clustering effect of hospitals. Third, all data were collected by individuals employed by and working at the participating hospitals, with no mechanism for duplicate abstraction to ensure reliability. Fourth, only teaching hospitals participated in this study. Adherence to guidelines and use of prophylaxis may be higher at teaching hospitals than at nonteaching hospitals.39 As a result, our sample may have less variation than the general population of TKA patients, limiting our power to detect associations between thromboprophylaxis and VTE. Finally, the case‐control design has inherent limitations in detecting causal associations, largely due to its susceptibility to unmeasured confounders and incorrect ascertainment of pre‐outcome exposures. To avoid the latter problem, we excluded VTEs that were diagnosed on the date of surgery, before prophylaxis is routinely started.

Despite these limitations, our findings suggest that there may be opportunities to prevent postoperative VTE, even among high‐risk patients at teaching hospitals that have achieved 100% compliance with The Joint Commission's Surgical Care Improvement Project process measures.40, 41 Specifically, delivery of FDA‐approved pharmacologic prophylaxis (vs mechanical prophylaxis alone) and early ambulation (vs later) may further decrease the risk of postoperative VTE. These hypotheses merit further testing in randomized controlled trials or cluster‐randomized quality improvement trials. Patients should be informed of the increased risk of VTE after bilateral TKA, although this additional risk may be outweighed by a reduction in the cumulative recovery time and a lower cumulative risk of developing a prosthetic joint infection.42, 43 Finally, AHRQ's PSI‐12 appears to be a useful tool for ascertaining VTE cases and identifying potential opportunities for improvement, when the present‐on‐admission status is also available.

Symptomatic venous thromboembolism (VTE) is a common complication following total knee arthroplasty (TKA).17 In fact, the high incidence of thrombosis after TKA has made this operation the principal condition used to study the efficacy of new anticoagulants, and it is a principal target of quality improvement oversight and measurement.8 The Agency for Healthcare Research and Quality (AHRQ) has developed a Patient Safety Indicator (PSI‐12) to assist hospitals, payers, and other stakeholders identify patients who experienced VTE after major surgery. The Centers for Medicare * Medicaid Services has deemed that because a VTE that develops after TKA is potentially preventable, it withholds the additional payment for this complication.9

Prior the introduction of new oral anticoagulants, most guidelines from North America recommended the use of postoperative low‐molecular‐weight heparin (LMWH), fondaparinux, or warfarin for at least 10 days after TKA.2, 10 However, there is some ongoing controversy about whether pharmacological prophylaxis is necessary after total joint replacement surgery, and whether it is effective in preventing pulmonary embolism.1114 In addition, there is controversy regarding the effectiveness of mechanical prophylaxis alone as a means of preventing VTE.2, 4, 14, 15

Pharmacological thromboprophylaxis using LMWH or fondaparinux calls for using a fixed‐dose that does not depend on the patient's weight or body mass index (BMI). This stands in sharp contrast to the consistent recommendation to use weight‐based dosing of LMWH/fondaparinux in patients who have acute VTE.16 The absence of any adjustment in the dose of thromboprophylaxis based on weight may be particularly important after TKA because the majority of these patients are obese or extremely obese,1719 making the dose of LMWH/fondaparinux potentially insufficient. It is noteworthy that surgeons who perform bariatric surgery currently recommend a higher dose of LMWH, usually 40 mg of enoxaparin every 12 hours.20, 21

We conducted this case‐control study to address 3 hypotheses. First, we hypothesized that use of standard pharmacologic thromboprophylaxis drugs is associated with a lower risk of acute VTE compared with mechanical prophylaxis alone. Second, we hypothesized that among patients given LMWH/fondaparinux, excessive obesity (BMI >35) is associated with a higher risk of developing VTE. Third, based on prior studies that identified immobilization as a risk factor for VTE, we hypothesized that delayed ambulation after TKA is associated with higher risk for VTE.

METHODS

RESULTS

A total of 593 TKA records were abstracted by the 15 participating hospitals. All patients underwent TKA on the day of admission or the day after admission. A total of 16 cases (12 PE and 4 DVT) were diagnosed with VTE on the day of surgery, or the day after surgery, and were deemed nonpreventable in the multivariable analysis. There were 114 additional cases with VTE (44 PE, 68 DVT, 2 both) diagnosed 2 or more days after surgery, and 463 controls that had no VTE diagnosed by the index hospital within 90 days after surgery.

In bivariate analyses (Table 1), the mean age of cases was significantly greater for controls (65.5 10.4 vs 63.5 10.4, P < 0.05). More cases underwent bilateral simultaneous TKA compared with controls (23% vs 7%, P < 0.001). The mean BMI was marginally higher among VTE cases than among controls (34.6 8.0 vs 33.3 7.1, P = 0.07). Among cases with PE, a significantly greater percentage were morbidly obese than among controls (30% vs 16%, P value = 0.01), whereas there was not a difference for the DVT cases.

Fewer VTE cases began ambulation on or before the second postoperative day compared with controls (47% vs 73%, P < 0.001). There was no difference in the number or types of comorbidities between cases and controls. All patients received at least 1 type of pharmacologic or mechanical prophylaxis within the first 24 hours after TKA. Although the difference was not statistically significant, controls had marginally higher odds of receiving FDA‐approved pharmacologic prophylaxis than cases (P = 0.07; Table 2). Table 3 presents the criterion that led to 242 cases not meeting the definition of FDA‐approved pharmacologic prophylaxis definition. Administering a suboptimal dose was the most common reason. Also, about half of the patients received only mechanical prophylaxis.

In the primary multivariable analysis (Table 4), neither age, gender, nor obesity (defined as BMI >30, BMI >35, or BMI >40) was a significant predictor of VTE. Undergoing bilateral simultaneous TKA versus unilateral TKA was associated with higher risk of VTE (OR = 4.2; 95% CI: 1.909.10), whereas early ambulation on or before the second postoperative day versus later (OR = 0.30; 95% CI: 0.100.90). Receiving FDA‐approved pharmacologic prophylaxis (right dose and time described in Table 4) versus any other prophylaxis regimen was adversely associated with VTE (OR = 0.50; 95% CI: 0.300.80, P = 0.01). There was no significant effect of receipt of FDA‐approved pharmacologic prophylaxis on being diagnosed with VTE among the cases that were severely or morbidly obese (P for interaction = 0.92). In a secondary analysis, the adjusted odds of being diagnosed with VTE were not significantly different for severely (OR = 0.9; CI 0.531.5) or morbidly obese (OR = 1.5; CI 0.802.80) patients.

In a sensitivity analysis, we did not find any significant changes in the results when the 12 cases that developed VTE on the day of, or day after, TKA were included.

DISCUSSION

Venous thromboembolism is a frequent and potentially serious complication following TKA. In population‐based studies that report the number of patients who develop symptomatic acute VTE, the incidence is approximately 2.0%2.5%.3, 2224 Thromboprophylaxis reduces the risk of developing asymptomatic VTE by more than 60%, and pharmacologic prophylaxis using LMWH, fondaparinux, or warfarin alone is recommended by the ACCP and other organizations, with use of mechanical pneumatic compression, low‐dose unfractionated heparin, or aspirin as alternative options.25 Nevertheless, because extremely obese patients are not commonly enrolled in clinical trials and because current guidelines do not recommend any adjustment in the dose of LMWH or fondaparinux based on weight, we hypothesized that LMWH/fondaparinux would be significantly less effective in severely or morbidly obese patients. We also hypothesized that pharmacologic prophylaxis would be superior to mechanical prophylaxis alone,26 and that delayed ambulation after TKA would be associated with a higher risk of developing VTE.

Two widely cited clinical guidelines that pertain to prophylaxis of venous thromboembolism after total knee arthroplasty are the ACCP guidelines2 and the American Academy of Orthopedic Surgeons (AAOS) guidelines.27 Although we acknowledge that there are differences in these and other guidelines, recommendations and quality measures,13, 28, 29 the aim of the current study was not to evaluate or compare specific guidelines. We simply classified the thromboprophylaxis regimens into logical groups, the 2 most frequent being use of LMWH/fondaparinux (mechanical) and mechanical prophylaxis alone, and then performed the case‐control analysis. We followed FDA‐approved labeling to assess whether pharmacologic therapy was provided at the proper dose in the proper time period.

A principal finding of this study was that FDA‐approved pharmacologic prophylaxis using LMWH, fondaparinux, or warfarin, was associated with significantly lower odds of developing VTE compared to all other prophylaxis regimens.

When the effect of FDA‐approved pharmacologic prophylaxis was analyzed in severely or morbidly obese patients versus less obese patients, there was no significant difference in the risk of VTE across the BMI levels that were compared. Further, among the patients whose pharmacologic prophylaxis was LMWH or fondaparinux, severe or morbid obesity was not associated with significantly higher odds of developing VTE. Although it is logical to think that heavier patients require a larger dose of LMWH or fondaparinux, the findings of this study suggest that current FDA‐approved doses of these drugs are adequate even in morbidly obese patients.

Two other findings were noteworthy. First, early mobilization with active ambulation in the first 2 days after TKA was strongly associated with lower odds of developing VTE. This finding is similar to the report by Chandrasekaran et al that sitting out of bed or walking for at least 1530 minutes twice a day on the first postoperative day after TKA significantly reduced the incidence of thromboembolic complications (OR = 0.35; 95% CI: 0.11, 1.03, P = 0.03) compared those confined to bed.22, 30 In our study, the beneficial effect of mobilization disappeared if ambulation commenced on day 3 or later after surgery. This finding emphasizes the importance of early mobilization in prevention of VTE, as has been reported after total hip arthroplasty.31

The other important finding was that bilateral simultaneous TKA was strongly associated with VTE, with over 4‐fold greater odds of developing VTE compared with unilateral TKA. This effect did not disappear when we adjusted for obesity or the time to mobilization. This finding was not unexpected and is consistent with other reports in the literature showing a higher incidence of VTE after bilateral TKA compared with unilateral TKA.3235

This study has several limitations. We were unable to ascertain postdischarge VTE unless a patient was readmitted to the same hospital. It has been reported that between 35% to 45% of postoperative VTEs occur after hospital discharge,22, 23 and some of these complications are treated at other institutions or in the outpatient arena.36 Second, it has been shown that hospital volume and hospital specialization are associated with the incidence of VTE after TKA procedures.37, 38 To minimize the risk of confounding by hospital characteristics, we conditioned our analysis on hospital and adjusted for the clustering effect of hospitals. Third, all data were collected by individuals employed by and working at the participating hospitals, with no mechanism for duplicate abstraction to ensure reliability. Fourth, only teaching hospitals participated in this study. Adherence to guidelines and use of prophylaxis may be higher at teaching hospitals than at nonteaching hospitals.39 As a result, our sample may have less variation than the general population of TKA patients, limiting our power to detect associations between thromboprophylaxis and VTE. Finally, the case‐control design has inherent limitations in detecting causal associations, largely due to its susceptibility to unmeasured confounders and incorrect ascertainment of pre‐outcome exposures. To avoid the latter problem, we excluded VTEs that were diagnosed on the date of surgery, before prophylaxis is routinely started.

Despite these limitations, our findings suggest that there may be opportunities to prevent postoperative VTE, even among high‐risk patients at teaching hospitals that have achieved 100% compliance with The Joint Commission's Surgical Care Improvement Project process measures.40, 41 Specifically, delivery of FDA‐approved pharmacologic prophylaxis (vs mechanical prophylaxis alone) and early ambulation (vs later) may further decrease the risk of postoperative VTE. These hypotheses merit further testing in randomized controlled trials or cluster‐randomized quality improvement trials. Patients should be informed of the increased risk of VTE after bilateral TKA, although this additional risk may be outweighed by a reduction in the cumulative recovery time and a lower cumulative risk of developing a prosthetic joint infection.42, 43 Finally, AHRQ's PSI‐12 appears to be a useful tool for ascertaining VTE cases and identifying potential opportunities for improvement, when the present‐on‐admission status is also available.

Symptomatic venous thromboembolism (VTE) is a common complication following total knee arthroplasty (TKA).17 In fact, the high incidence of thrombosis after TKA has made this operation the principal condition used to study the efficacy of new anticoagulants, and it is a principal target of quality improvement oversight and measurement.8 The Agency for Healthcare Research and Quality (AHRQ) has developed a Patient Safety Indicator (PSI‐12) to assist hospitals, payers, and other stakeholders identify patients who experienced VTE after major surgery. The Centers for Medicare * Medicaid Services has deemed that because a VTE that develops after TKA is potentially preventable, it withholds the additional payment for this complication.9

Prior the introduction of new oral anticoagulants, most guidelines from North America recommended the use of postoperative low‐molecular‐weight heparin (LMWH), fondaparinux, or warfarin for at least 10 days after TKA.2, 10 However, there is some ongoing controversy about whether pharmacological prophylaxis is necessary after total joint replacement surgery, and whether it is effective in preventing pulmonary embolism.1114 In addition, there is controversy regarding the effectiveness of mechanical prophylaxis alone as a means of preventing VTE.2, 4, 14, 15

Pharmacological thromboprophylaxis using LMWH or fondaparinux calls for using a fixed‐dose that does not depend on the patient's weight or body mass index (BMI). This stands in sharp contrast to the consistent recommendation to use weight‐based dosing of LMWH/fondaparinux in patients who have acute VTE.16 The absence of any adjustment in the dose of thromboprophylaxis based on weight may be particularly important after TKA because the majority of these patients are obese or extremely obese,1719 making the dose of LMWH/fondaparinux potentially insufficient. It is noteworthy that surgeons who perform bariatric surgery currently recommend a higher dose of LMWH, usually 40 mg of enoxaparin every 12 hours.20, 21

We conducted this case‐control study to address 3 hypotheses. First, we hypothesized that use of standard pharmacologic thromboprophylaxis drugs is associated with a lower risk of acute VTE compared with mechanical prophylaxis alone. Second, we hypothesized that among patients given LMWH/fondaparinux, excessive obesity (BMI >35) is associated with a higher risk of developing VTE. Third, based on prior studies that identified immobilization as a risk factor for VTE, we hypothesized that delayed ambulation after TKA is associated with higher risk for VTE.

METHODS

RESULTS

A total of 593 TKA records were abstracted by the 15 participating hospitals. All patients underwent TKA on the day of admission or the day after admission. A total of 16 cases (12 PE and 4 DVT) were diagnosed with VTE on the day of surgery, or the day after surgery, and were deemed nonpreventable in the multivariable analysis. There were 114 additional cases with VTE (44 PE, 68 DVT, 2 both) diagnosed 2 or more days after surgery, and 463 controls that had no VTE diagnosed by the index hospital within 90 days after surgery.

In bivariate analyses (Table 1), the mean age of cases was significantly greater for controls (65.5 10.4 vs 63.5 10.4, P < 0.05). More cases underwent bilateral simultaneous TKA compared with controls (23% vs 7%, P < 0.001). The mean BMI was marginally higher among VTE cases than among controls (34.6 8.0 vs 33.3 7.1, P = 0.07). Among cases with PE, a significantly greater percentage were morbidly obese than among controls (30% vs 16%, P value = 0.01), whereas there was not a difference for the DVT cases.

Fewer VTE cases began ambulation on or before the second postoperative day compared with controls (47% vs 73%, P < 0.001). There was no difference in the number or types of comorbidities between cases and controls. All patients received at least 1 type of pharmacologic or mechanical prophylaxis within the first 24 hours after TKA. Although the difference was not statistically significant, controls had marginally higher odds of receiving FDA‐approved pharmacologic prophylaxis than cases (P = 0.07; Table 2). Table 3 presents the criterion that led to 242 cases not meeting the definition of FDA‐approved pharmacologic prophylaxis definition. Administering a suboptimal dose was the most common reason. Also, about half of the patients received only mechanical prophylaxis.

In the primary multivariable analysis (Table 4), neither age, gender, nor obesity (defined as BMI >30, BMI >35, or BMI >40) was a significant predictor of VTE. Undergoing bilateral simultaneous TKA versus unilateral TKA was associated with higher risk of VTE (OR = 4.2; 95% CI: 1.909.10), whereas early ambulation on or before the second postoperative day versus later (OR = 0.30; 95% CI: 0.100.90). Receiving FDA‐approved pharmacologic prophylaxis (right dose and time described in Table 4) versus any other prophylaxis regimen was adversely associated with VTE (OR = 0.50; 95% CI: 0.300.80, P = 0.01). There was no significant effect of receipt of FDA‐approved pharmacologic prophylaxis on being diagnosed with VTE among the cases that were severely or morbidly obese (P for interaction = 0.92). In a secondary analysis, the adjusted odds of being diagnosed with VTE were not significantly different for severely (OR = 0.9; CI 0.531.5) or morbidly obese (OR = 1.5; CI 0.802.80) patients.

In a sensitivity analysis, we did not find any significant changes in the results when the 12 cases that developed VTE on the day of, or day after, TKA were included.

DISCUSSION

Venous thromboembolism is a frequent and potentially serious complication following TKA. In population‐based studies that report the number of patients who develop symptomatic acute VTE, the incidence is approximately 2.0%2.5%.3, 2224 Thromboprophylaxis reduces the risk of developing asymptomatic VTE by more than 60%, and pharmacologic prophylaxis using LMWH, fondaparinux, or warfarin alone is recommended by the ACCP and other organizations, with use of mechanical pneumatic compression, low‐dose unfractionated heparin, or aspirin as alternative options.25 Nevertheless, because extremely obese patients are not commonly enrolled in clinical trials and because current guidelines do not recommend any adjustment in the dose of LMWH or fondaparinux based on weight, we hypothesized that LMWH/fondaparinux would be significantly less effective in severely or morbidly obese patients. We also hypothesized that pharmacologic prophylaxis would be superior to mechanical prophylaxis alone,26 and that delayed ambulation after TKA would be associated with a higher risk of developing VTE.

Two widely cited clinical guidelines that pertain to prophylaxis of venous thromboembolism after total knee arthroplasty are the ACCP guidelines2 and the American Academy of Orthopedic Surgeons (AAOS) guidelines.27 Although we acknowledge that there are differences in these and other guidelines, recommendations and quality measures,13, 28, 29 the aim of the current study was not to evaluate or compare specific guidelines. We simply classified the thromboprophylaxis regimens into logical groups, the 2 most frequent being use of LMWH/fondaparinux (mechanical) and mechanical prophylaxis alone, and then performed the case‐control analysis. We followed FDA‐approved labeling to assess whether pharmacologic therapy was provided at the proper dose in the proper time period.

A principal finding of this study was that FDA‐approved pharmacologic prophylaxis using LMWH, fondaparinux, or warfarin, was associated with significantly lower odds of developing VTE compared to all other prophylaxis regimens.

When the effect of FDA‐approved pharmacologic prophylaxis was analyzed in severely or morbidly obese patients versus less obese patients, there was no significant difference in the risk of VTE across the BMI levels that were compared. Further, among the patients whose pharmacologic prophylaxis was LMWH or fondaparinux, severe or morbid obesity was not associated with significantly higher odds of developing VTE. Although it is logical to think that heavier patients require a larger dose of LMWH or fondaparinux, the findings of this study suggest that current FDA‐approved doses of these drugs are adequate even in morbidly obese patients.

Two other findings were noteworthy. First, early mobilization with active ambulation in the first 2 days after TKA was strongly associated with lower odds of developing VTE. This finding is similar to the report by Chandrasekaran et al that sitting out of bed or walking for at least 1530 minutes twice a day on the first postoperative day after TKA significantly reduced the incidence of thromboembolic complications (OR = 0.35; 95% CI: 0.11, 1.03, P = 0.03) compared those confined to bed.22, 30 In our study, the beneficial effect of mobilization disappeared if ambulation commenced on day 3 or later after surgery. This finding emphasizes the importance of early mobilization in prevention of VTE, as has been reported after total hip arthroplasty.31

The other important finding was that bilateral simultaneous TKA was strongly associated with VTE, with over 4‐fold greater odds of developing VTE compared with unilateral TKA. This effect did not disappear when we adjusted for obesity or the time to mobilization. This finding was not unexpected and is consistent with other reports in the literature showing a higher incidence of VTE after bilateral TKA compared with unilateral TKA.3235

This study has several limitations. We were unable to ascertain postdischarge VTE unless a patient was readmitted to the same hospital. It has been reported that between 35% to 45% of postoperative VTEs occur after hospital discharge,22, 23 and some of these complications are treated at other institutions or in the outpatient arena.36 Second, it has been shown that hospital volume and hospital specialization are associated with the incidence of VTE after TKA procedures.37, 38 To minimize the risk of confounding by hospital characteristics, we conditioned our analysis on hospital and adjusted for the clustering effect of hospitals. Third, all data were collected by individuals employed by and working at the participating hospitals, with no mechanism for duplicate abstraction to ensure reliability. Fourth, only teaching hospitals participated in this study. Adherence to guidelines and use of prophylaxis may be higher at teaching hospitals than at nonteaching hospitals.39 As a result, our sample may have less variation than the general population of TKA patients, limiting our power to detect associations between thromboprophylaxis and VTE. Finally, the case‐control design has inherent limitations in detecting causal associations, largely due to its susceptibility to unmeasured confounders and incorrect ascertainment of pre‐outcome exposures. To avoid the latter problem, we excluded VTEs that were diagnosed on the date of surgery, before prophylaxis is routinely started.

Despite these limitations, our findings suggest that there may be opportunities to prevent postoperative VTE, even among high‐risk patients at teaching hospitals that have achieved 100% compliance with The Joint Commission's Surgical Care Improvement Project process measures.40, 41 Specifically, delivery of FDA‐approved pharmacologic prophylaxis (vs mechanical prophylaxis alone) and early ambulation (vs later) may further decrease the risk of postoperative VTE. These hypotheses merit further testing in randomized controlled trials or cluster‐randomized quality improvement trials. Patients should be informed of the increased risk of VTE after bilateral TKA, although this additional risk may be outweighed by a reduction in the cumulative recovery time and a lower cumulative risk of developing a prosthetic joint infection.42, 43 Finally, AHRQ's PSI‐12 appears to be a useful tool for ascertaining VTE cases and identifying potential opportunities for improvement, when the present‐on‐admission status is also available.