Affiliations
University HealthSystem Consortium, Chicago, Illinois
Email
bsadeghi@ucdavis.edu
Given name(s)
Banafsheh
Family name
Sadeghi
Degrees
MD, PhD

VTE Codes in Academic Medical Centers

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Incidence of hospital‐acquired venous thromboembolic codes in medical patients hospitalized in academic medical centers

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

Setting and Cases

We conducted a retrospective analysis of discharges from the 83 academic medical centers belonging to the UHC (formerly, the University HealthSystem Consortium, https://www.uhc.edu)[13] between October 1, 2009 and March 31, 2011. UHC collects demographic, clinical, and billing data from these centers including medical diagnoses and procedures coded using the ICD‐9‐Clinical Modification (ICD‐9‐CM), a POA indicator for each diagnosis; UHC also collects data on medication use. This study was approved by the institutional review board at the University of California Davis.

Patients in our analysis were age 18 years and discharged with a medical medical severity diagnostic‐related group (MS‐DRG) code, hospitalized for 48 hours, and did not have a surgical or obstetric MS‐DRG code (except when assigned a surgical MS‐DRG code solely due to insertion of an inferior vena cava filter, with no other major procedures performed). Cases excluded discharges with a principal diagnosis of acute VTE/SVT (defined here as including PE, LE‐DVT, UE‐DVT, SVT, chronic VTE, and thrombosis not otherwise specified), as coding guidelines prohibit assigning a HA‐VTE as the principal diagnosis for the index hospitalization.[14]

Hospital‐Acquired Venous Thromboembolism or Superficial Venous Thrombosis

Cases were classified as having a HA‐VTE/SVT if there was 1 VTE/SVT coded in a secondary diagnosis position (other diagnosis) with a corresponding POA indicator equal to either N (not POA) or U (documentation insufficient to clarify whether VTE was POA or not). This usage corresponds to CMS guidelines and reimbursement policies for hospital‐acquired conditions.[15] Among cases with 1 HA‐VTE (or SVT), we assigned 1 HA‐VTE diagnosis using a hierarchy based on the highest level of clinical importance: first, PE; then LE‐DVT; then UE‐DVT; then SVT; then chronic VTE; then, finally, unspecified VTE. We subsequently excluded cases with primarily chronic VTE from our analysis because these were likely miscodes (ie, it is unclear how a chronic VTE could not be POA) and there were only 30 such cases. Cases with HA‐PE or HA‐LE DVT were analyzed separately as an important subset of HA‐VTE (plus SVT), because HA‐PE/LE‐DVT is both life‐threatening and theoretically preventable with VTEP.

Severity of Illness and Other Measures of Comorbidity

For each case we used proprietary software (3M Health Information Systems, Murray UT) to classify severity of illness (SOI). The SOI scale, based on physiologic derangement and organ system loss of function,[16] has 4 levels: minor, major, severe, and extreme. Defined within specific disease groups (All Patient Refined DRGs), it is often compared across diseases as well.[17] We also assessed whether patients had a cancer diagnosis, spent time in the intensive care unit (ICU), and died in the hospital.

Central Venous Catheter Use in Patients With Upper‐Extremity Deep Venous Thrombosis or Superficial Venous Thrombosis

Because UE‐DVT and SVT are frequently associated with a CVC or PICC, we assessed central venous catheterization among patients with an UE‐DVT or SVT of the cephalic, basilic, or antecubital veins using diagnosis codes for complications related to dialysis devices, implants, and grafts.

Pharmacologic Thromboprophylaxis

Pharmacy records of the subset of HA‐VTE/SVT cases with PE or LE‐DVT were analyzed to determine if VTEP was administered on hospital day 1 or 2, as per Joint Commission performance requirements.[4] Medications that met criteria as VTEP included unfractionated heparin, 5000 IU, given 2 or 3 a day; enoxaparin, 40 mg, given daily; dalteparin, 2500 or 5000 IU, given daily; fondaparinux, 2.5 mg, given daily; and warfarin. We could not reliably determine if VTEP was used throughout the entire hospitalization, or whether mechanical prophylaxis was used at all.

Statistical Analysis

This was a descriptive analysis to determine the incidence of HA‐VTE/SVT and describe the demographic and clinical characteristics of this population. We calculated means and standard deviations (SD) for continuous variables and proportions for binary variables (including HA‐VTE/SVT incidence). All comparisons between populations were performed as either 2‐tailed t tests or 2 analyses. All analysis was conducted using SAS software, version 9.2 (SAS Institute, Inc., Cary, NC).

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).

Patients With No HA‐VTE Code and Patients With a HA‐PE/LE‐DVT Code (ICD‐9‐CM)
CharacteristicNo HA‐VTE, n = 2,512,221HA‐PE/LE DVT, n = 6,297aP Valueb
  • NOTE: Data are presented as n (%) or mean SD. Abbreviations: API, Asian or Pacific Islander; HA‐PE/LE DVT, hospital‐acquired pulmonary embolism or lower‐extremity deep venous thrombosis; HA‐VTE, hospital‐acquired venous thromboembolism; ICD‐9‐CM, International Classification of Diseases, Ninth Revision, Clinical Modification; ICU, intensive care unit; LMWH, low‐molecular‐weight heparin; SD, standard deviation; SOI, severity of illness.

  • The first 2 columns, no HA‐VTE and HA‐PE/LE DVT, were compared as noted in the third column. Data on upper‐extremity or superficial thrombosis are not shown in this table.

  • For all variables except age and length of stay, P values are calculated by 2; for age and length of stay, P value is calculated by rank‐sum test.

  • Prophylaxis with LMWH, fondaparinux, unfractionated heparin, or warfarin on the first or second day of hospitalization. Prophylaxis was not estimated in the population that did not develop a HA‐VTE.

Proportion of hospitalizations, %99.490.25 
Age, y48.2 27.162.5 20.0<0.001
Female sex1,347,219 (53.6)3,104 (49.3)<0.001
Race  <0.001
Caucasian1,455,215 (57.9)3,963 (64.7) 
Black600,991 (23.9)1,425 (23.3) 
Hispanic206,553 (8.2)263 (4.3) 
API59,560 (2.4)88 (1.4) 
Other189,902 (7.6)389 (6.4) 
Admission SOI  <0.001
Minor461,411 (18.4)181 (2.9) 
Major922,734 (36.7)1,081 (17.2) 
Severe880,542 (35.1)2,975 (47.2) 
Extreme247,244 (9.8)2,060 (32.7) 
Unknown290 (0.01)0 (0.0) 
Had an active diagnosis of cancer331,705 (13.2)2,162 (34.3)<0.001
Length of stay, d7.31 9.3118.7 19.5<0.001
Spent time in the ICU441,412 (17.6)3,011 (47.8)<0.001
Died in hospital57,954 (2.3)1,036 (16.5)<0.001
Received prophylaxiscc3,454 (54.9)c

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.

Disclosures

Nothing to report.

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References
  1. Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuünemann HJ;American College of Chest Physicians AntithromboticTherapy and Prevention of Thrombosis Panel. Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines [published corrections appear in Chest. 2012;141(4):1129 and 2012;142(6):1698]. Chest. 2012;141(2 suppl):7S–47S.
  2. Samama MM, Cohen AT, Darmon JY, et al;Prophylaxis in Medical Patients with Enoxaparin Study Group. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. N Engl J Med. 1999;341(11):793800.
  3. Leizorovicz A, Cohen AT, Turpie AG, Olsson CG, Vaitkus PT, Goldhaber SZ. Randomized, placebo‐controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation. 2004;110(7):874879.
  4. The Joint Commission.Specifications Manual for National Hospital Inpatient Quality Measures. Available at: http://www.jointcommission.org/specifications_manual_for_national_hospital_inpatient_quality_measures.aspx. Accessed July 18, 2012.
  5. Maynard G, Stein J. Preventing Hospital‐Acquired Venous Thromboembolism: A Guide for Effective Quality Improvement. Prepared by the Society of Hospital Medicine. Rockville, MD: Agency for Healthcare Research and Quality; AHRQ Publication No. 08‐0075.
  6. Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 suppl):338S400S.
  7. Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e195Se226S.
  8. Centers for Medicare 46(6 part 1):19461962.
  9. Spyropoulos AC, Anderson FA, Fitzgerald G, et al. Predictive and associative models to identify hospitalized medical patients at risk for VTE. Chest. 2011;140(3):706714.
  10. Khanna R, Vittinghoff E, Maselli J, Auerbach A. Unintended consequences of a standard admission order set on venous thromboembolism prophylaxis and patient outcomes. J Gen Intern Med. 2012;27(3):318324.
  11. United Health Consortium Website. Available at: https://www.uhc.edu. Accessed March 8, 2012.
  12. ICD‐9‐CM Official Guidelines for Coding and Reporting. Available at: http://www.cdc.gov/nchs/data/icd9/icdguide10.pdf. Published 2010. Accessed June 4, 2013.
  13. Centers for Medicare 27(5):587612.
  14. Overview of Disease Severity Measures Disseminated with the Nationwide Inpatient Sample (NIS) and Kids' Inpatient Database (KID). Available at: http://www.hcup‐us.ahrq.gov/db/nation/nis/OverviewofSeveritySystems.pdf. Published December 9, 2005. Accessed June 4, 2013.
  15. Barba R, Zapatero A, Losa JE, et al. Venous thromboembolism in acutely ill hospitalized medical patients. Thromb Res. 2010;126(4):276279.
  16. Lederle FA, Zylla D, MacDonald R, Wilt TJ. Venous thromboembolism prophylaxis in hospitalized medical patients and those with stroke: a background review for an American College of Physicians Clinical Practice Guideline. Ann Intern Med. 2011;155(9):602615.
  17. Rothberg MB, Lindenauer PK, Lahti M, Pekow PS, Selker HP. Risk factor model to predict venous thromboembolism in hospitalized medical patients. J Hosp Med. 2011;6(4):202209.
  18. Bilimoria KY, Chung J, Ju MH, et al. Evaluation of surveillance bias and the validity of the venous thromboembolism quality measure. JAMA. 2013;310(14):14821489.
  19. Evans RS, Sharp JH, Linford LH, et al. Reduction of peripherally inserted central catheter‐associated DVT. Chest. 2013;143(3):627633.
  20. Lavau‐Denes S, Lacroix P, Maubon A, et al. Prophylaxis of catheter‐related deep vein thrombosis in cancer patients with low‐dose warfarin, low molecular weight heparin, or control: a randomized, controlled, phase III study. Cancer Chemother Pharmacol. 2013;72(1):6573.
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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

Setting and Cases

We conducted a retrospective analysis of discharges from the 83 academic medical centers belonging to the UHC (formerly, the University HealthSystem Consortium, https://www.uhc.edu)[13] between October 1, 2009 and March 31, 2011. UHC collects demographic, clinical, and billing data from these centers including medical diagnoses and procedures coded using the ICD‐9‐Clinical Modification (ICD‐9‐CM), a POA indicator for each diagnosis; UHC also collects data on medication use. This study was approved by the institutional review board at the University of California Davis.

Patients in our analysis were age 18 years and discharged with a medical medical severity diagnostic‐related group (MS‐DRG) code, hospitalized for 48 hours, and did not have a surgical or obstetric MS‐DRG code (except when assigned a surgical MS‐DRG code solely due to insertion of an inferior vena cava filter, with no other major procedures performed). Cases excluded discharges with a principal diagnosis of acute VTE/SVT (defined here as including PE, LE‐DVT, UE‐DVT, SVT, chronic VTE, and thrombosis not otherwise specified), as coding guidelines prohibit assigning a HA‐VTE as the principal diagnosis for the index hospitalization.[14]

Hospital‐Acquired Venous Thromboembolism or Superficial Venous Thrombosis

Cases were classified as having a HA‐VTE/SVT if there was 1 VTE/SVT coded in a secondary diagnosis position (other diagnosis) with a corresponding POA indicator equal to either N (not POA) or U (documentation insufficient to clarify whether VTE was POA or not). This usage corresponds to CMS guidelines and reimbursement policies for hospital‐acquired conditions.[15] Among cases with 1 HA‐VTE (or SVT), we assigned 1 HA‐VTE diagnosis using a hierarchy based on the highest level of clinical importance: first, PE; then LE‐DVT; then UE‐DVT; then SVT; then chronic VTE; then, finally, unspecified VTE. We subsequently excluded cases with primarily chronic VTE from our analysis because these were likely miscodes (ie, it is unclear how a chronic VTE could not be POA) and there were only 30 such cases. Cases with HA‐PE or HA‐LE DVT were analyzed separately as an important subset of HA‐VTE (plus SVT), because HA‐PE/LE‐DVT is both life‐threatening and theoretically preventable with VTEP.

Severity of Illness and Other Measures of Comorbidity

For each case we used proprietary software (3M Health Information Systems, Murray UT) to classify severity of illness (SOI). The SOI scale, based on physiologic derangement and organ system loss of function,[16] has 4 levels: minor, major, severe, and extreme. Defined within specific disease groups (All Patient Refined DRGs), it is often compared across diseases as well.[17] We also assessed whether patients had a cancer diagnosis, spent time in the intensive care unit (ICU), and died in the hospital.

Central Venous Catheter Use in Patients With Upper‐Extremity Deep Venous Thrombosis or Superficial Venous Thrombosis

Because UE‐DVT and SVT are frequently associated with a CVC or PICC, we assessed central venous catheterization among patients with an UE‐DVT or SVT of the cephalic, basilic, or antecubital veins using diagnosis codes for complications related to dialysis devices, implants, and grafts.

Pharmacologic Thromboprophylaxis

Pharmacy records of the subset of HA‐VTE/SVT cases with PE or LE‐DVT were analyzed to determine if VTEP was administered on hospital day 1 or 2, as per Joint Commission performance requirements.[4] Medications that met criteria as VTEP included unfractionated heparin, 5000 IU, given 2 or 3 a day; enoxaparin, 40 mg, given daily; dalteparin, 2500 or 5000 IU, given daily; fondaparinux, 2.5 mg, given daily; and warfarin. We could not reliably determine if VTEP was used throughout the entire hospitalization, or whether mechanical prophylaxis was used at all.

Statistical Analysis

This was a descriptive analysis to determine the incidence of HA‐VTE/SVT and describe the demographic and clinical characteristics of this population. We calculated means and standard deviations (SD) for continuous variables and proportions for binary variables (including HA‐VTE/SVT incidence). All comparisons between populations were performed as either 2‐tailed t tests or 2 analyses. All analysis was conducted using SAS software, version 9.2 (SAS Institute, Inc., Cary, NC).

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).

Patients With No HA‐VTE Code and Patients With a HA‐PE/LE‐DVT Code (ICD‐9‐CM)
CharacteristicNo HA‐VTE, n = 2,512,221HA‐PE/LE DVT, n = 6,297aP Valueb
  • NOTE: Data are presented as n (%) or mean SD. Abbreviations: API, Asian or Pacific Islander; HA‐PE/LE DVT, hospital‐acquired pulmonary embolism or lower‐extremity deep venous thrombosis; HA‐VTE, hospital‐acquired venous thromboembolism; ICD‐9‐CM, International Classification of Diseases, Ninth Revision, Clinical Modification; ICU, intensive care unit; LMWH, low‐molecular‐weight heparin; SD, standard deviation; SOI, severity of illness.

  • The first 2 columns, no HA‐VTE and HA‐PE/LE DVT, were compared as noted in the third column. Data on upper‐extremity or superficial thrombosis are not shown in this table.

  • For all variables except age and length of stay, P values are calculated by 2; for age and length of stay, P value is calculated by rank‐sum test.

  • Prophylaxis with LMWH, fondaparinux, unfractionated heparin, or warfarin on the first or second day of hospitalization. Prophylaxis was not estimated in the population that did not develop a HA‐VTE.

Proportion of hospitalizations, %99.490.25 
Age, y48.2 27.162.5 20.0<0.001
Female sex1,347,219 (53.6)3,104 (49.3)<0.001
Race  <0.001
Caucasian1,455,215 (57.9)3,963 (64.7) 
Black600,991 (23.9)1,425 (23.3) 
Hispanic206,553 (8.2)263 (4.3) 
API59,560 (2.4)88 (1.4) 
Other189,902 (7.6)389 (6.4) 
Admission SOI  <0.001
Minor461,411 (18.4)181 (2.9) 
Major922,734 (36.7)1,081 (17.2) 
Severe880,542 (35.1)2,975 (47.2) 
Extreme247,244 (9.8)2,060 (32.7) 
Unknown290 (0.01)0 (0.0) 
Had an active diagnosis of cancer331,705 (13.2)2,162 (34.3)<0.001
Length of stay, d7.31 9.3118.7 19.5<0.001
Spent time in the ICU441,412 (17.6)3,011 (47.8)<0.001
Died in hospital57,954 (2.3)1,036 (16.5)<0.001
Received prophylaxiscc3,454 (54.9)c

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.

Disclosures

Nothing to report.

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

Setting and Cases

We conducted a retrospective analysis of discharges from the 83 academic medical centers belonging to the UHC (formerly, the University HealthSystem Consortium, https://www.uhc.edu)[13] between October 1, 2009 and March 31, 2011. UHC collects demographic, clinical, and billing data from these centers including medical diagnoses and procedures coded using the ICD‐9‐Clinical Modification (ICD‐9‐CM), a POA indicator for each diagnosis; UHC also collects data on medication use. This study was approved by the institutional review board at the University of California Davis.

Patients in our analysis were age 18 years and discharged with a medical medical severity diagnostic‐related group (MS‐DRG) code, hospitalized for 48 hours, and did not have a surgical or obstetric MS‐DRG code (except when assigned a surgical MS‐DRG code solely due to insertion of an inferior vena cava filter, with no other major procedures performed). Cases excluded discharges with a principal diagnosis of acute VTE/SVT (defined here as including PE, LE‐DVT, UE‐DVT, SVT, chronic VTE, and thrombosis not otherwise specified), as coding guidelines prohibit assigning a HA‐VTE as the principal diagnosis for the index hospitalization.[14]

Hospital‐Acquired Venous Thromboembolism or Superficial Venous Thrombosis

Cases were classified as having a HA‐VTE/SVT if there was 1 VTE/SVT coded in a secondary diagnosis position (other diagnosis) with a corresponding POA indicator equal to either N (not POA) or U (documentation insufficient to clarify whether VTE was POA or not). This usage corresponds to CMS guidelines and reimbursement policies for hospital‐acquired conditions.[15] Among cases with 1 HA‐VTE (or SVT), we assigned 1 HA‐VTE diagnosis using a hierarchy based on the highest level of clinical importance: first, PE; then LE‐DVT; then UE‐DVT; then SVT; then chronic VTE; then, finally, unspecified VTE. We subsequently excluded cases with primarily chronic VTE from our analysis because these were likely miscodes (ie, it is unclear how a chronic VTE could not be POA) and there were only 30 such cases. Cases with HA‐PE or HA‐LE DVT were analyzed separately as an important subset of HA‐VTE (plus SVT), because HA‐PE/LE‐DVT is both life‐threatening and theoretically preventable with VTEP.

Severity of Illness and Other Measures of Comorbidity

For each case we used proprietary software (3M Health Information Systems, Murray UT) to classify severity of illness (SOI). The SOI scale, based on physiologic derangement and organ system loss of function,[16] has 4 levels: minor, major, severe, and extreme. Defined within specific disease groups (All Patient Refined DRGs), it is often compared across diseases as well.[17] We also assessed whether patients had a cancer diagnosis, spent time in the intensive care unit (ICU), and died in the hospital.

Central Venous Catheter Use in Patients With Upper‐Extremity Deep Venous Thrombosis or Superficial Venous Thrombosis

Because UE‐DVT and SVT are frequently associated with a CVC or PICC, we assessed central venous catheterization among patients with an UE‐DVT or SVT of the cephalic, basilic, or antecubital veins using diagnosis codes for complications related to dialysis devices, implants, and grafts.

Pharmacologic Thromboprophylaxis

Pharmacy records of the subset of HA‐VTE/SVT cases with PE or LE‐DVT were analyzed to determine if VTEP was administered on hospital day 1 or 2, as per Joint Commission performance requirements.[4] Medications that met criteria as VTEP included unfractionated heparin, 5000 IU, given 2 or 3 a day; enoxaparin, 40 mg, given daily; dalteparin, 2500 or 5000 IU, given daily; fondaparinux, 2.5 mg, given daily; and warfarin. We could not reliably determine if VTEP was used throughout the entire hospitalization, or whether mechanical prophylaxis was used at all.

Statistical Analysis

This was a descriptive analysis to determine the incidence of HA‐VTE/SVT and describe the demographic and clinical characteristics of this population. We calculated means and standard deviations (SD) for continuous variables and proportions for binary variables (including HA‐VTE/SVT incidence). All comparisons between populations were performed as either 2‐tailed t tests or 2 analyses. All analysis was conducted using SAS software, version 9.2 (SAS Institute, Inc., Cary, NC).

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).

Patients With No HA‐VTE Code and Patients With a HA‐PE/LE‐DVT Code (ICD‐9‐CM)
CharacteristicNo HA‐VTE, n = 2,512,221HA‐PE/LE DVT, n = 6,297aP Valueb
  • NOTE: Data are presented as n (%) or mean SD. Abbreviations: API, Asian or Pacific Islander; HA‐PE/LE DVT, hospital‐acquired pulmonary embolism or lower‐extremity deep venous thrombosis; HA‐VTE, hospital‐acquired venous thromboembolism; ICD‐9‐CM, International Classification of Diseases, Ninth Revision, Clinical Modification; ICU, intensive care unit; LMWH, low‐molecular‐weight heparin; SD, standard deviation; SOI, severity of illness.

  • The first 2 columns, no HA‐VTE and HA‐PE/LE DVT, were compared as noted in the third column. Data on upper‐extremity or superficial thrombosis are not shown in this table.

  • For all variables except age and length of stay, P values are calculated by 2; for age and length of stay, P value is calculated by rank‐sum test.

  • Prophylaxis with LMWH, fondaparinux, unfractionated heparin, or warfarin on the first or second day of hospitalization. Prophylaxis was not estimated in the population that did not develop a HA‐VTE.

Proportion of hospitalizations, %99.490.25 
Age, y48.2 27.162.5 20.0<0.001
Female sex1,347,219 (53.6)3,104 (49.3)<0.001
Race  <0.001
Caucasian1,455,215 (57.9)3,963 (64.7) 
Black600,991 (23.9)1,425 (23.3) 
Hispanic206,553 (8.2)263 (4.3) 
API59,560 (2.4)88 (1.4) 
Other189,902 (7.6)389 (6.4) 
Admission SOI  <0.001
Minor461,411 (18.4)181 (2.9) 
Major922,734 (36.7)1,081 (17.2) 
Severe880,542 (35.1)2,975 (47.2) 
Extreme247,244 (9.8)2,060 (32.7) 
Unknown290 (0.01)0 (0.0) 
Had an active diagnosis of cancer331,705 (13.2)2,162 (34.3)<0.001
Length of stay, d7.31 9.3118.7 19.5<0.001
Spent time in the ICU441,412 (17.6)3,011 (47.8)<0.001
Died in hospital57,954 (2.3)1,036 (16.5)<0.001
Received prophylaxiscc3,454 (54.9)c

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.

Disclosures

Nothing to report.

References
  1. Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuünemann HJ;American College of Chest Physicians AntithromboticTherapy and Prevention of Thrombosis Panel. Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines [published corrections appear in Chest. 2012;141(4):1129 and 2012;142(6):1698]. Chest. 2012;141(2 suppl):7S–47S.
  2. Samama MM, Cohen AT, Darmon JY, et al;Prophylaxis in Medical Patients with Enoxaparin Study Group. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. N Engl J Med. 1999;341(11):793800.
  3. Leizorovicz A, Cohen AT, Turpie AG, Olsson CG, Vaitkus PT, Goldhaber SZ. Randomized, placebo‐controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation. 2004;110(7):874879.
  4. The Joint Commission.Specifications Manual for National Hospital Inpatient Quality Measures. Available at: http://www.jointcommission.org/specifications_manual_for_national_hospital_inpatient_quality_measures.aspx. Accessed July 18, 2012.
  5. Maynard G, Stein J. Preventing Hospital‐Acquired Venous Thromboembolism: A Guide for Effective Quality Improvement. Prepared by the Society of Hospital Medicine. Rockville, MD: Agency for Healthcare Research and Quality; AHRQ Publication No. 08‐0075.
  6. Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 suppl):338S400S.
  7. Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e195Se226S.
  8. Centers for Medicare 46(6 part 1):19461962.
  9. Spyropoulos AC, Anderson FA, Fitzgerald G, et al. Predictive and associative models to identify hospitalized medical patients at risk for VTE. Chest. 2011;140(3):706714.
  10. Khanna R, Vittinghoff E, Maselli J, Auerbach A. Unintended consequences of a standard admission order set on venous thromboembolism prophylaxis and patient outcomes. J Gen Intern Med. 2012;27(3):318324.
  11. United Health Consortium Website. Available at: https://www.uhc.edu. Accessed March 8, 2012.
  12. ICD‐9‐CM Official Guidelines for Coding and Reporting. Available at: http://www.cdc.gov/nchs/data/icd9/icdguide10.pdf. Published 2010. Accessed June 4, 2013.
  13. Centers for Medicare 27(5):587612.
  14. Overview of Disease Severity Measures Disseminated with the Nationwide Inpatient Sample (NIS) and Kids' Inpatient Database (KID). Available at: http://www.hcup‐us.ahrq.gov/db/nation/nis/OverviewofSeveritySystems.pdf. Published December 9, 2005. Accessed June 4, 2013.
  15. Barba R, Zapatero A, Losa JE, et al. Venous thromboembolism in acutely ill hospitalized medical patients. Thromb Res. 2010;126(4):276279.
  16. Lederle FA, Zylla D, MacDonald R, Wilt TJ. Venous thromboembolism prophylaxis in hospitalized medical patients and those with stroke: a background review for an American College of Physicians Clinical Practice Guideline. Ann Intern Med. 2011;155(9):602615.
  17. Rothberg MB, Lindenauer PK, Lahti M, Pekow PS, Selker HP. Risk factor model to predict venous thromboembolism in hospitalized medical patients. J Hosp Med. 2011;6(4):202209.
  18. Bilimoria KY, Chung J, Ju MH, et al. Evaluation of surveillance bias and the validity of the venous thromboembolism quality measure. JAMA. 2013;310(14):14821489.
  19. Evans RS, Sharp JH, Linford LH, et al. Reduction of peripherally inserted central catheter‐associated DVT. Chest. 2013;143(3):627633.
  20. Lavau‐Denes S, Lacroix P, Maubon A, et al. Prophylaxis of catheter‐related deep vein thrombosis in cancer patients with low‐dose warfarin, low molecular weight heparin, or control: a randomized, controlled, phase III study. Cancer Chemother Pharmacol. 2013;72(1):6573.
References
  1. Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuünemann HJ;American College of Chest Physicians AntithromboticTherapy and Prevention of Thrombosis Panel. Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines [published corrections appear in Chest. 2012;141(4):1129 and 2012;142(6):1698]. Chest. 2012;141(2 suppl):7S–47S.
  2. Samama MM, Cohen AT, Darmon JY, et al;Prophylaxis in Medical Patients with Enoxaparin Study Group. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. N Engl J Med. 1999;341(11):793800.
  3. Leizorovicz A, Cohen AT, Turpie AG, Olsson CG, Vaitkus PT, Goldhaber SZ. Randomized, placebo‐controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation. 2004;110(7):874879.
  4. The Joint Commission.Specifications Manual for National Hospital Inpatient Quality Measures. Available at: http://www.jointcommission.org/specifications_manual_for_national_hospital_inpatient_quality_measures.aspx. Accessed July 18, 2012.
  5. Maynard G, Stein J. Preventing Hospital‐Acquired Venous Thromboembolism: A Guide for Effective Quality Improvement. Prepared by the Society of Hospital Medicine. Rockville, MD: Agency for Healthcare Research and Quality; AHRQ Publication No. 08‐0075.
  6. Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126(3 suppl):338S400S.
  7. Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e195Se226S.
  8. Centers for Medicare 46(6 part 1):19461962.
  9. Spyropoulos AC, Anderson FA, Fitzgerald G, et al. Predictive and associative models to identify hospitalized medical patients at risk for VTE. Chest. 2011;140(3):706714.
  10. Khanna R, Vittinghoff E, Maselli J, Auerbach A. Unintended consequences of a standard admission order set on venous thromboembolism prophylaxis and patient outcomes. J Gen Intern Med. 2012;27(3):318324.
  11. United Health Consortium Website. Available at: https://www.uhc.edu. Accessed March 8, 2012.
  12. ICD‐9‐CM Official Guidelines for Coding and Reporting. Available at: http://www.cdc.gov/nchs/data/icd9/icdguide10.pdf. Published 2010. Accessed June 4, 2013.
  13. Centers for Medicare 27(5):587612.
  14. Overview of Disease Severity Measures Disseminated with the Nationwide Inpatient Sample (NIS) and Kids' Inpatient Database (KID). Available at: http://www.hcup‐us.ahrq.gov/db/nation/nis/OverviewofSeveritySystems.pdf. Published December 9, 2005. Accessed June 4, 2013.
  15. Barba R, Zapatero A, Losa JE, et al. Venous thromboembolism in acutely ill hospitalized medical patients. Thromb Res. 2010;126(4):276279.
  16. Lederle FA, Zylla D, MacDonald R, Wilt TJ. Venous thromboembolism prophylaxis in hospitalized medical patients and those with stroke: a background review for an American College of Physicians Clinical Practice Guideline. Ann Intern Med. 2011;155(9):602615.
  17. Rothberg MB, Lindenauer PK, Lahti M, Pekow PS, Selker HP. Risk factor model to predict venous thromboembolism in hospitalized medical patients. J Hosp Med. 2011;6(4):202209.
  18. Bilimoria KY, Chung J, Ju MH, et al. Evaluation of surveillance bias and the validity of the venous thromboembolism quality measure. JAMA. 2013;310(14):14821489.
  19. Evans RS, Sharp JH, Linford LH, et al. Reduction of peripherally inserted central catheter‐associated DVT. Chest. 2013;143(3):627633.
  20. Lavau‐Denes S, Lacroix P, Maubon A, et al. Prophylaxis of catheter‐related deep vein thrombosis in cancer patients with low‐dose warfarin, low molecular weight heparin, or control: a randomized, controlled, phase III study. Cancer Chemother Pharmacol. 2013;72(1):6573.
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Address for correspondence and reprint requests: Raman Khanna, MD, MAS, Assistant Clinical Professor of Medicine, University of California San Francisco, Department of Medicine, Division of Hospital Medicine, 533 Parnassus, U136, San Francisco, CA; Telephone: 415‐476‐4806; Fax: 415‐514‐2094; E‐mail: rkhanna@medicine.ucsf.edu.
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Venous Thromboembolism After TKA

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Mechanical and suboptimal pharmacologic prophylaxis and delayed mobilization but not morbid obesity are associated with venous thromboembolism after total knee arthroplasty: A case‐control study

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

Study Design

The University of California Davis, in partnership with the University HealthSystem Consortium (UHC), conducted a retrospective case‐control study of risk factors for acute symptomatic VTE within 90 days following TKA. Fifteen volunteer hospitals nationwide agreed to abstract medical records of up to 40 sampled cases or controls. Inclusion criteria were admission between October 1, 2008 and March 31, 2010; presence of a principal International Classification of Diseases, 9th Revision, Clinical Modification (ICD‐9‐CM) procedure code of 81.54 or 81.55; and age 40 years or more. Patients with a pregnancy‐related principal diagnosis (Major Diagnostic Category 14) or inferior vena cava interruption on or before the date of the first operating room procedure were excluded.

Cases were defined as having: a) one or more secondary diagnosis codes for acute VTE, as defined by AHRQ PSI‐12, version 4.1 (415.11, 415.19, 451.11, 451.19, 451.2, 451.81, 451.9, 453.40453.42, 453.8, 453.9), coupled with a present‐on‐admission flag of no (POA = N); or b) were readmitted with a principal diagnosis of VTE (same codes) within 90 days of the date of surgery. A probability sample of VTE cases (up to a maximum of 20), and 20 eligible TKA patients who did not develop acute VTE during the index hospitalization or within 90 days of surgery, were randomly selected for abstraction. Only 1 case flagged by the PSI algorithm was excluded because VTE could not be confirmed by abstraction.

Chart Abstraction

A chart abstraction tool was constructed and personnel at each site were taught how to obtain the desired information. Data elements included age, gender, height and weight, and type of TKA (unilateral, bilateral, or revision). BMI was calculated and categorized as severely obese (World Health Organization [WHO] class II or more, BMI 35) versus not severely obese (BMI <35), and as morbidly obese (WHO class III, BMI >40) or not morbidly obese (<40). Information about use of pharmacologic (LMWH, fondaparinux, or warfarin) and mechanical thromboprophylaxis was collected and classified as follows. First, the type of prophylaxis was categorized as: (1) LMWH (enoxaparin, dalteparin)/fondaparinux with or without mechanical prophylaxis (pneumatic compression devices, graduated compression stockings, or foot pump); (2) warfarin alone, with or without mechanical prophylaxis; (3) LMWH/fondaparinux and warfarin with or without mechanical pharmacologic prophylaxis; (4) mechanical prophylaxis alone (without any pharmacological prophylaxis but with or without aspirin); and (5) aspirin only, without any other pharmacologic or mechanical prophylaxis. Second, patients who received LMWH, fondaparinux, or warfarin pharmacologic prophylaxis were further classified as receiving FDA‐approved pharmacologic prophylaxis or other prophylaxis. The criteria for FDA‐approved pharmacologic prophylaxis were receipt of the recommended dose at the recommended starting time (per package insert), either before or after surgery, and continued administration until at least the day of hospital discharge, consistent with the 2008 American College of Chest Physicians (ACCP) guidelines for prevention of VTE in orthopedic patients.2 For warfarin, FDA‐approved dosing required a starting dose of 210 mg per day beginning either preoperatively or on the evening after surgery, and given daily thereafter, targeting an international normalized ratio (INR) of 2.03.0. No patient received aspirin alone for prophylaxis. In the analysis of risk factors for VTE, the effect of FDA‐approved pharmacologic prophylaxis was compared against other pharmacologic prophylaxis or mechanical prophylaxis alone. Time of ambulation was defined as early if it occurred on or before the second postoperative day, late if it occurred after the second postoperative day, or none if the patient did not ambulate before discharge.

Outcomes

The principal outcome was validated symptomatic objectively confirmed VTE, manifested as either pulmonary embolism (PE) or lower extremity deep vein thrombosis (DVT) or both. Patients who were diagnosed with VTE on the day of surgery or the day after surgery were not included in the principal analysis, reasoning that postoperative prophylaxis started 1224 hours after surgery is unlikely to prevent early VTE events. In a secondary sensitivity analysis, the effect of including these early postoperative VTE events on the estimated risk was determined.

Statistical Analysis

For continuous variables, bivariate comparisons were made with the use of Student t test. For categorical variables, we applied the chi‐square test and estimated unadjusted odds ratios (ORs) and Cornfield's 95% confidence intervals (CIs). We specifically analyzed whether gender, age, type of TKA, race/ethnicity, primary payer, severe or morbid obesity, postoperative ambulation, personal or family history of VTE, and comorbid conditions were associated with the development of any VTE, DVT, or PE.

Multivariable models were developed using logistic regression. In addition to age and gender, other terms included receipt of FDA‐approved pharmacologic prophylaxis, degree of obesity (severe if BMI >35, morbid if BMI >40), type of TKA (unilateral vs bilateral) and early versus late versus no ambulation. A patient was considered receiving FDA‐approved pharmacologic prophylaxis if the first postoperative dose and the last postoperative dose before discharge of LMWH, fondaparinux, or warfarin were given based on the recommended time and dose. Two‐way interactions between FDA‐approved pharmacologic prophylaxis and extent of obesity were tested, as well as interactions between LMWH/fondaparinux prophylaxis and extent of obesity. We adjusted all of the point estimates and confidence intervals for the correlation of data within each hospital by using the STRATA option in SAS; statistical analyses were performed using the SAS‐PC program, SAS 9.2 (SAS Institute, Inc, Cary, NC).

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.

Results of Bivariate Analysis of Clinical and Demographic Variables in Relation to Case (VTE) or Control (no VTE) Status After TKA
VariableVTE n = 130 (%)No VTE n = 463 (%)Total N = 593 (%)
  • Abbreviations: BMI, body mass index; CVA, cerebrovascular accident; DVT, deep vein thrombosis; LOS, length of stay; PE, pulmonary embolism; TKA, total knee arthroplasty; TKR, total knee replacement; VTE, venous thromboembolism.

  • P value between VTE and no VTE, <0.05. P value between VTE and no VTE groups, <0.001.

GenderMale45 (34)175 (38)220 (37)
Female85288373
Age (y)*Mean65.563.563.9
Standard deviation10.410.410.5
LOS (d)*Mean6.13.44.0
Standard deviation4.71.52.8
Type of TKRPrimary TKR‐unilateral100 (76)425 (92)525 (89)
Primary TKR‐bilateral29 (23)35 (7)64 (11)
Revision for mechanical problem1 (1)3 (1)4 (1)
RaceAfrican American25 (19)80 (17)105 (18)
Asian4 (3)8 (2)12 (2)
White91 (70)337 (73)428 (72)
Hispanic7 (5)28 (6)35 (6)
Unknown/others5 (4)18 (4)23 (4)
Primary payerUninsured/self‐pay2 (1)2 (<1)4 (1)
Medicaid/managed care11 (8)40 (7)51 (9)
Medicare/managed care66 (52)220 (47)286 (48)
Private44 (34)156 (34)200 (34)
US/state/local government1 (1)5 (1)6 (1)
Others/unknown6 (4)40 (8)46 (8)
BMIMean34.633.333.6
 Standard deviation8.07.17.3
ObesityBMI 3051 (38)172 (37)223 (38)
30 to 3529 (22)122 (26)151 (25)
35 to 4021 (18)95 (20)116 (20)
>4029 (22)74 (16)103 (17)
AmbulationTaking steps with or without walker (day 1 or 2 after surgery)62 (47)340 (73)402 (77)
Taking steps with or without walker (day 3 or more after surgery)58 (45)106 (23)164 (28)
Weight bearing only or no ambulation predischarge10 (8)17 (4)27 (5)
No. of days from surgery to taking stepsMean2.01.31.45
Standard deviation2.30.71.4
Comorbidities/risk factorsDiabetes30 (22)99 (22)129 (22)
Hypertension90 (70)313 (67)403 (68)
History of malignancy9 (8)54 (11)63 (11)
Current neoplasm4 (3)9 (2)13 (2)
Documented history/risk of bleeding or hematoma3 (2)7 (2)10 (2)
History of any other surgery1 (1)1 (<1)2 (<1)
Baseline inability to ambulate without assistance from staff03 (1)3 (<1)
Trauma, head trauma, new fractures000
Current use of oral contraceptive or system estrogen08 (2)8 (1)
Past stroke/CVA with residual weakness1 (1)7 (2)8 (1)
Prior history of DVT6 (5)20 (4)26 (4)
Prior history of PE2 (2)11 (2)13 (2)
Family history of VTE05 (1)5 (1)
Known thrombophilia01 (<1)1 (<1)
None of the above33 (25)96 (21)129 (22)

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.

Pharmacological and Nonpharmacological Prophylaxis, and FDA‐Approved Pharmacologic vs All Other Prophylaxis, in TKA Cases With Thromboembolism and TKA Controls Without Thromboembolism
ThromboprophylaxisThromboembolism
VTE = Yes n = 130 (%)VTE = No n = 463 (%)
  • NOTE: Numbers are mutually exclusive within each column. Abbreviations: FDA, US Food and Drug Administration; LWMH, low‐molecular‐weight heparin; TKA, total knee arthroplasty; VTE, venous thromboembolism.

  • There was no case of aspirin alone in our sample.

Pharmacologic prophylaxis
LMWH/fondaparinux61 (46)223 (48)
Warfarin alone (no LMWH)*44 (33)145 (31)
None25 (19)95 (20)
Nonpharmacologic prophylaxis
Intermittent pneumatic compression or graduated compression stockings/foot pump27 (21)93 (20)
FDA‐approved pharmacologic prophylaxis
LWMH/fondaparinux/warfarin prophylaxis67 (48)284 (61)
No FDA‐approved pharmacologic prophylaxis
Suboptimal pharmacologic or mechanical prophylaxis63 (52)179 (39)
Patients Who Did Not Receive FDA‐Approved Pharmacologic Prophylaxis Based on the FDA‐Approved Labeling for Proper Dose, Timing, and Duration
Prophylaxis StatusCases and Controls Who Did Not Receive FDA‐Approved Pharmacologic Prophylaxis (N = 242)
  • Abbreviations: FDA, US Food and Drug Administration.

  • Numbers are not mutually exclusive. Wrong dose if did not meet FDA‐recommended dose: First post‐op dose of enoxaparin was 30 mg per 12 hours, or last post‐op dose before discharge was 30 mg per 12 hours, or 40 mg per day; or first post‐op dose of fondaparinux was 2.5 mg per day; or first post‐op dose of warfarin was 210 mg per day; or first post‐op dose of dalteparin was 2500 mg per 12 hours. Wrong time window if did not meet FDA‐recommended timing: First post‐op dose of enoxaparin was given between 720 and 1440 minutes postsurgery; or first post‐op dose of fondaparinux was given less than or equal to 480 minutes postsurgery; or first post‐op dose of warfarin was given between 0 and 720 minutes postsurgery; or first post‐op dose of dalteparin was given between 240 and 360 minutes postsurgery

Received FDA‐approved pharmacologic prophylaxis but did not meet FDA‐approved proper dose, timing, and duration Variablen*
118 (49%)Wrong dose87
Dose not within the recommended time window17
Not continued at discharge50
Received no pharmacologic prophylaxis (only mechanical)124 (51%)

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.

Results of Multivariable (Conditional Logit) Analysis of Factors Associated With Thromboembolism After TKA
VariableOdds RatioP Value
  • Abbreviations: BMI, body mass index; FDA, US Food and Drug Administration; TKA, total knee arthroplasty.

  • If the first post‐op dose of enoxaparin was given between 720 and 1440 minutes postsurgery, or the first post‐op dose of enoxaparin was 30 mg per 12 hours, or last post‐op dose before discharge was 30 mg per 12 hours or 40 mg per day; or the first post‐op dose of fondaparinux was given less than or equal to 480 minutes postsurgery, or the first post‐op dose of fondaparinux was 2.5 mg per day; or the first post‐op dose of dalteparin was 2500 mg per 12 hours, or the first post‐op dose of dalteparin was given between 240 and 360 minutes postsurgery; or the first post‐op dose of warfarin was given between 0 and 720 minutes postsurgery, or the first post‐op dose of warfarin was 210 mg per day.

Older age1.02 (0.991.05)0.20
Female gender1.70 (0.92.9)0.90
BMI over 35 (vs 35 or less)0.9 (0.51.6)0.66
Bilateral TKA (vs unilateral TKA)4.2 (1.99.1)0.0004
Receiving FDA‐approved pharmacologic prophylaxis* vs mechanical0.5 (0.30.8)0.01
Ambulation on or before second postoperative day0.3 (0.10.9)0.005

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.

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References
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  3. Howie C, Hughes H, Watts AC. Venous thromboembolism associated with hip and knee replacement over a ten‐year period: a population‐based study. J Bone Joint Surg Br. 2005;87(12):16751680.
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  5. Watanabe H, Sekiya H, Kariya Y, Hoshino Y, Sugimoto H, Hayasaka S. The incidence of venous thromboembolism before and after total knee arthroplasty using 16‐row multidetector computed tomography. J Arthroplasty. 2011;26(8):14881493.
  6. White RH, Romano PS, Zhou H, Rodrigo J, Bargar W. Incidence and time course of thromboembolic outcomes following total hip or knee arthroplasty. Arch Intern Med. 1998;158(14):15251531.
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  8. White RH, Sadeghi B, Tancredi DJ, et al. How valid is the ICD‐9‐CM based AHRQ patient safety indicator for postoperative venous thromboembolism? Med Care. 2009;47(12):12371243.
  9. Department of Health and Human Services, Centers for Medicare 17(4):359365.
  10. Eikelboom J, Karthikeyan G, Fagel N, Hirsh J. American Association of Orthopedic Surgeons and American College of Chest Physicians guidelines for venous thromboembolism prevention in hip and knee arthroplasty differ. What are the implications for clinicians and patients? Chest. 2009;135(2):15121520.
  11. Jämsen E, Varonen M, Huhtala H, et al. Incidence of prosthetic joint infections after primary knee arthroplasty. J Arthroplasty. 2010;25(1):8792.
  12. Lachiewicz PF. Comparison of ACCP and AAOS guidelines for VTE prophylaxis after total hip and total knee arthroplasty. Orthopedics. 2009;32(12 suppl):7478.
  13. Sobieraj‐Teague M, Eikelboom JW, Hirsh J. How can we reduce disagreement among guidelines for venous thromboembolism prevention? J Thromb Haemost. 2010;8(4):675677.
  14. Limpus A, Chaboyer W, McDonald E, Thalib L. Mechanical thromboprophylaxis in critically ill patients: a systematic review and meta‐analysis. Am J Crit Care. 2006;15(4):402410; quiz/discussion, 411–412.
  15. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines (8th ed). Chest. 2008;133(6 suppl):454S545S.
  16. Altintaş F, Gürbüz H, Erdemli B, et al. Venous thromboembolism prophylaxis in major orthopaedic surgery: a multicenter, prospective, observational study. Acta Orthop Traumatol Turc. 2008;42(5):322327.
  17. Namba RS, Paxton L, Fithian DC, Stone ML. Obesity and perioperative morbidity in total hip and total knee arthroplasty patients. J Arthroplasty. 2005;20(suppl 3):4650.
  18. White RH, Henderson MC. Risk factors for venous thromboembolism after total hip and knee replacement surgery. Curr Opin Pulm Med. 2002;8(5):365371.
  19. Simone E, Madan A, Tichansky D, Kuhl D, Lee M. Comparison of two low‐molecular‐weight heparin dosing regimens for patients undergoing laparoscopic bariatric surgery. Surg Endosc. 2008;22(11):23922395.
  20. Rowan B, Kuhl D, Lee M, Tichansky D, Madan A. Anti‐Xa levels in bariatric surgery patients receiving prophylactic enoxaparin. Obes Surg. 2008;18(2):162166.
  21. Samama CM, Ravaud P, Parent F, Barre J, Mertl P, Mismetti P. Epidemiology of venous thromboembolism after lower limb arthroplasty: the FOTO study. J Thromb Haemost. 2007;5(12):23602367.
  22. White RH, Zhou H, Romano PS. Incidence of symptomatic venous thromboembolism after different elective or urgent surgical procedures. Thromb Haemost. 2003;90(3):446455.
  23. White RH. The epidemiology of venous thromboembolism. Circulation.2003;107(23 suppl 1):I4I8.
  24. Falck‐Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e278Se325S.
  25. Blanchard J, Meuwly J‐Y, Leyvraz P‐F, et al. Prevention of deep‐vein thrombosis after total knee replacement: randomised comparison between a low‐molecular‐weight heparin and mechanical prophylaxis with a foot‐pump system. J Bone Joint Surg Br. 1999;81‐B(4):654659.
  26. AAOS. Pulmonary Embolism After Knee Arthroscopy: Rare but Serious. American Academy of Orthopaedic Surgeons/American Association of Orthopaedic Surgeons Web site. Available at: http://www6aaosorg/news/pemr/releases/releasecfm?releasenum=9692011.
  27. Eikelboom JW, Karthikeyan G, Fagel N, Hirsh J. American Association of Orthopedic Surgeons and American College of Chest Physicians guidelines for venous thromboembolism prevention in hip and knee arthroplasty differ: what are the implications for clinicians and patients? Chest. 2009;135(2):513520.
  28. Premier—A supporting partnership organization of the Surgical Care Improvement Project (SCIP). Premier Inc Web site. Available at: http://www.premierinc.com/safety/topics/scip/. Accessed April 10, 2012.
  29. Chandrasekaran S, Ariaretnam SK, Tsung J, Dickison D. Early mobilization after total knee replacement reduces the incidence of deep venous thrombosis. Aust N Z J Surg. 2009;79(7–8):526529.
  30. White RH, Gettner S, Newman JM, Trauner KB, Romano PS. Predictors of rehospitalization for symptomatic venous thromboembolism after total hip arthroplasty. N Engl J Med. 2000;343(24):17581764.
  31. Barrett J, Baron JA, Losina E, Wright J, Mahomed NN, Katz JN. Bilateral total knee replacement: staging and pulmonary embolism. J Bone Joint Surg Am. 2006;88(10):21462151.
  32. Kim YH, Kim JS. Incidence and natural history of deep‐vein thrombosis after total knee arthroplasty. A prospective, randomised study. J Bone Joint Surg Br. 2002;84(4):566570.
  33. Memtsoudis SG, Gonzalez Della Valle A, Besculides MC, Gaber L, Sculco TP. In‐hospital complications and mortality of unilateral, bilateral, and revision TKA: based on an estimate of 4,159,661 discharges. Clin Orthop Relat Res. 2008;466(11):26172627.
  34. Restrepo C, Parvizi J, Dietrich T, Einhorn TA. Safety of simultaneous bilateral total knee arthroplasty. A meta‐analysis. J Bone Joint Surg Am. 2007;89(6):12201226.
  35. Dushey CH, Bornstein LJ, Alexiades MM, Westrich GH. Short‐term coagulation complications following total knee arthroplasty: a comparison of patient‐reported and surgeon‐verified complication rates. J Arthroplasty. 2011 Jan 20.
  36. Baser O, Supina D, Sengupta N, Wang L, Kwong L. Clinical and cost outcomes of venous thromboembolism in Medicare patients undergoing total hip replacement or total knee replacement surgery. Curr Med Res Opin. 2011;27(2):423429.
  37. Hagen TP, Vaughan‐Sarrazin MS, Cram P. Relation between hospital orthopaedic specialisation and outcomes in patients aged 65 and older: retrospective analysis of US Medicare data. BMJ. 2010;340:c165.
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  41. Fabi DW, Mohan V, Goldstein WM, Dunn JH, Murphy BP. Unilateral vs bilateral total knee arthroplasty risk factors increasing morbidity. J Arthroplasty. 2011;26(5):668673.
  42. Powell RS, Pulido P, Tuason MS, Colwell CW, Ezzet KA. Bilateral vs unilateral total knee arthroplasty: a patient‐based comparison of pain levels and recovery of ambulatory skills. J Arthroplasty. 2006;21(5):642649.
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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

Study Design

The University of California Davis, in partnership with the University HealthSystem Consortium (UHC), conducted a retrospective case‐control study of risk factors for acute symptomatic VTE within 90 days following TKA. Fifteen volunteer hospitals nationwide agreed to abstract medical records of up to 40 sampled cases or controls. Inclusion criteria were admission between October 1, 2008 and March 31, 2010; presence of a principal International Classification of Diseases, 9th Revision, Clinical Modification (ICD‐9‐CM) procedure code of 81.54 or 81.55; and age 40 years or more. Patients with a pregnancy‐related principal diagnosis (Major Diagnostic Category 14) or inferior vena cava interruption on or before the date of the first operating room procedure were excluded.

Cases were defined as having: a) one or more secondary diagnosis codes for acute VTE, as defined by AHRQ PSI‐12, version 4.1 (415.11, 415.19, 451.11, 451.19, 451.2, 451.81, 451.9, 453.40453.42, 453.8, 453.9), coupled with a present‐on‐admission flag of no (POA = N); or b) were readmitted with a principal diagnosis of VTE (same codes) within 90 days of the date of surgery. A probability sample of VTE cases (up to a maximum of 20), and 20 eligible TKA patients who did not develop acute VTE during the index hospitalization or within 90 days of surgery, were randomly selected for abstraction. Only 1 case flagged by the PSI algorithm was excluded because VTE could not be confirmed by abstraction.

Chart Abstraction

A chart abstraction tool was constructed and personnel at each site were taught how to obtain the desired information. Data elements included age, gender, height and weight, and type of TKA (unilateral, bilateral, or revision). BMI was calculated and categorized as severely obese (World Health Organization [WHO] class II or more, BMI 35) versus not severely obese (BMI <35), and as morbidly obese (WHO class III, BMI >40) or not morbidly obese (<40). Information about use of pharmacologic (LMWH, fondaparinux, or warfarin) and mechanical thromboprophylaxis was collected and classified as follows. First, the type of prophylaxis was categorized as: (1) LMWH (enoxaparin, dalteparin)/fondaparinux with or without mechanical prophylaxis (pneumatic compression devices, graduated compression stockings, or foot pump); (2) warfarin alone, with or without mechanical prophylaxis; (3) LMWH/fondaparinux and warfarin with or without mechanical pharmacologic prophylaxis; (4) mechanical prophylaxis alone (without any pharmacological prophylaxis but with or without aspirin); and (5) aspirin only, without any other pharmacologic or mechanical prophylaxis. Second, patients who received LMWH, fondaparinux, or warfarin pharmacologic prophylaxis were further classified as receiving FDA‐approved pharmacologic prophylaxis or other prophylaxis. The criteria for FDA‐approved pharmacologic prophylaxis were receipt of the recommended dose at the recommended starting time (per package insert), either before or after surgery, and continued administration until at least the day of hospital discharge, consistent with the 2008 American College of Chest Physicians (ACCP) guidelines for prevention of VTE in orthopedic patients.2 For warfarin, FDA‐approved dosing required a starting dose of 210 mg per day beginning either preoperatively or on the evening after surgery, and given daily thereafter, targeting an international normalized ratio (INR) of 2.03.0. No patient received aspirin alone for prophylaxis. In the analysis of risk factors for VTE, the effect of FDA‐approved pharmacologic prophylaxis was compared against other pharmacologic prophylaxis or mechanical prophylaxis alone. Time of ambulation was defined as early if it occurred on or before the second postoperative day, late if it occurred after the second postoperative day, or none if the patient did not ambulate before discharge.

Outcomes

The principal outcome was validated symptomatic objectively confirmed VTE, manifested as either pulmonary embolism (PE) or lower extremity deep vein thrombosis (DVT) or both. Patients who were diagnosed with VTE on the day of surgery or the day after surgery were not included in the principal analysis, reasoning that postoperative prophylaxis started 1224 hours after surgery is unlikely to prevent early VTE events. In a secondary sensitivity analysis, the effect of including these early postoperative VTE events on the estimated risk was determined.

Statistical Analysis

For continuous variables, bivariate comparisons were made with the use of Student t test. For categorical variables, we applied the chi‐square test and estimated unadjusted odds ratios (ORs) and Cornfield's 95% confidence intervals (CIs). We specifically analyzed whether gender, age, type of TKA, race/ethnicity, primary payer, severe or morbid obesity, postoperative ambulation, personal or family history of VTE, and comorbid conditions were associated with the development of any VTE, DVT, or PE.

Multivariable models were developed using logistic regression. In addition to age and gender, other terms included receipt of FDA‐approved pharmacologic prophylaxis, degree of obesity (severe if BMI >35, morbid if BMI >40), type of TKA (unilateral vs bilateral) and early versus late versus no ambulation. A patient was considered receiving FDA‐approved pharmacologic prophylaxis if the first postoperative dose and the last postoperative dose before discharge of LMWH, fondaparinux, or warfarin were given based on the recommended time and dose. Two‐way interactions between FDA‐approved pharmacologic prophylaxis and extent of obesity were tested, as well as interactions between LMWH/fondaparinux prophylaxis and extent of obesity. We adjusted all of the point estimates and confidence intervals for the correlation of data within each hospital by using the STRATA option in SAS; statistical analyses were performed using the SAS‐PC program, SAS 9.2 (SAS Institute, Inc, Cary, NC).

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.

Results of Bivariate Analysis of Clinical and Demographic Variables in Relation to Case (VTE) or Control (no VTE) Status After TKA
VariableVTE n = 130 (%)No VTE n = 463 (%)Total N = 593 (%)
  • Abbreviations: BMI, body mass index; CVA, cerebrovascular accident; DVT, deep vein thrombosis; LOS, length of stay; PE, pulmonary embolism; TKA, total knee arthroplasty; TKR, total knee replacement; VTE, venous thromboembolism.

  • P value between VTE and no VTE, <0.05. P value between VTE and no VTE groups, <0.001.

GenderMale45 (34)175 (38)220 (37)
Female85288373
Age (y)*Mean65.563.563.9
Standard deviation10.410.410.5
LOS (d)*Mean6.13.44.0
Standard deviation4.71.52.8
Type of TKRPrimary TKR‐unilateral100 (76)425 (92)525 (89)
Primary TKR‐bilateral29 (23)35 (7)64 (11)
Revision for mechanical problem1 (1)3 (1)4 (1)
RaceAfrican American25 (19)80 (17)105 (18)
Asian4 (3)8 (2)12 (2)
White91 (70)337 (73)428 (72)
Hispanic7 (5)28 (6)35 (6)
Unknown/others5 (4)18 (4)23 (4)
Primary payerUninsured/self‐pay2 (1)2 (<1)4 (1)
Medicaid/managed care11 (8)40 (7)51 (9)
Medicare/managed care66 (52)220 (47)286 (48)
Private44 (34)156 (34)200 (34)
US/state/local government1 (1)5 (1)6 (1)
Others/unknown6 (4)40 (8)46 (8)
BMIMean34.633.333.6
 Standard deviation8.07.17.3
ObesityBMI 3051 (38)172 (37)223 (38)
30 to 3529 (22)122 (26)151 (25)
35 to 4021 (18)95 (20)116 (20)
>4029 (22)74 (16)103 (17)
AmbulationTaking steps with or without walker (day 1 or 2 after surgery)62 (47)340 (73)402 (77)
Taking steps with or without walker (day 3 or more after surgery)58 (45)106 (23)164 (28)
Weight bearing only or no ambulation predischarge10 (8)17 (4)27 (5)
No. of days from surgery to taking stepsMean2.01.31.45
Standard deviation2.30.71.4
Comorbidities/risk factorsDiabetes30 (22)99 (22)129 (22)
Hypertension90 (70)313 (67)403 (68)
History of malignancy9 (8)54 (11)63 (11)
Current neoplasm4 (3)9 (2)13 (2)
Documented history/risk of bleeding or hematoma3 (2)7 (2)10 (2)
History of any other surgery1 (1)1 (<1)2 (<1)
Baseline inability to ambulate without assistance from staff03 (1)3 (<1)
Trauma, head trauma, new fractures000
Current use of oral contraceptive or system estrogen08 (2)8 (1)
Past stroke/CVA with residual weakness1 (1)7 (2)8 (1)
Prior history of DVT6 (5)20 (4)26 (4)
Prior history of PE2 (2)11 (2)13 (2)
Family history of VTE05 (1)5 (1)
Known thrombophilia01 (<1)1 (<1)
None of the above33 (25)96 (21)129 (22)

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.

Pharmacological and Nonpharmacological Prophylaxis, and FDA‐Approved Pharmacologic vs All Other Prophylaxis, in TKA Cases With Thromboembolism and TKA Controls Without Thromboembolism
ThromboprophylaxisThromboembolism
VTE = Yes n = 130 (%)VTE = No n = 463 (%)
  • NOTE: Numbers are mutually exclusive within each column. Abbreviations: FDA, US Food and Drug Administration; LWMH, low‐molecular‐weight heparin; TKA, total knee arthroplasty; VTE, venous thromboembolism.

  • There was no case of aspirin alone in our sample.

Pharmacologic prophylaxis
LMWH/fondaparinux61 (46)223 (48)
Warfarin alone (no LMWH)*44 (33)145 (31)
None25 (19)95 (20)
Nonpharmacologic prophylaxis
Intermittent pneumatic compression or graduated compression stockings/foot pump27 (21)93 (20)
FDA‐approved pharmacologic prophylaxis
LWMH/fondaparinux/warfarin prophylaxis67 (48)284 (61)
No FDA‐approved pharmacologic prophylaxis
Suboptimal pharmacologic or mechanical prophylaxis63 (52)179 (39)
Patients Who Did Not Receive FDA‐Approved Pharmacologic Prophylaxis Based on the FDA‐Approved Labeling for Proper Dose, Timing, and Duration
Prophylaxis StatusCases and Controls Who Did Not Receive FDA‐Approved Pharmacologic Prophylaxis (N = 242)
  • Abbreviations: FDA, US Food and Drug Administration.

  • Numbers are not mutually exclusive. Wrong dose if did not meet FDA‐recommended dose: First post‐op dose of enoxaparin was 30 mg per 12 hours, or last post‐op dose before discharge was 30 mg per 12 hours, or 40 mg per day; or first post‐op dose of fondaparinux was 2.5 mg per day; or first post‐op dose of warfarin was 210 mg per day; or first post‐op dose of dalteparin was 2500 mg per 12 hours. Wrong time window if did not meet FDA‐recommended timing: First post‐op dose of enoxaparin was given between 720 and 1440 minutes postsurgery; or first post‐op dose of fondaparinux was given less than or equal to 480 minutes postsurgery; or first post‐op dose of warfarin was given between 0 and 720 minutes postsurgery; or first post‐op dose of dalteparin was given between 240 and 360 minutes postsurgery

Received FDA‐approved pharmacologic prophylaxis but did not meet FDA‐approved proper dose, timing, and duration Variablen*
118 (49%)Wrong dose87
Dose not within the recommended time window17
Not continued at discharge50
Received no pharmacologic prophylaxis (only mechanical)124 (51%)

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.

Results of Multivariable (Conditional Logit) Analysis of Factors Associated With Thromboembolism After TKA
VariableOdds RatioP Value
  • Abbreviations: BMI, body mass index; FDA, US Food and Drug Administration; TKA, total knee arthroplasty.

  • If the first post‐op dose of enoxaparin was given between 720 and 1440 minutes postsurgery, or the first post‐op dose of enoxaparin was 30 mg per 12 hours, or last post‐op dose before discharge was 30 mg per 12 hours or 40 mg per day; or the first post‐op dose of fondaparinux was given less than or equal to 480 minutes postsurgery, or the first post‐op dose of fondaparinux was 2.5 mg per day; or the first post‐op dose of dalteparin was 2500 mg per 12 hours, or the first post‐op dose of dalteparin was given between 240 and 360 minutes postsurgery; or the first post‐op dose of warfarin was given between 0 and 720 minutes postsurgery, or the first post‐op dose of warfarin was 210 mg per day.

Older age1.02 (0.991.05)0.20
Female gender1.70 (0.92.9)0.90
BMI over 35 (vs 35 or less)0.9 (0.51.6)0.66
Bilateral TKA (vs unilateral TKA)4.2 (1.99.1)0.0004
Receiving FDA‐approved pharmacologic prophylaxis* vs mechanical0.5 (0.30.8)0.01
Ambulation on or before second postoperative day0.3 (0.10.9)0.005

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

Study Design

The University of California Davis, in partnership with the University HealthSystem Consortium (UHC), conducted a retrospective case‐control study of risk factors for acute symptomatic VTE within 90 days following TKA. Fifteen volunteer hospitals nationwide agreed to abstract medical records of up to 40 sampled cases or controls. Inclusion criteria were admission between October 1, 2008 and March 31, 2010; presence of a principal International Classification of Diseases, 9th Revision, Clinical Modification (ICD‐9‐CM) procedure code of 81.54 or 81.55; and age 40 years or more. Patients with a pregnancy‐related principal diagnosis (Major Diagnostic Category 14) or inferior vena cava interruption on or before the date of the first operating room procedure were excluded.

Cases were defined as having: a) one or more secondary diagnosis codes for acute VTE, as defined by AHRQ PSI‐12, version 4.1 (415.11, 415.19, 451.11, 451.19, 451.2, 451.81, 451.9, 453.40453.42, 453.8, 453.9), coupled with a present‐on‐admission flag of no (POA = N); or b) were readmitted with a principal diagnosis of VTE (same codes) within 90 days of the date of surgery. A probability sample of VTE cases (up to a maximum of 20), and 20 eligible TKA patients who did not develop acute VTE during the index hospitalization or within 90 days of surgery, were randomly selected for abstraction. Only 1 case flagged by the PSI algorithm was excluded because VTE could not be confirmed by abstraction.

Chart Abstraction

A chart abstraction tool was constructed and personnel at each site were taught how to obtain the desired information. Data elements included age, gender, height and weight, and type of TKA (unilateral, bilateral, or revision). BMI was calculated and categorized as severely obese (World Health Organization [WHO] class II or more, BMI 35) versus not severely obese (BMI <35), and as morbidly obese (WHO class III, BMI >40) or not morbidly obese (<40). Information about use of pharmacologic (LMWH, fondaparinux, or warfarin) and mechanical thromboprophylaxis was collected and classified as follows. First, the type of prophylaxis was categorized as: (1) LMWH (enoxaparin, dalteparin)/fondaparinux with or without mechanical prophylaxis (pneumatic compression devices, graduated compression stockings, or foot pump); (2) warfarin alone, with or without mechanical prophylaxis; (3) LMWH/fondaparinux and warfarin with or without mechanical pharmacologic prophylaxis; (4) mechanical prophylaxis alone (without any pharmacological prophylaxis but with or without aspirin); and (5) aspirin only, without any other pharmacologic or mechanical prophylaxis. Second, patients who received LMWH, fondaparinux, or warfarin pharmacologic prophylaxis were further classified as receiving FDA‐approved pharmacologic prophylaxis or other prophylaxis. The criteria for FDA‐approved pharmacologic prophylaxis were receipt of the recommended dose at the recommended starting time (per package insert), either before or after surgery, and continued administration until at least the day of hospital discharge, consistent with the 2008 American College of Chest Physicians (ACCP) guidelines for prevention of VTE in orthopedic patients.2 For warfarin, FDA‐approved dosing required a starting dose of 210 mg per day beginning either preoperatively or on the evening after surgery, and given daily thereafter, targeting an international normalized ratio (INR) of 2.03.0. No patient received aspirin alone for prophylaxis. In the analysis of risk factors for VTE, the effect of FDA‐approved pharmacologic prophylaxis was compared against other pharmacologic prophylaxis or mechanical prophylaxis alone. Time of ambulation was defined as early if it occurred on or before the second postoperative day, late if it occurred after the second postoperative day, or none if the patient did not ambulate before discharge.

Outcomes

The principal outcome was validated symptomatic objectively confirmed VTE, manifested as either pulmonary embolism (PE) or lower extremity deep vein thrombosis (DVT) or both. Patients who were diagnosed with VTE on the day of surgery or the day after surgery were not included in the principal analysis, reasoning that postoperative prophylaxis started 1224 hours after surgery is unlikely to prevent early VTE events. In a secondary sensitivity analysis, the effect of including these early postoperative VTE events on the estimated risk was determined.

Statistical Analysis

For continuous variables, bivariate comparisons were made with the use of Student t test. For categorical variables, we applied the chi‐square test and estimated unadjusted odds ratios (ORs) and Cornfield's 95% confidence intervals (CIs). We specifically analyzed whether gender, age, type of TKA, race/ethnicity, primary payer, severe or morbid obesity, postoperative ambulation, personal or family history of VTE, and comorbid conditions were associated with the development of any VTE, DVT, or PE.

Multivariable models were developed using logistic regression. In addition to age and gender, other terms included receipt of FDA‐approved pharmacologic prophylaxis, degree of obesity (severe if BMI >35, morbid if BMI >40), type of TKA (unilateral vs bilateral) and early versus late versus no ambulation. A patient was considered receiving FDA‐approved pharmacologic prophylaxis if the first postoperative dose and the last postoperative dose before discharge of LMWH, fondaparinux, or warfarin were given based on the recommended time and dose. Two‐way interactions between FDA‐approved pharmacologic prophylaxis and extent of obesity were tested, as well as interactions between LMWH/fondaparinux prophylaxis and extent of obesity. We adjusted all of the point estimates and confidence intervals for the correlation of data within each hospital by using the STRATA option in SAS; statistical analyses were performed using the SAS‐PC program, SAS 9.2 (SAS Institute, Inc, Cary, NC).

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.

Results of Bivariate Analysis of Clinical and Demographic Variables in Relation to Case (VTE) or Control (no VTE) Status After TKA
VariableVTE n = 130 (%)No VTE n = 463 (%)Total N = 593 (%)
  • Abbreviations: BMI, body mass index; CVA, cerebrovascular accident; DVT, deep vein thrombosis; LOS, length of stay; PE, pulmonary embolism; TKA, total knee arthroplasty; TKR, total knee replacement; VTE, venous thromboembolism.

  • P value between VTE and no VTE, <0.05. P value between VTE and no VTE groups, <0.001.

GenderMale45 (34)175 (38)220 (37)
Female85288373
Age (y)*Mean65.563.563.9
Standard deviation10.410.410.5
LOS (d)*Mean6.13.44.0
Standard deviation4.71.52.8
Type of TKRPrimary TKR‐unilateral100 (76)425 (92)525 (89)
Primary TKR‐bilateral29 (23)35 (7)64 (11)
Revision for mechanical problem1 (1)3 (1)4 (1)
RaceAfrican American25 (19)80 (17)105 (18)
Asian4 (3)8 (2)12 (2)
White91 (70)337 (73)428 (72)
Hispanic7 (5)28 (6)35 (6)
Unknown/others5 (4)18 (4)23 (4)
Primary payerUninsured/self‐pay2 (1)2 (<1)4 (1)
Medicaid/managed care11 (8)40 (7)51 (9)
Medicare/managed care66 (52)220 (47)286 (48)
Private44 (34)156 (34)200 (34)
US/state/local government1 (1)5 (1)6 (1)
Others/unknown6 (4)40 (8)46 (8)
BMIMean34.633.333.6
 Standard deviation8.07.17.3
ObesityBMI 3051 (38)172 (37)223 (38)
30 to 3529 (22)122 (26)151 (25)
35 to 4021 (18)95 (20)116 (20)
>4029 (22)74 (16)103 (17)
AmbulationTaking steps with or without walker (day 1 or 2 after surgery)62 (47)340 (73)402 (77)
Taking steps with or without walker (day 3 or more after surgery)58 (45)106 (23)164 (28)
Weight bearing only or no ambulation predischarge10 (8)17 (4)27 (5)
No. of days from surgery to taking stepsMean2.01.31.45
Standard deviation2.30.71.4
Comorbidities/risk factorsDiabetes30 (22)99 (22)129 (22)
Hypertension90 (70)313 (67)403 (68)
History of malignancy9 (8)54 (11)63 (11)
Current neoplasm4 (3)9 (2)13 (2)
Documented history/risk of bleeding or hematoma3 (2)7 (2)10 (2)
History of any other surgery1 (1)1 (<1)2 (<1)
Baseline inability to ambulate without assistance from staff03 (1)3 (<1)
Trauma, head trauma, new fractures000
Current use of oral contraceptive or system estrogen08 (2)8 (1)
Past stroke/CVA with residual weakness1 (1)7 (2)8 (1)
Prior history of DVT6 (5)20 (4)26 (4)
Prior history of PE2 (2)11 (2)13 (2)
Family history of VTE05 (1)5 (1)
Known thrombophilia01 (<1)1 (<1)
None of the above33 (25)96 (21)129 (22)

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.

Pharmacological and Nonpharmacological Prophylaxis, and FDA‐Approved Pharmacologic vs All Other Prophylaxis, in TKA Cases With Thromboembolism and TKA Controls Without Thromboembolism
ThromboprophylaxisThromboembolism
VTE = Yes n = 130 (%)VTE = No n = 463 (%)
  • NOTE: Numbers are mutually exclusive within each column. Abbreviations: FDA, US Food and Drug Administration; LWMH, low‐molecular‐weight heparin; TKA, total knee arthroplasty; VTE, venous thromboembolism.

  • There was no case of aspirin alone in our sample.

Pharmacologic prophylaxis
LMWH/fondaparinux61 (46)223 (48)
Warfarin alone (no LMWH)*44 (33)145 (31)
None25 (19)95 (20)
Nonpharmacologic prophylaxis
Intermittent pneumatic compression or graduated compression stockings/foot pump27 (21)93 (20)
FDA‐approved pharmacologic prophylaxis
LWMH/fondaparinux/warfarin prophylaxis67 (48)284 (61)
No FDA‐approved pharmacologic prophylaxis
Suboptimal pharmacologic or mechanical prophylaxis63 (52)179 (39)
Patients Who Did Not Receive FDA‐Approved Pharmacologic Prophylaxis Based on the FDA‐Approved Labeling for Proper Dose, Timing, and Duration
Prophylaxis StatusCases and Controls Who Did Not Receive FDA‐Approved Pharmacologic Prophylaxis (N = 242)
  • Abbreviations: FDA, US Food and Drug Administration.

  • Numbers are not mutually exclusive. Wrong dose if did not meet FDA‐recommended dose: First post‐op dose of enoxaparin was 30 mg per 12 hours, or last post‐op dose before discharge was 30 mg per 12 hours, or 40 mg per day; or first post‐op dose of fondaparinux was 2.5 mg per day; or first post‐op dose of warfarin was 210 mg per day; or first post‐op dose of dalteparin was 2500 mg per 12 hours. Wrong time window if did not meet FDA‐recommended timing: First post‐op dose of enoxaparin was given between 720 and 1440 minutes postsurgery; or first post‐op dose of fondaparinux was given less than or equal to 480 minutes postsurgery; or first post‐op dose of warfarin was given between 0 and 720 minutes postsurgery; or first post‐op dose of dalteparin was given between 240 and 360 minutes postsurgery

Received FDA‐approved pharmacologic prophylaxis but did not meet FDA‐approved proper dose, timing, and duration Variablen*
118 (49%)Wrong dose87
Dose not within the recommended time window17
Not continued at discharge50
Received no pharmacologic prophylaxis (only mechanical)124 (51%)

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.

Results of Multivariable (Conditional Logit) Analysis of Factors Associated With Thromboembolism After TKA
VariableOdds RatioP Value
  • Abbreviations: BMI, body mass index; FDA, US Food and Drug Administration; TKA, total knee arthroplasty.

  • If the first post‐op dose of enoxaparin was given between 720 and 1440 minutes postsurgery, or the first post‐op dose of enoxaparin was 30 mg per 12 hours, or last post‐op dose before discharge was 30 mg per 12 hours or 40 mg per day; or the first post‐op dose of fondaparinux was given less than or equal to 480 minutes postsurgery, or the first post‐op dose of fondaparinux was 2.5 mg per day; or the first post‐op dose of dalteparin was 2500 mg per 12 hours, or the first post‐op dose of dalteparin was given between 240 and 360 minutes postsurgery; or the first post‐op dose of warfarin was given between 0 and 720 minutes postsurgery, or the first post‐op dose of warfarin was 210 mg per day.

Older age1.02 (0.991.05)0.20
Female gender1.70 (0.92.9)0.90
BMI over 35 (vs 35 or less)0.9 (0.51.6)0.66
Bilateral TKA (vs unilateral TKA)4.2 (1.99.1)0.0004
Receiving FDA‐approved pharmacologic prophylaxis* vs mechanical0.5 (0.30.8)0.01
Ambulation on or before second postoperative day0.3 (0.10.9)0.005

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.

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  17. Namba RS, Paxton L, Fithian DC, Stone ML. Obesity and perioperative morbidity in total hip and total knee arthroplasty patients. J Arthroplasty. 2005;20(suppl 3):4650.
  18. White RH, Henderson MC. Risk factors for venous thromboembolism after total hip and knee replacement surgery. Curr Opin Pulm Med. 2002;8(5):365371.
  19. Simone E, Madan A, Tichansky D, Kuhl D, Lee M. Comparison of two low‐molecular‐weight heparin dosing regimens for patients undergoing laparoscopic bariatric surgery. Surg Endosc. 2008;22(11):23922395.
  20. Rowan B, Kuhl D, Lee M, Tichansky D, Madan A. Anti‐Xa levels in bariatric surgery patients receiving prophylactic enoxaparin. Obes Surg. 2008;18(2):162166.
  21. Samama CM, Ravaud P, Parent F, Barre J, Mertl P, Mismetti P. Epidemiology of venous thromboembolism after lower limb arthroplasty: the FOTO study. J Thromb Haemost. 2007;5(12):23602367.
  22. White RH, Zhou H, Romano PS. Incidence of symptomatic venous thromboembolism after different elective or urgent surgical procedures. Thromb Haemost. 2003;90(3):446455.
  23. White RH. The epidemiology of venous thromboembolism. Circulation.2003;107(23 suppl 1):I4I8.
  24. Falck‐Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e278Se325S.
  25. Blanchard J, Meuwly J‐Y, Leyvraz P‐F, et al. Prevention of deep‐vein thrombosis after total knee replacement: randomised comparison between a low‐molecular‐weight heparin and mechanical prophylaxis with a foot‐pump system. J Bone Joint Surg Br. 1999;81‐B(4):654659.
  26. AAOS. Pulmonary Embolism After Knee Arthroscopy: Rare but Serious. American Academy of Orthopaedic Surgeons/American Association of Orthopaedic Surgeons Web site. Available at: http://www6aaosorg/news/pemr/releases/releasecfm?releasenum=9692011.
  27. Eikelboom JW, Karthikeyan G, Fagel N, Hirsh J. American Association of Orthopedic Surgeons and American College of Chest Physicians guidelines for venous thromboembolism prevention in hip and knee arthroplasty differ: what are the implications for clinicians and patients? Chest. 2009;135(2):513520.
  28. Premier—A supporting partnership organization of the Surgical Care Improvement Project (SCIP). Premier Inc Web site. Available at: http://www.premierinc.com/safety/topics/scip/. Accessed April 10, 2012.
  29. Chandrasekaran S, Ariaretnam SK, Tsung J, Dickison D. Early mobilization after total knee replacement reduces the incidence of deep venous thrombosis. Aust N Z J Surg. 2009;79(7–8):526529.
  30. White RH, Gettner S, Newman JM, Trauner KB, Romano PS. Predictors of rehospitalization for symptomatic venous thromboembolism after total hip arthroplasty. N Engl J Med. 2000;343(24):17581764.
  31. Barrett J, Baron JA, Losina E, Wright J, Mahomed NN, Katz JN. Bilateral total knee replacement: staging and pulmonary embolism. J Bone Joint Surg Am. 2006;88(10):21462151.
  32. Kim YH, Kim JS. Incidence and natural history of deep‐vein thrombosis after total knee arthroplasty. A prospective, randomised study. J Bone Joint Surg Br. 2002;84(4):566570.
  33. Memtsoudis SG, Gonzalez Della Valle A, Besculides MC, Gaber L, Sculco TP. In‐hospital complications and mortality of unilateral, bilateral, and revision TKA: based on an estimate of 4,159,661 discharges. Clin Orthop Relat Res. 2008;466(11):26172627.
  34. Restrepo C, Parvizi J, Dietrich T, Einhorn TA. Safety of simultaneous bilateral total knee arthroplasty. A meta‐analysis. J Bone Joint Surg Am. 2007;89(6):12201226.
  35. Dushey CH, Bornstein LJ, Alexiades MM, Westrich GH. Short‐term coagulation complications following total knee arthroplasty: a comparison of patient‐reported and surgeon‐verified complication rates. J Arthroplasty. 2011 Jan 20.
  36. Baser O, Supina D, Sengupta N, Wang L, Kwong L. Clinical and cost outcomes of venous thromboembolism in Medicare patients undergoing total hip replacement or total knee replacement surgery. Curr Med Res Opin. 2011;27(2):423429.
  37. Hagen TP, Vaughan‐Sarrazin MS, Cram P. Relation between hospital orthopaedic specialisation and outcomes in patients aged 65 and older: retrospective analysis of US Medicare data. BMJ. 2010;340:c165.
  38. Amin A, Stemkowski S, Lin J, Yang G. Thromboprophylaxis rates in US medical centers: success or failure? J Thromb Haemost. 2007;5(8):16101616.
  39. Knapp RM. Quality and safety performance in teaching hospitals. Am Surg. 2006;72(11):10511054; discussion 1061–1059, 1133–1048.
  40. Pardini‐Kiely K, Greenlee E, Hopkins J, Szaflarski NL, Tabb K. Improving and sustaining core measure performance through effective accountability of clinical microsystems in an academic medical center. Jt Comm J Qual Patient Saf. 2010;36(9):387398.
  41. Fabi DW, Mohan V, Goldstein WM, Dunn JH, Murphy BP. Unilateral vs bilateral total knee arthroplasty risk factors increasing morbidity. J Arthroplasty. 2011;26(5):668673.
  42. Powell RS, Pulido P, Tuason MS, Colwell CW, Ezzet KA. Bilateral vs unilateral total knee arthroplasty: a patient‐based comparison of pain levels and recovery of ambulatory skills. J Arthroplasty. 2006;21(5):642649.
References
  1. Bjornara BT, Gudmundsen TE, Dahl OE. Frequency and timing of clinical venous thromboembolism after major joint surgery. J Bone Joint Surg Br. 2006;88(3):386391.
  2. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines (8th ed). Chest. 2008;133(6 suppl):381S453S.
  3. Howie C, Hughes H, Watts AC. Venous thromboembolism associated with hip and knee replacement over a ten‐year period: a population‐based study. J Bone Joint Surg Br. 2005;87(12):16751680.
  4. Pellegrini VD, Sharrock NE, Paiement GD, Morris R, Warwick DJ. Venous thromboembolic disease after total hip and knee arthroplasty: current perspectives in a regulated environment. Instr Course Lect. 2008;57:637661.
  5. Watanabe H, Sekiya H, Kariya Y, Hoshino Y, Sugimoto H, Hayasaka S. The incidence of venous thromboembolism before and after total knee arthroplasty using 16‐row multidetector computed tomography. J Arthroplasty. 2011;26(8):14881493.
  6. White RH, Romano PS, Zhou H, Rodrigo J, Bargar W. Incidence and time course of thromboembolic outcomes following total hip or knee arthroplasty. Arch Intern Med. 1998;158(14):15251531.
  7. Milbrink J, Bergqvist D. The incidence of symptomatic venous thromboembolic events in orthopaedic surgery when using routine thromboprophylaxis. Vasa. 2008;37(4):353357.
  8. White RH, Sadeghi B, Tancredi DJ, et al. How valid is the ICD‐9‐CM based AHRQ patient safety indicator for postoperative venous thromboembolism? Med Care. 2009;47(12):12371243.
  9. Department of Health and Human Services, Centers for Medicare 17(4):359365.
  10. Eikelboom J, Karthikeyan G, Fagel N, Hirsh J. American Association of Orthopedic Surgeons and American College of Chest Physicians guidelines for venous thromboembolism prevention in hip and knee arthroplasty differ. What are the implications for clinicians and patients? Chest. 2009;135(2):15121520.
  11. Jämsen E, Varonen M, Huhtala H, et al. Incidence of prosthetic joint infections after primary knee arthroplasty. J Arthroplasty. 2010;25(1):8792.
  12. Lachiewicz PF. Comparison of ACCP and AAOS guidelines for VTE prophylaxis after total hip and total knee arthroplasty. Orthopedics. 2009;32(12 suppl):7478.
  13. Sobieraj‐Teague M, Eikelboom JW, Hirsh J. How can we reduce disagreement among guidelines for venous thromboembolism prevention? J Thromb Haemost. 2010;8(4):675677.
  14. Limpus A, Chaboyer W, McDonald E, Thalib L. Mechanical thromboprophylaxis in critically ill patients: a systematic review and meta‐analysis. Am J Crit Care. 2006;15(4):402410; quiz/discussion, 411–412.
  15. Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines (8th ed). Chest. 2008;133(6 suppl):454S545S.
  16. Altintaş F, Gürbüz H, Erdemli B, et al. Venous thromboembolism prophylaxis in major orthopaedic surgery: a multicenter, prospective, observational study. Acta Orthop Traumatol Turc. 2008;42(5):322327.
  17. Namba RS, Paxton L, Fithian DC, Stone ML. Obesity and perioperative morbidity in total hip and total knee arthroplasty patients. J Arthroplasty. 2005;20(suppl 3):4650.
  18. White RH, Henderson MC. Risk factors for venous thromboembolism after total hip and knee replacement surgery. Curr Opin Pulm Med. 2002;8(5):365371.
  19. Simone E, Madan A, Tichansky D, Kuhl D, Lee M. Comparison of two low‐molecular‐weight heparin dosing regimens for patients undergoing laparoscopic bariatric surgery. Surg Endosc. 2008;22(11):23922395.
  20. Rowan B, Kuhl D, Lee M, Tichansky D, Madan A. Anti‐Xa levels in bariatric surgery patients receiving prophylactic enoxaparin. Obes Surg. 2008;18(2):162166.
  21. Samama CM, Ravaud P, Parent F, Barre J, Mertl P, Mismetti P. Epidemiology of venous thromboembolism after lower limb arthroplasty: the FOTO study. J Thromb Haemost. 2007;5(12):23602367.
  22. White RH, Zhou H, Romano PS. Incidence of symptomatic venous thromboembolism after different elective or urgent surgical procedures. Thromb Haemost. 2003;90(3):446455.
  23. White RH. The epidemiology of venous thromboembolism. Circulation.2003;107(23 suppl 1):I4I8.
  24. Falck‐Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e278Se325S.
  25. Blanchard J, Meuwly J‐Y, Leyvraz P‐F, et al. Prevention of deep‐vein thrombosis after total knee replacement: randomised comparison between a low‐molecular‐weight heparin and mechanical prophylaxis with a foot‐pump system. J Bone Joint Surg Br. 1999;81‐B(4):654659.
  26. AAOS. Pulmonary Embolism After Knee Arthroscopy: Rare but Serious. American Academy of Orthopaedic Surgeons/American Association of Orthopaedic Surgeons Web site. Available at: http://www6aaosorg/news/pemr/releases/releasecfm?releasenum=9692011.
  27. Eikelboom JW, Karthikeyan G, Fagel N, Hirsh J. American Association of Orthopedic Surgeons and American College of Chest Physicians guidelines for venous thromboembolism prevention in hip and knee arthroplasty differ: what are the implications for clinicians and patients? Chest. 2009;135(2):513520.
  28. Premier—A supporting partnership organization of the Surgical Care Improvement Project (SCIP). Premier Inc Web site. Available at: http://www.premierinc.com/safety/topics/scip/. Accessed April 10, 2012.
  29. Chandrasekaran S, Ariaretnam SK, Tsung J, Dickison D. Early mobilization after total knee replacement reduces the incidence of deep venous thrombosis. Aust N Z J Surg. 2009;79(7–8):526529.
  30. White RH, Gettner S, Newman JM, Trauner KB, Romano PS. Predictors of rehospitalization for symptomatic venous thromboembolism after total hip arthroplasty. N Engl J Med. 2000;343(24):17581764.
  31. Barrett J, Baron JA, Losina E, Wright J, Mahomed NN, Katz JN. Bilateral total knee replacement: staging and pulmonary embolism. J Bone Joint Surg Am. 2006;88(10):21462151.
  32. Kim YH, Kim JS. Incidence and natural history of deep‐vein thrombosis after total knee arthroplasty. A prospective, randomised study. J Bone Joint Surg Br. 2002;84(4):566570.
  33. Memtsoudis SG, Gonzalez Della Valle A, Besculides MC, Gaber L, Sculco TP. In‐hospital complications and mortality of unilateral, bilateral, and revision TKA: based on an estimate of 4,159,661 discharges. Clin Orthop Relat Res. 2008;466(11):26172627.
  34. Restrepo C, Parvizi J, Dietrich T, Einhorn TA. Safety of simultaneous bilateral total knee arthroplasty. A meta‐analysis. J Bone Joint Surg Am. 2007;89(6):12201226.
  35. Dushey CH, Bornstein LJ, Alexiades MM, Westrich GH. Short‐term coagulation complications following total knee arthroplasty: a comparison of patient‐reported and surgeon‐verified complication rates. J Arthroplasty. 2011 Jan 20.
  36. Baser O, Supina D, Sengupta N, Wang L, Kwong L. Clinical and cost outcomes of venous thromboembolism in Medicare patients undergoing total hip replacement or total knee replacement surgery. Curr Med Res Opin. 2011;27(2):423429.
  37. Hagen TP, Vaughan‐Sarrazin MS, Cram P. Relation between hospital orthopaedic specialisation and outcomes in patients aged 65 and older: retrospective analysis of US Medicare data. BMJ. 2010;340:c165.
  38. Amin A, Stemkowski S, Lin J, Yang G. Thromboprophylaxis rates in US medical centers: success or failure? J Thromb Haemost. 2007;5(8):16101616.
  39. Knapp RM. Quality and safety performance in teaching hospitals. Am Surg. 2006;72(11):10511054; discussion 1061–1059, 1133–1048.
  40. Pardini‐Kiely K, Greenlee E, Hopkins J, Szaflarski NL, Tabb K. Improving and sustaining core measure performance through effective accountability of clinical microsystems in an academic medical center. Jt Comm J Qual Patient Saf. 2010;36(9):387398.
  41. Fabi DW, Mohan V, Goldstein WM, Dunn JH, Murphy BP. Unilateral vs bilateral total knee arthroplasty risk factors increasing morbidity. J Arthroplasty. 2011;26(5):668673.
  42. Powell RS, Pulido P, Tuason MS, Colwell CW, Ezzet KA. Bilateral vs unilateral total knee arthroplasty: a patient‐based comparison of pain levels and recovery of ambulatory skills. J Arthroplasty. 2006;21(5):642649.
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Journal of Hospital Medicine - 7(9)
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Journal of Hospital Medicine - 7(9)
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Mechanical and suboptimal pharmacologic prophylaxis and delayed mobilization but not morbid obesity are associated with venous thromboembolism after total knee arthroplasty: A case‐control study
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Mechanical and suboptimal pharmacologic prophylaxis and delayed mobilization but not morbid obesity are associated with venous thromboembolism after total knee arthroplasty: A case‐control study
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