Richard H. White, MD, FACP

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

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

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

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

METHODS

RESULTS

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

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

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

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

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

DISCUSSION

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

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

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

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

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

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

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

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

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

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

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

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

METHODS

RESULTS

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

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

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

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

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

DISCUSSION

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

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

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

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

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

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

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

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

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

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

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

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

METHODS

RESULTS

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

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

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

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

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

DISCUSSION

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

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

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

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

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

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

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

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