Preventing Venous Thromboembolic Disease in Patients Undergoing Elective Hip and Knee Arthroplasty
Routine Duplex Ultrasonography Screening
We recommend against routine post-operative duplex ultrasonography screening of patients who undergo elective hip or knee arthroplasty.
Strong Evidence Strong Evidence
We cannot recommend the routine use of ultrasound for the screening of patients after knee or hip arthroplasty for VTED. The best available evidence comes from two randomized controlled studies, both of high quality and moderate applicability (see Table 14 for a summary of the results of these studies, Table 15 through Table 18 for a detailed presentation of results, and Table 47 in Appendix XIII for our appraisal of their quality and applicability), that compared routine ultrasound screening to not screening. The control group was prolonged prophylaxis in one study, and a sham ultrasound in the other. In the ultrasound groups, treatment of asymptomatic DVTs was based on the ultrasound findings. Neither study found a statistically significant difference in symptomatic PE rates (Table 15) between the ultrasound-screened and unscreened patients, despite the fact that they had adequate statistical power.

Similar results are found when screening is accomplished using venography (Table 14 summarizes the results of the studies that evaluated the effects of ultrasound and venographic screening on patient outcomes). Two retrospective comparative studies of low quality and moderate applicability (see Table 47 in Appendix XIII) compared results of patients who were screened for DVT by venography against results of patients who were not screened (Table 16). Treatment of asymptomatic DVT varied according to venographic results. Rates of readmission for PE and DVT did not significantly differ between those who received screening venography and those who did not.

The available evidence also suggests that D-dimer is not a useful screening test for DVT after arthroplasty. Three studies, one of high quality and two of moderate quality and all of moderate applicability (Table 48 in Appendix XIII), evaluated the screening performance of D-dimer. Two used ultrasound as the reference standard, while one used venography.
One study of high quality and moderate applicability evaluated the screening performance of magnetic resonance (MR) venography as compared to standard venography. These data indicated that MR venography may be a good “rule in” test but not a good “rule out” test.

Given the lack of utility of ultrasound for diagnosis of unsuspected DVT’s and the lack of any commonly available alternative screening test with greater utility, we do not recommend routine screening for DVT in the hip and knee arthroplasty postoperative patient population.

The reasons we excluded some studies initially considered for this recommendation appears in Appendix XIV, Table 57.
Patient History and Risk
Patients undergoing elective hip or knee arthroplasty are already at high risk for venous thromboembolism. The practitioner might further assess the risk of venous thromboembolism by determining whether these patients had a previous venous thromboembolism.
Limited Evidence Limited Evidence
Patients undergoing elective hip or knee arthroplasty are at high risk for venous thromboembolic disease (VTED). Only one risk factor, previous history of VTED, has sufficient evidence indicating that some of these patients may be at even higher risk.

The relevant evidence comes from two studies that evaluated patients with a personal history of VTED – one of medium and one of low strength. The Pedersen study of over 68,000 patients found a relative risk of 8.1, and the Warwick study of over 14,000 patients found a hazard ratio of 4.92 for post-operative VTED in patients with a previous history of VTED (see Table 20 for a summary of the results of these studies).

Twenty-nine studies addressed whether patients with one or more potential risk factors, other than previous VTED, have higher rates of VTED. The list of potential VTED risk factors for which we sought evidence is listed in Table 19. The studies were all of low or very low quality (see Table 49 in Appendix XIII for a summary of our appraisal of the quality and applicability of these studies). A statistically significant increase in VTED resulting from these other risk factors that confer an increased risk of VTED in surgeries other than primary hip or knee arthroplasty was not found in studies of hip or knee arthroplasty patients. This might be because these other VTED risk factors confer a lower overall risk than primary hip or knee arthroplasty surgery itself. Therefore, their effects may not be seen against the relatively high background risk already being experienced by patients receiving elective hip or knee arthroplasty. Therefore, we are unable to recommend further risk stratification based on these factors.

No data specific to hip or knee arthroplasty were found addressing many potential risk factors, and in many instances where it was found, it was of very low quality and it was contradictory (see Table 19 for a summary of the results of these studies and Table 21 for a detailed presentation of their results). Data from patients undergoing surgical procedures other than primary hip and knee arthroplasty were found also of very low quality (Table 23) and therefore were unreliable. We excluded some of the studies we retrieved to address this recommendation. These studies, and the reasons for their exclusion are listed in Appendix XIV, Table 58.
Assessment of Risk Factors
Current evidence is not clear about whether factors other than a history of previous venous thromboembolism increase the risk of venous thromboembolism in patients undergoing elective hip or knee arthroplasty and, therefore, we cannot recommend for or against routinely assessing these patients for these factors.
Inconclusive
Patients undergoing elective hip or knee arthroplasty are at high risk for venous thromboembolic disease (VTED). Only one risk factor, previous history of VTED, has sufficient evidence indicating that some of these patients may be at even higher risk.

The relevant evidence comes from two studies that evaluated patients with a personal history of VTED – one of medium and one of low strength. The Pedersen study of over 68,000 patients found a relative risk of 8.1, and the Warwick study of over 14,000 patients found a hazard ratio of 4.92 for post-operative VTED in patients with a previous history of VTED (see Table 20 for a summary of the results of these studies).

Twenty-nine studies addressed whether patients with one or more potential risk factors, other than previous VTED, have higher rates of VTED. The list of potential VTED risk factors for which we sought evidence is listed in Table 19. The studies were all of low or very low quality (see Table 49 in Appendix XIII for a summary of our appraisal of the quality and applicability of these studies). A statistically significant increase in VTED resulting from these other risk factors that confer an increased risk of VTED in surgeries other than primary hip or knee arthroplasty was not found in studies of hip or knee arthroplasty patients. This might be because these other VTED risk factors confer a lower overall risk than primary hip or knee arthroplasty surgery itself. Therefore, their effects may not be seen against the relatively high background risk already being experienced by patients receiving elective hip or knee arthroplasty. Therefore, we are unable to recommend further risk stratification based on these factors.

No data specific to hip or knee arthroplasty were found addressing many potential risk factors, and in many instances where it was found, it was of very low quality and it was contradictory (see Table 19 for a summary of the results of these studies and Table 21 for a detailed presentation of their results). Data from patients undergoing surgical procedures other than primary hip and knee arthroplasty were found also of very low quality (Table 23) and therefore were unreliable. We excluded some of the studies we retrieved to address this recommendation. These studies, and the reasons for their exclusion are listed in Appendix XIV, Table 58.
Patient assessment of Bleeding Disorders
Patients undergoing elective hip or knee arthroplasty are at risk for bleeding and bleeding-associated complications. In the absence of reliable evidence, it is the opinion of this work group that patients be assessed for known bleeding disorders like hemophilia and for the presence of active liver disease which further increase the risk for bleeding and bleeding-associated complications.
Consensus Consensus
Bleeding complications related to the soft tissue envelope around the surgical site and the effects of bleeding on functional outcomes are an important concern. A hematoma can lead to joint stiffness and a compromised functional outcome or to a periprosthetic joint infection (with its associated morbidity). Although these potential risks have historically not been addressed in other guidelines on this topic, given the seriousness of these concerns, this work group believed it necessary to address them.

We found very little data that addressed risk factors for bleeding in patients undergoing elective hip or knee replacement surgery (see Table 24 for the list of risk factors for which we sought evidence and for a summary of these results. Two studies of very low quality (see Table 50 in Appendix XIII) addressed patients with hemophilia, with the only comparative study finding it to be a significant predictor of hemarthrosis. One comparative study of very low quality addressed cirrhosis of the liver and found it to be a significant predictor of perioperative blood loss (Table 25). 

Therefore, patients with a known bleeding disorder or active liver disease may have an increased risk for bleeding. Evaluating patients for these factors has minimal cost and low risk to the patient; we believe that these actions are consistent with the current practice of most orthopaedic surgeons. Recommendation 7 discusses the recommended thromboprophylaxis strategy for these patients.

Evidence about whether factors other than the presence of a known bleeding disorder or active liver disease affect the risk for bleeding in patients undergoing primary hip and knee arthroplasty is unclear. Six low quality studies among non-arthroplasty surgical patients did not find convincing evidence that preoperative coagulation screening predicts postoperative bleeding (Table 50 in Appendix XIII summarizes our evaluation of the quality and applicability of these studies).
  • bleeding time predicted blood loss in one of three studies
  • fibrinogen predicted blood loss in one of three studies
  • platelet count predicted blood loss in one of six studies
  • prothrombin time predicted blood loss in one of six studies (Table 27).
In other very low quality (and, therefore, unreliable) studies of non-arthroplasty surgical patients (Table 26):
  • thrombocytopenia was a significant predictor of postoperative intracranial hematoma among intracranial surgery patients,
  • a history of gastrointestinal (GI) bleed was not a significant predictor of postoperative upper GI bleeding among non-ulcer surgery patients,
  • a history of bleeding with previous surgery did predict excessive bleeding among cardiac bypass patients, while
  • epistaxis and a history of bleeding with dental extraction each did not predict major bleeding among Type 1 von Willebrand disease patients undergoing surgery.
No data were found addressing the other risk factors (see Table 24 for the list of risk factors for which we sought evidence).

The data on hemorrhage-related complications are also sparse. Three low quality and fourteen very low quality studies addressed whether patients with one or more potential risk factors have higher rates of hemorrhage-associated complications. (The results of these studies are summarized in Table 28, Table 29 and Table 30, which provide a detailed description of these studies’ results. Our evaluation of their quality and applicability is shown in Appendix XIII, Table 51)  Low hemoglobin levels and more complex revision procedures did predict a higher risk of transfusion, but none of the factors studied could be directly tied to hemorrhage-associated complications such as deep periprosthetic joint infection.

Due to the inconclusive evidence regarding other risk factors for bleeding or hemorrhage-associated complications among elective hip and knee arthroplasty patients, we are unable to recommend for or against further risk stratification.

The clinician should be aware of established contraindications against the use of individual anticoagulant agents.

We excluded some of the studies we retrieved to address this recommendation. These studies, and the reasons for their exclusion are listed in Appendix XIV, Table 59- Table 60.
 
Additional Risk Factors Related to Bleeding Disorders
Current evidence is not clear about whether factors other than the presence of a known bleeding disorder or active liver disease increase the chance of bleeding in these patients and, therefore, we are unable to recommend for or against using them to assess a patient’s risk of bleeding.
Inconclusive
Bleeding complications related to the soft tissue envelope around the surgical site and the effects of bleeding on functional outcomes are an important concern. A hematoma can lead to joint stiffness and a compromised functional outcome or to a periprosthetic joint infection (with its associated morbidity). Although these potential risks have historically not been addressed in other guidelines on this topic, given the seriousness of these concerns, this work group believed it necessary to address them.

We found very little data that addressed risk factors for bleeding in patients undergoing elective hip or knee replacement surgery (see Table 24 for the list of risk factors for which we sought evidence and for a summary of these results. Two studies of very low quality (see Table 50 in Appendix XIII) addressed patients with hemophilia, with the only comparative study finding it to be a significant predictor of hemarthrosis. One comparative study of very low quality addressed cirrhosis of the liver and found it to be a significant predictor of perioperative blood loss (Table 25). 

Therefore, patients with a known bleeding disorder or active liver disease may have an increased risk for bleeding. Evaluating patients for these factors has minimal cost and low risk to the patient; we believe that these actions are consistent with the current practice of most orthopaedic surgeons. Recommendation 7 discusses the recommended thromboprophylaxis strategy for these patients.

Evidence about whether factors other than the presence of a known bleeding disorder or active liver disease affect the risk for bleeding in patients undergoing primary hip and knee arthroplasty is unclear. Six low quality studies among non-arthroplasty surgical patients did not find convincing evidence that preoperative coagulation screening predicts postoperative bleeding (Table 50 in Appendix XIII summarizes our evaluation of the quality and applicability of these studies).
  • bleeding time predicted blood loss in one of three studies
  • fibrinogen predicted blood loss in one of three studies
  • platelet count predicted blood loss in one of six studies
  • prothrombin time predicted blood loss in one of six studies (Table 27).
In other very low quality (and, therefore, unreliable) studies of non-arthroplasty surgical patients (Table 26):
  • thrombocytopenia was a significant predictor of postoperative intracranial hematoma among intracranial surgery patients,
  • a history of gastrointestinal (GI) bleed was not a significant predictor of postoperative upper GI bleeding among non-ulcer surgery patients,
  • a history of bleeding with previous surgery did predict excessive bleeding among cardiac bypass patients, while
  • epistaxis and a history of bleeding with dental extraction each did not predict major bleeding among Type 1 von Willebrand disease patients undergoing surgery.
No data were found addressing the other risk factors (see Table 24 for the list of risk factors for which we sought evidence).

The data on hemorrhage-related complications are also sparse. Three low quality and fourteen very low quality studies addressed whether patients with one or more potential risk factors have higher rates of hemorrhage-associated complications. (The results of these studies are summarized in Table 28, Table 29 and Table 30, which provide a detailed description of these studies’ results. Our evaluation of their quality and applicability is shown in Appendix XIII, Table 51)  Low hemoglobin levels and more complex revision procedures did predict a higher risk of transfusion, but none of the factors studied could be directly tied to hemorrhage-associated complications such as deep periprosthetic joint infection.

Due to the inconclusive evidence regarding other risk factors for bleeding or hemorrhage-associated complications among elective hip and knee arthroplasty patients, we are unable to recommend for or against further risk stratification.

The clinician should be aware of established contraindications against the use of individual anticoagulant agents.

We excluded some of the studies we retrieved to address this recommendation. These studies, and the reasons for their exclusion are listed in Appendix XIV, Table 59- Table 60.
Antiplatelet Agents
We suggest that patients discontinue antiplatelet agents (e.g., aspirin, clopidogrel) before undergoing elective hip or knee arthroplasty.
Moderate Evidence Moderate Evidence
Among non-arthroplasty surgical patients, preoperative antiplatelet use predicted higher perioperative blood loss in three studies of moderate to high quality. Reoperation rates due to bleeding only varied in one of the three studies (see Table 26 for a detailed presentation of these results, and Table 52 in Appendix XIII for our appraisal of the quality and applicability of these studies).

Although this evidence is not specific to elective hip or knee arthroplasty patients, the work group believed the evidence is still applicable to these patients who are at risk for bleeding and bleeding-associated complications.

We excluded some of the studies we retrieved to address this recommendation. These studies and the reasons for their exclusion are listed in Appendix XIV, Table 61.
Pharmacologic Agents and Mechanical Compressive Devices
We suggest the use of pharmacologic agents and/or mechanical compressive devices for the prevention of venous thromboembolism in patients undergoing elective hip or knee arthroplasty, and who are not at elevated risk beyond that of the surgery itself for venous thromboembolism or bleeding.
Moderate Evidence Moderate Evidence
We recognize the diversity of opinion concerning the clinical importance of DVT as an isolated event or as a surrogate outcome for PE or post-thrombotic syndrome, (for further discussion, please see the Methods section), and understand that for clinical, and sometimes for even medico-legal reasons, DVT prevention may be the clinician’s immediate concern. There is moderate evidence to suggest that pharmacological agents and/or mechanical compression devices reduce DVT rates in patients undergoing elective knee or hip arthroplasty. This is why we are suggesting prophylaxis. Readers of this guideline should recognize, however, that the available, published evidence does not establish whether these prophylactic strategies affect  rates of all-cause mortality, fatal PE, symptomatic PE, or symptomatic DVT in patients undergoing elective hip or knee arthroplasty.

We also note that the present recommendation for prophylaxis is of a “Moderate” (rather than “Strong”) grade partly because it is based on a surrogate outcome we do not consider “critical” (we considered  major bleeding, pulmonary emboli, and all cause mortality as “critical,” and symptomatic DVT, any DVT, and proximal DVT as not critical). The “critical” outcomes are all patient-oriented. The non-critical outcomes are not.

The inability to recommend a specific prophylactic strategy is a direct result of the network meta-analyses we performed. We performed numerous such analyses with sensitivity analyses that included separately analyzing data from patients who underwent hip and knee arthroplasty, analyzing these data combined, evaluating the impact of study quality on the results, and by comparing the  results of each prophylactic strategy to placebo (or no treatment) and, when placebo/no treatment data were not available, comparing the results of  each strategy to results obtained with enoxaparin (as discussed in the Methods section, this use of two comparators allows us to check the logical consistency of our models). The results of these analyses did not consistently suggest that any one strategy is preferable to another (please see Figure 38 - Figure 55 and Table 32 - Table 34; and, for the results of our sensitivity analyses, see Appendix XV).

We also analyzed data on other outcomes but, due to lack of data,  network meta-analysis was not possible for them. In total, then, our analyses of the different prophylactic strategies is comprised of 112 high-or medium quality randomized controlled studies that enrolled patients undergoing elective hip and/or knee arthroplasty (see Appendix XIII, Table 53). As with the network meta-analyses, the data did not suggest that any specific prophylactic strategy was superior or inferior.

Part of the reason that current data do not permit a conclusion about specific prophylactic strageties is that, in our final network meta-analyses, no pharmacological agents showed a statistically significant effect in preventing all-cause mortality, symptomatic pulmonary emboli, symptomatic DVT, and major bleeding, when data from  hip and knee studies were analyzed separately or when they were combined. This may be because these events are rare. In addition, infection rates and re-operations (for any reason) were not reported. Reoperations due to bleeding were reported, but were often part of the study authors’ definition of major bleeding.

Many of the commonly used agents such as sodium warfarin and various low molecular weight heparinoids did not show efficacy for preventing VTED. This may be partially explained by the lack of comparison studies with placebo controls and by the rarity of the events of interest. In the final model with PE as the outcome, there were 181 events among 42,390 patients across 25 trials, and only 3 of these trials had a placebo or no prophylaxis arm.

There were a limited number of studies that evaluated mechanical compression devices.  In one study on total hip arthroplasties,48 there was a lower risk of major bleeding in the mechanical group. However, this study was only of moderate quality, partially because only 37% of the compression group had this device alone, with the remainder of the patients receiving low dose aspirin (81 mg/day) as well. There were also difficulties with the comparability of the control and intervention groups (that some of the studies we examined were not of high quality is another reason why the present recommendation is of  “Moderate” strength).

In some analyses of mechanical compression device studies, less bleeding was found in comparison to no treatment. This may not appear intuitively logical, but might be occurring because of problems with randomization and the patient populations which may not be generalizable to the standard population of patients typically undergoing total hip and knee arthroplasties.  The effect may also be occurring for some presently unknown physiological reasons.  Other potentially confounding factors with these studies are enumerated below.

Conclusions about specific prophylactic strategies are also difficult because, in addition to the above-mentioned challenges posed by the rarity of the events of interest and the lack of reporting of critical outcomes, the available studies:
  • Enrolled a select group of patients and did not necessarily include patients who had a high risk for VTED or bleeding and may not be representative of a typical patient population
  • Used different drug doses (e.g. Enoxaparin at 30 mg bid vs. 40 mg per day).
  • Used different timing of administration of agents (short-term vs. longer-term dosing)
  • Used different routes of administration
Comparing different prophylactic strategies is difficult because there is a paucity of placebo-controlled trials because of early acceptance of prophylaxis being the standard of care.

Also, we are unable to recommend specific pharmacologic agents and/or mechanical devices because the results of our analyses with DVT as the outcome were not robust on sensitivity analyses. Due to the rarity of the critical outcomes of interest and the limited number of placebo-controlled trials, we had to rely on the analysis of DVT (i.e., any DVT), a surrogate measure, to evaluate the relative efficacy of the prophylactic strategies. However, the results of these analyses depend on the structure of the model used, as agents shown to significantly reduce the occurrence of DVT in one model are often not statistically significant in an alternate model (see Table 97 in Appendix XV).

Some clinical practice guidelines make recommendations about the duration of pharmacologic prophylaxis. The available evidence is partially from manufacturer-funded trials, and is of only one agent. The latter is particularly problematic because the potential differences in the risks and benefits of various pharmacological agents may become more prominent as the duration of prophylaxis increases.  We are, therefore, reluctant to make such a recommendation until more is known about the relative risk/benefit profiles of these different agents. Rather, the work group recommends that patients and physicians discuss the appropriate duration of prophylaxis for each individual situation. This physician-patient discussion is low cost and consistent with current practice.

As of April 1, 2011, several of the analyzed agents are not approved for marketing or the treatment of any medical condition in the United States. The United States Food and Drug Administration’s (FDA) current policy regarding disclosure of marketing applications can be found in “Current Disclosure Policies for Marketing Applications” on the FDA website.

We excluded some studies we retrieved for this recommendation. The reasons for doing so are shown in Appendix XIV, Table 62).
 
Prophylactic Strategies
Current evidence is unclear about which prophylactic strategy (or strategies) is/are optimal or suboptimal. Therefore, we are unable to recommend for or against specific prophylactics in these patients.
Inconclusive
We recognize the diversity of opinion concerning the clinical importance of DVT as an isolated event or as a surrogate outcome for PE or post-thrombotic syndrome, (for further discussion, please see the Methods section of the full guideline document), and understand that for clinical, and sometimes for even medico-legal reasons, DVT prevention may be the clinician’s immediate concern. There is moderate evidence to suggest that pharmacological agents and/or mechanical compression devices reduce DVT rates in patients undergoing elective knee or hip arthroplasty. This is why we are suggesting prophylaxis. Readers of this guideline should recognize, however, that the available, published evidence does not establish whether these prophylactic strategies affect  rates of all-cause mortality, fatal PE, symptomatic PE, or symptomatic DVT in patients undergoing elective hip or knee arthroplasty.

We also note that the present recommendation for prophylaxis is of a “Moderate” (rather than “Strong”) grade partly because it is based on a surrogate outcome we do not consider “critical” (we considered  major bleeding, pulmonary emboli, and all cause mortality as “critical,” and symptomatic DVT, any DVT, and proximal DVT as not critical). The “critical” outcomes are all patient-oriented. The non-critical outcomes are not.

The inability to recommend a specific prophylactic strategy is a direct result of the network meta-analyses we performed. We performed numerous such analyses with sensitivity analyses that included separately analyzing data from patients who underwent hip and knee arthroplasty, analyzing these data combined, evaluating the impact of study quality on the results, and by comparing the  results of each prophylactic strategy to placebo (or no treatment) and, when placebo/no treatment data were not available, comparing the results of  each strategy to results obtained with enoxaparin (as discussed in the Methods section, this use of two comparators allows us to check the logical consistency of our models). The results of these analyses did not consistently suggest that any one strategy is preferable to another (please see Figure 38 - Figure 55 and Table 32 - Table 34; and, for the results of our sensitivity analyses, see Appendix XV).

We also analyzed data on other outcomes but, due to lack of data,  network meta-analysis was not possible for them. In total, then, our analyses of the different prophylactic strategies is comprised of 112 high-or medium quality randomized controlled studies that enrolled patients undergoing elective hip and/or knee arthroplasty (see Appendix XIII, Table 53). As with the network meta-analyses, the data did not suggest that any specific prophylactic strategy was superior or inferior.

Part of the reason that current data do not permit a conclusion about specific prophylactic strageties is that, in our final network meta-analyses, no pharmacological agents showed a statistically significant effect in preventing all-cause mortality, symptomatic pulmonary emboli, symptomatic DVT, and major bleeding, when data from  hip and knee studies were analyzed separately or when they were combined. This may be because these events are rare. In addition, infection rates and re-operations (for any reason) were not reported. Reoperations due to bleeding were reported, but were often part of the study authors’ definition of major bleeding.

Many of the commonly used agents such as sodium warfarin and various low molecular weight heparinoids did not show efficacy for preventing VTED. This may be partially explained by the lack of comparison studies with placebo controls and by the rarity of the events of interest. In the final model with PE as the outcome, there were 181 events among 42,390 patients across 25 trials, and only 3 of these trials had a placebo or no prophylaxis arm.

There were a limited number of studies that evaluated mechanical compression devices.  In one study on total hip arthroplasties,48 there was a lower risk of major bleeding in the mechanical group. However, this study was only of moderate quality, partially because only 37% of the compression group had this device alone, with the remainder of the patients receiving low dose aspirin (81 mg/day) as well. There were also difficulties with the comparability of the control and intervention groups (that some of the studies we examined were not of high quality is another reason why the present recommendation is of  “Moderate” strength).

In some analyses of mechanical compression device studies, less bleeding was found in comparison to no treatment. This may not appear intuitively logical, but might be occurring because of problems with randomization and the patient populations which may not be generalizable to the standard population of patients typically undergoing total hip and knee arthroplasties.  The effect may also be occurring for some presently unknown physiological reasons.  Other potentially confounding factors with these studies are enumerated below.

Conclusions about specific prophylactic strategies are also difficult because, in addition to the above-mentioned challenges posed by the rarity of the events of interest and the lack of reporting of critical outcomes, the available studies:
  • Enrolled a select group of patients and did not necessarily include patients who had a high risk for VTED or bleeding and may not be representative of a typical patient population
  • Used different drug doses (e.g. Enoxaparin at 30 mg bid vs. 40 mg per day).
  • Used different timing of administration of agents (short-term vs. longer-term dosing)
  • Used different routes of administration
Comparing different prophylactic strategies is difficult because there is a paucity of placebo-controlled trials because of early acceptance of prophylaxis being the standard of care.

Also, we are unable to recommend specific pharmacologic agents and/or mechanical devices because the results of our analyses with DVT as the outcome were not robust on sensitivity analyses. Due to the rarity of the critical outcomes of interest and the limited number of placebo-controlled trials, we had to rely on the analysis of DVT (i.e., any DVT), a surrogate measure, to evaluate the relative efficacy of the prophylactic strategies. However, the results of these analyses depend on the structure of the model used, as agents shown to significantly reduce the occurrence of DVT in one model are often not statistically significant in an alternate model (see Table 97 in Appendix XV).

Some clinical practice guidelines make recommendations about the duration of pharmacologic prophylaxis. The available evidence is partially from manufacturer-funded trials, and is of only one agent. The latter is particularly problematic because the potential differences in the risks and benefits of various pharmacological agents may become more prominent as the duration of prophylaxis increases.  We are, therefore, reluctant to make such a recommendation until more is known about the relative risk/benefit profiles of these different agents. Rather, the work group recommends that patients and physicians discuss the appropriate duration of prophylaxis for each individual situation. This physician-patient discussion is low cost and consistent with current practice.

As of April 1, 2011, several of the analyzed agents are not approved for marketing or the treatment of any medical condition in the United States. The United States Food and Drug Administration’s (FDA) current policy regarding disclosure of marketing applications can be found in “Current Disclosure Policies for Marketing Applications” on the FDA website.

We excluded some studies we retrieved for this recommendation. The reasons for doing so are shown in Appendix XIV, Table 62).
Duration of Prophylactic Strategies
In the absence of reliable evidence about how long to employ these prophylactic strategies, it is the opinion of this work group that patients and physicians discuss the duration of prophylaxis.
Consensus Consensus
We recognize the diversity of opinion concerning the clinical importance of DVT as an isolated event or as a surrogate outcome for PE or post-thrombotic syndrome, (for further discussion, please see the Methods section), and understand that for clinical, and sometimes for even medico-legal reasons, DVT prevention may be the clinician’s immediate concern. There is moderate evidence to suggest that pharmacological agents and/or mechanical compression devices reduce DVT rates in patients undergoing elective knee or hip arthroplasty. This is why we are suggesting prophylaxis. Readers of this guideline should recognize, however, that the available, published evidence does not establish whether these prophylactic strategies affect  rates of all-cause mortality, fatal PE, symptomatic PE, or symptomatic DVT in patients undergoing elective hip or knee arthroplasty.

We also note that the present recommendation for prophylaxis is of a “Moderate” (rather than “Strong”) grade partly because it is based on a surrogate outcome we do not consider “critical” (we considered  major bleeding, pulmonary emboli, and all cause mortality as “critical,” and symptomatic DVT, any DVT, and proximal DVT as not critical). The “critical” outcomes are all patient-oriented. The non-critical outcomes are not.

The inability to recommend a specific prophylactic strategy is a direct result of the network meta-analyses we performed. We performed numerous such analyses with sensitivity analyses that included separately analyzing data from patients who underwent hip and knee arthroplasty, analyzing these data combined, evaluating the impact of study quality on the results, and by comparing the  results of each prophylactic strategy to placebo (or no treatment) and, when placebo/no treatment data were not available, comparing the results of  each strategy to results obtained with enoxaparin (as discussed in the Methods section, this use of two comparators allows us to check the logical consistency of our models). The results of these analyses did not consistently suggest that any one strategy is preferable to another (please see Figure 38 - Figure 55 and Table 32 - Table 34; and, for the results of our sensitivity analyses, see Appendix XV).

We also analyzed data on other outcomes but, due to lack of data,  network meta-analysis was not possible for them. In total, then, our analyses of the different prophylactic strategies is comprised of 112 high-or medium quality randomized controlled studies that enrolled patients undergoing elective hip and/or knee arthroplasty (see Appendix XIII, Table 53). As with the network meta-analyses, the data did not suggest that any specific prophylactic strategy was superior or inferior.

Part of the reason that current data do not permit a conclusion about specific prophylactic strageties is that, in our final network meta-analyses, no pharmacological agents showed a statistically significant effect in preventing all-cause mortality, symptomatic pulmonary emboli, symptomatic DVT, and major bleeding, when data from  hip and knee studies were analyzed separately or when they were combined. This may be because these events are rare. In addition, infection rates and re-operations (for any reason) were not reported. Reoperations due to bleeding were reported, but were often part of the study authors’ definition of major bleeding.

Many of the commonly used agents such as sodium warfarin and various low molecular weight heparinoids did not show efficacy for preventing VTED. This may be partially explained by the lack of comparison studies with placebo controls and by the rarity of the events of interest. In the final model with PE as the outcome, there were 181 events among 42,390 patients across 25 trials, and only 3 of these trials had a placebo or no prophylaxis arm.

There were a limited number of studies that evaluated mechanical compression devices.  In one study on total hip arthroplasties,48 there was a lower risk of major bleeding in the mechanical group. However, this study was only of moderate quality, partially because only 37% of the compression group had this device alone, with the remainder of the patients receiving low dose aspirin (81 mg/day) as well. There were also difficulties with the comparability of the control and intervention groups (that some of the studies we examined were not of high quality is another reason why the present recommendation is of  “Moderate” strength).

In some analyses of mechanical compression device studies, less bleeding was found in comparison to no treatment. This may not appear intuitively logical, but might be occurring because of problems with randomization and the patient populations which may not be generalizable to the standard population of patients typically undergoing total hip and knee arthroplasties.  The effect may also be occurring for some presently unknown physiological reasons.  Other potentially confounding factors with these studies are enumerated below.

Conclusions about specific prophylactic strategies are also difficult because, in addition to the above-mentioned challenges posed by the rarity of the events of interest and the lack of reporting of critical outcomes, the available studies:
  • Enrolled a select group of patients and did not necessarily include patients who had a high risk for VTED or bleeding and may not be representative of a typical patient population
  • Used different drug doses (e.g. Enoxaparin at 30 mg bid vs. 40 mg per day).
  • Used different timing of administration of agents (short-term vs. longer-term dosing)
  • Used different routes of administration
Comparing different prophylactic strategies is difficult because there is a paucity of placebo-controlled trials because of early acceptance of prophylaxis being the standard of care.

Also, we are unable to recommend specific pharmacologic agents and/or mechanical devices because the results of our analyses with DVT as the outcome were not robust on sensitivity analyses. Due to the rarity of the critical outcomes of interest and the limited number of placebo-controlled trials, we had to rely on the analysis of DVT (i.e., any DVT), a surrogate measure, to evaluate the relative efficacy of the prophylactic strategies. However, the results of these analyses depend on the structure of the model used, as agents shown to significantly reduce the occurrence of DVT in one model are often not statistically significant in an alternate model (see Table 97 in Appendix XV).

Some clinical practice guidelines make recommendations about the duration of pharmacologic prophylaxis. The available evidence is partially from manufacturer-funded trials, and is of only one agent. The latter is particularly problematic because the potential differences in the risks and benefits of various pharmacological agents may become more prominent as the duration of prophylaxis increases.  We are, therefore, reluctant to make such a recommendation until more is known about the relative risk/benefit profiles of these different agents. Rather, the work group recommends that patients and physicians discuss the appropriate duration of prophylaxis for each individual situation. This physician-patient discussion is low cost and consistent with current practice.

As of April 1, 2011, several of the analyzed agents are not approved for marketing or the treatment of any medical condition in the United States. The United States Food and Drug Administration’s (FDA) current policy regarding disclosure of marketing applications can be found in “Current Disclosure Policies for Marketing Applications” on the FDA website.

We excluded some studies we retrieved for this recommendation. The reasons for doing so are shown in Appendix XIV, Table 62).
Management of Repeated VTED
In the absence of reliable evidence, it is the opinion of this work group that patients undergoing elective hip or knee arthroplasty, and who have also had a previous venous thromboembolism, receive pharmacologic prophylaxis and mechanical compressive devices.
Consensus Consensus
Given that patients who are receiving a hip or knee arthroplasty are already at high risk for VTED, a further risk increase in these patients is of concern. Although none of the studies we located enrolled such patients, the work group deemed that an even greater risk of VTED in these patients justified issuing a consensus-based recommendation for these  patients. The consensus of the work group is that both pharmacologic prophylaxis and mechanical compressive devices are appropriate for these patients, assuming that their risk of  VTED is greater than their risk of bleeding. Since patients undergoing hip or knee arthroplasty will be receiving some form of prophylaxis anyway, the added costs of using both pharmacologic and mechanical compressive devices will not always be large. Furthermore, the approach in this recommendation is consistent with current practice.
Bleeding Disorders and use of Mechanical Compressive Devices
In the absence of reliable evidence, it is the opinion of this work group that patients undergoing elective hip or knee arthroplasty, and who also have a known bleeding disorder (e.g., hemophilia) and/or active liver disease, use mechanical compressive devices for preventing venous thromboembolism.
Consensus Consensus
As discussed in Recommendation 3, patients who have a known bleeding disorder or active liver disease are at elevated risk for bleeding. Due to the serious complications that can occur in these patients, the work group deemed it appropriate to issue a consensus-based recommendation in spite of a lack of relevant, published data. It is the consensus of the work group that mechanical compressive devices are appropriate for these patients, as pharmacologic prophylaxis may exacerbate the risk of bleeding. Using mechanical compressive devices is of low risk and consistent with current practice. Consultation with a hematologist or other specialist may be warranted in some cases, especially when a patient is both at an elevated risk of bleeding and at an elevated risk of VTED.
Early Mobilization
In the absence of reliable evidence, it is the opinion of this work group that patients undergo early mobilization following elective hip and knee arthroplasty. Early mobilization is of low cost, minimal risk to the patient, and consistent with current practice.
Consensus Consensus
VTED is a potentially catastrophic complication faced by all patients who undergo elective hip and knee arthroplasty. Risk factors that predispose to VTED are embodied by “Virchow’s Triad” – hypercoagulability, endothelial injury, and stasis.  Early mobilization following hip or knee arthroplasty addresses the stasis limb of Virchow’s triad; movement of the operated limb promotes regional blood flow. Mobilization should begin as soon postoperatively as possible. Practices should be in place to ensure that appropriate support are provided throughout the hospital stay to minimize the risk of falls during transfer and ambulation.

Although one moderate quality study and five low quality studies compared VTED rates based on timing of mobilization, their results are conflicting (these results are summarized in Table 35, our evaluation of their quality and applicability is shown in Table 54, and a more detailed presentation of their results is in Table 36). One study of moderate quality suggests patients mobilizing within 2-4 hours of surgery do not have lower VTED readmission rates vs. patients mobilizing the afternoon or evening of surgery. Three low quality studies suggest that there is no difference in VTED due to timing of mobilization, while two other low quality studies did find lower rates of PE or VTED readmission among patients who mobilized earlier. Based on the fact that early mobilization has minimal cost, low risk to the patient, and is consistent with current clinical practice, issuing a consensus based consensus-based recommendation is warranted.

Table 63 in Appendix XIV summarizes the reasons for excluding some of the studies we initially considered for this recommendation.
Neuraxial Anesthesia
We suggest the use of neuraxial (such as intrathecal, epidural, and spinal) anesthesia for patients undergoing elective hip or knee arthroplasty to help limit blood loss, even though evidence suggests that neuraxial anesthesia does not affect the occurrence of venous thromboembolic disease.
Moderate Evidence Moderate Evidence
There is one high quality study and two moderate quality studies that addressed neuraxial anesthesia and VTE disease (Table 37 summarizes their results, Table 38 through Table 44 present a detailed description of their results, and Table 55 in Appendix XIII summarizes the results of our quality and applicability evaluations). None of these studies found a statistically significant difference in outcomes between regional (epidural or spinal) and general anesthesia.

Fifteen randomized controlled trials of high quality and moderate applicability compared peri-operative blood loss among patients receiving general, epidural, or a combination of general and epidural, or a combination of general anesthesia and lumbar plexus block.  There were eight high quality studies comparing epidural and general anesthesia.  Epidural anesthesia resulted in lower intra-operative blood loss. The combination of epidural and general anesthesia resulted in lower intra-operative blood loss compared to general anesthesia alone in two high quality studies. The combination of lumbar plexus block and general anesthesia resulted in lower intra- and post-operative blood loss compared to general anesthesia alone in two high quality studies. Hypotensive epidural anesthesia resulted in lower post-operative blood loss compared to spinal anesthesia in two high quality studies.

Table 64 in Appendix XIV summarizes the reasons for excluding some of the studies we initially considered for this recommendation.
Inferior Vena Cava Filters
Current evidence does not provide clear guidance about whether inferior vena cava (IVC) filters prevent pulmonary embolism in patients undergoing elective hip and knee arthroplasty who also have a contraindication to chemoprophylaxis and/or known residual venous thromboembolic disease. Therefore, we are unable to recommend for or against the use of such filters.
Inconclusive
No studies met the inclusion criteria for VTED-related outcomes in arthroplasty patients. Two studies of non-arthroplasty patients compared PE and death rates between patients who received IVC filters and those who did not (see Table 45 for a summary of the results of these studies, Table 46 for a detailed presentation of the results of these studies, and Table 56 in Appendix XIII for our evaluations of their quality and applicability). One was a low quality study of bariatric surgery patients, which found no differences in VTED outcomes between patients with and without IVC filters. The other was a low quality study of trauma patients which reported lower rates of PE and fatal PE in patients who received IVC filters. The work group did not make a consensus recommendation for or against the use of inferior vena cava filters because these filters require surgery to place in the patient. Surgery adds cost and potential harms to the patient, and consensus recommendations are only allowed for low cost and low risk interventions. Therefore, based on the limited and conflicting data regarding the benefits of IVC filters in preventing pulmonary embolism, and the fact that none of the studies included arthroplasty patients, we are unable to recommend for or against their use in hip and knee arthroplasty patients (the reasons we excluded some studies that were initially considered for this recommendation are provided in Appendix XIV, Table 65).

ACKNOWLEDGEMENTS

Guideline Work Group:
Joshua J. Jacobs, MD, Chair
Michael A. Mont, MD, Vice Chair
Kevin J. Bozic, MD, MBA
Craig J. Della Valle, MD
Stuart B. Goodman, MD
Courtland G. Lewis, MD
Adolph, "Chick" J. Yates Jr., MD
Lisa N. Boggio, MD, MS

AAOS Guidelines Oversight Committee:
William C. Watters III, MD, Chair

AAOS Staff:
Charles M. Turkelson, PhD,
Director of Research and Scientific Affairs
Janet L. Wies, MPH, Manager, Clinical Practice Guidelines
Patrick Sluka, MPH, Lead Research Analyst
Kristin Hitchcock, MSI, AAOS Medical Librarian