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Table of Contents
REVIEW ARTICLE
Year : 2018  |  Volume : 15  |  Issue : 2  |  Page : 59-68

Chemical thromboprophylaxis in total knee replacement: A critical review


Department of Orthopaedics, Indraprastha Apollo Hospitals, New Delhi, India

Date of Web Publication5-Jul-2018

Correspondence Address:
Amit Kumar Agarwal
Department of Orthopaedics, Indraprastha Apollo Hospitals, Sarita Vihar, New Delhi - 110 076
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/am.am_27_18

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  Abstract 


Venous thromboembolism (VTE) remains a devastating and potentially lethal complication following total knee replacement (TKR) surgery. Studies have shown that 40%–85% of patients develop venographically confirmed deep vein thrombosis after TKA if they do not receive any form of thromboprophylaxis (TP), and approximately 0.1%–1.7% also suffer from fatal complication such as pulmonary embolism (PE). There are various chemical-TP (CTP) recommendations in the literature for patients having TKR surgery. The present review provides the current evidence for CTP in post-TKR surgery. All guidelines provided by the American Academy of Orthopedic Surgeons, American College of Chest Physicians, and National Institute for Health and Clinical Excellence are reviewed and analyzed in detail. Newer oral anticoagulants results are also studied as well, in the quest for an effective and safe VTE prophylaxis after TKR surgery.

Keywords: Chemical prophylaxis, deep vein thrombosis, guidelines, pulmonary embolism, thromboprophylaxis, total knee replacement, venous thromboembolism


How to cite this article:
Vaishya R, Agarwal AK, Desai P, Vijay V. Chemical thromboprophylaxis in total knee replacement: A critical review. Apollo Med 2018;15:59-68

How to cite this URL:
Vaishya R, Agarwal AK, Desai P, Vijay V. Chemical thromboprophylaxis in total knee replacement: A critical review. Apollo Med [serial online] 2018 [cited 2021 Apr 11];15:59-68. Available from: https://www.apollomedicine.org/text.asp?2018/15/2/59/235994


  Introduction Top


Total knee replacement (TKR) has proved to be one of the most successful surgeries in terms of improving the quality of life of patients with advanced osteoarthritis of the knee. Recent studies suggest that demand of TKR will steadily increase in the coming years, and it is estimated that in the US itself, between 2005 and 2030, the prevalence of TKR will increase by 673% from 450,000 to 3480,000 operations annually.[1],[2] Deep vein thrombosis (DVT) and venous thromboembolism (VTE) are the common causes of morbidity in patients after TKR. VTE consists of conditions which may vary from asymptomatic DVT to fatal pulmonary embolism (PE). DVT of popliteal and femoral veins is found to be clinically more significant than of the calf veins. The distal DVT (below the knee) is much more dangerous than the proximal DVT, which is associated much more with PE.[3] Distal DVT rarely causes PE, unless and until it progresses up to the proximal veins.[4] However, asymptomatic distal DVT may be associated either with a postthrombotic syndrome or recurrent DVT. The incidence of DVT and PE confirmed by venography in patients of TKR who had not taken thromboprophylaxis (TP) has been estimated to be 41%–85% and 1.5%–10%, respectively.[5] It is now considered necessary to give some form of TP to all the patients undergoing TKR, but the practices vary substantially among joint replacement surgeons. A chemical-TP (CPT) has become almost a routine practice after total hip replacement (THR),[6] but the practice differs widely in case of TKR.[7] We still do not have a safe, effective, and inexpensive chemical TP agent [8] after TKR. In 2007, the American Academy of Orthopedic Surgeons (AAOS) had proposed a risk screening approach [9] in making a selection of the CPT agent (anticoagulant vs. aspirin). In 2008, the American College of Chest Physicians (ACCP) had described their guidelines [10] for the selection of TP after lower-limb arthroplasty, and their recommendation was to use routine anticoagulation for all the cases.

Various mechanical and pharmacologic methods of prophylaxis have been described over the past decades. Many clinical trials have reported conflicting results regarding the efficacy of different treatments, confusing surgeon about the optimal method of prophylaxis. Mechanical devices, mostly in the form of foot and calf pumps, have been shown to reduce the incidence of DVT after TKR.[11] These devices are usually used as adjuncts to CTP, and there are reports of inadequate patient compliance with regard to their use.[12] Hence, CTP remains a gold standard for the prevention of VTE after TKR. However, numerous controversies exist related to the most effective therapeutic agent, as well as the ideal timing, dosage, and duration of treatment.[13]

It is known that CTP in TKR decreases VTE by approximately 50% but causes increased bleeding.[14] Excessive bleeding may lead to infections, reoperation, delayed wound healing, and extended hospital stay.[15] The choice of antithrombotic agent thus involves a pivotal balance between the risks for VTE and bleeding. This article reviews the current evidence regarding CTP after TKR. Clinical guidelines from the AAOS, ACCP, and National Institute for Health and Clinical Excellence (NICE) are analyzed along with their differences. The results of the new oral anticoagulants are reviewed including the most recent developments in the search for the best VTE prophylaxis post-TKR surgery.


  Review Top


Chemical thromboprophylactic options for venous thromboembolism

The most common thromboprophylactic agents are low-molecular-weight heparin (LMWH), fondaparinux, and dose-adjusted warfarin.[16],[17],[18] Other TP agents include unfractionated heparin (UFH), aspirin, and new oral anticoagulants. Newer anticoagulants belong to two classes, depending on their action on target coagulation protein: (a) Factor Xa (FXa) inhibitors and (b) direct thrombin inhibitors (DTIs) [Figure 1]. LMWH has a long half-life, which allows once-a-day dose and it has good bioavailability too. Efficacy, as well as the safety of LMWH, has been well established.[19],[20] Still, the disadvantages of its use include the need for parenteral administration, low patient adherence,[21] expense, and potential thrombocytopenia.[22] Fondaparinux is an injectable “FXa inhibitor” and also has good bioavailability.[23] Warfarin is less expensive and given orally once a day but requires regular monitoring of prothrombin time and International Normalized Ratio (INR). Warfarin also has many interactions with drugs, herbs, and dietary products [24] and hence needs to be used with caution. Oral FXa inhibitors and DTIs are the newer class of oral anticoagulants which have more predictable anticoagulant effects and do not require monitoring in short-term TP. However, their disadvantages include costs and no specific antidotes are available for timely reversal if bleeding occurs. Rivaroxaban is an oral FXa inhibitor, which has been approved by the U.S. Food and Drug Administration (FDA) for TP in orthopedic surgery. Dabigatran is an oral DTI with a better drug interaction profile than warfarin [25] and is under review by the FDA for surgical TP [Table 1].
Figure 1: The intrinsic as well as extrinsic coagulation pathways along with mechanism of action of chemothromboprophylactic agents

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Table 1: Various chemothromboprophylactic agents and their properties

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Unfractionated heparin

Heparin is the oldest agent for prophylaxis of DVT used for major surgeries. UFH is often given by subcutaneous route at 5000 units dose two or three times a day for TP [26] of TKR. It has been shown to reduce the incidence of DVT in major orthopedic, general, and urologic surgery by 68%.[27] In patients having TKR, the incidence of DVT was 24% who had taken UFH compared to 47% who received placebo.[27]

Nowadays, UFH is not commonly used as a TP agent after TKR, mainly due to the need for daily monitoring (APTT) and multiple daily doses.[28] Moreover, there is an increased frequency of complications such as heparin-induced thrombocytopenia,[29] use of this agent has decreased in popularity. Further, a new anticoagulant option is available which does not require monitoring. They are either as effective or superior for the prevention of VTE in TKR and equally as safe.[30],[31],[32] A study comparing UFH to enoxaparin after TKR has shown that 40 mg of enoxaparin taken as once a day was as effective in reducing thromboembolic complications as 5000 units of UFH given three times a day for 7–9 days postoperatively.[30] UFH has been finding a less efficient thromboprophylactic agent when it was compared with 30 mg of enoxaparin given twice a day,[31] subcutaneously. Recent meta-analysis study shows that there is relative risk (RR) of 0.76 for VTE in TKA patients when compared LMWH to UFH.[32]

Aspirin

Aspirin is being popularly used as TP agent in TKR for many years.[33] Aspirin is a COX enzyme inhibitor. It inhibits thromboxane A2, reduces platelet aggregation, and thus limits thrombus formation.[34] Aspirin is inexpensive and is taken orally and does not require daily monitoring. However, aspirin is contraindicated in patients who are allergic to nonsteroidal anti-inflammatory drugs (NSAIDs). Caution should also be taken in patients with renal impairment or gastrointestinal bleeding before prescribing aspirin.[34] Its efficacy in decreasing VTE rates in elective TKR is limited.[35] In a randomized controlled trial (RCT), Geerts et al.[10] had shown that DVT rate in patients who had received only aspirin after TKR (venographically diagnosed) was 56%. It was only 8% less than the placebo control group (64.3%) and apparently higher than in patients taking LMWH (30.6%), warfarin (46.8%), or fondaparinux (12.5%).

Older editions of the ACCP guideline did not recommend aspirin as TP agent in TKR.[5] However, AAOS guideline recommended aspirin as one of the TP agents [36] since incidence of the symptomatic DVT or fatal PE in patients taking aspirin was found to be low as compared to patients taking LMWH or warfarin groups.[37],[38],[39],[40] Further, aspirin has the lowest risk of bleeding complication compared to all other pharmacological agents.[37] It is important because increased bleeding and hematoma formation lead to increased chance of postoperative infection, and an infected joint is considered as the most disastrous complication. Aspirin has offered good TP when combined with mechanical prophylaxis.[41],[42],[43],[44],[45],[46] Aspirin is one of the recommended pharmacological agents in the latest edition of the ACCP guideline [47] and the second edition of the AAOS guideline.[48] Aspirin is an effective antithrombotic agent at doses of 50–1500 mg daily.[49]

Warfarin

Warfarin is an oral thromboprophylactic agent. It inhibits coagulation pathway by acting on Vitamin K-dependent coagulation factor (factor II, VII, IX, X and protein C).[50] There is better patient compliance with warfarin, as it is an oral agent and does not requires daily injection. However, it has a bleeding risk, many potential drug interactions, and the requirement for constant INR monitoring. It should be taken with caution in patients on aspirin or other NSAIDs because it increases gastrointestinal bleeding. It also interacts with many commonly used drugs such as antibiotics, proton pump inhibitors, and cholestyramine.[50]

It has been used as a thromboprophylactic agent after TKR for more than 40 years.[51] Its efficiency is better compared to aspirin but lower when compared to LMWH in decreasing rates of proximal DVT and symptomatic PE. It is relatively safe regarding bleeding complications. Both ACCP and AAOS guidelines recommended warfarin as a thromboprophylactic agent for VTE.[47] Regular monitoring of the INR is needed. It usually takes a few days to reach a recommended INR. Patients who are on warfarin should be covered initially with a fast-acting anticoagulant (such as LMWH) till therapeutic INR is attained. Recommended INR range should be 2–3 according to the ACCP and 1.5–2 according to the AAOS guidelines. This discrepancy is mainly because ACCP was based on studies prescribing warfarin as a monotherapy,[52] whereas the AAOS considered a multimodal regimen. When multimodal regimen (such as pneumatic compression and early mobilization) is used, an INR of 1.5–2 is effective.[53] Higher INR values are associated with higher rates of postoperative bleeding, which lead to increased rate of infection.[54]

It was compared with LMWH as prophylaxis for TKR in many clinical trials.[55],[56],[57],[58],[59] All trials found that LMWH was a more effective agent to prevent DVT formation (P< 0.05), but there is no difference regarding warfarin in reducing symptomatic events including PE, in part, because all studies measured primary outcome as asymptomatic DVT. However, LMWH resulted in more bleeding episodes than warfarin, but this difference is not significant (P > 0.05). So many RCTs compared the effectiveness of warfarin to various LMWHs as a TP agent in TKR.[60],[61],[62],[63],[64],[65] They also found warfarin inferior to LMWH in the prevention of VTE in TKR; 38%–59% rate of DVT in warfarin group to 25%–45% in LMWH group.[61],[63],[64],[65] Moreover, rates of proximal DVT were 10.2% for warfarin and 6.7% for LMWH.[35]

Low-molecular-weight heparin

LMWH is produced from UFH through physical, chemical, or enzymatic depolarization.[5] Available LMWHs are enoxaparin, dalteparin, and tinzaparin. LMWHs have a low affinity for von Willebrand factor than UFH, so it produces less bleeding.[66] LMWHs have long plasma half lifetime, so there is more predictable anticoagulant effect compared to UFH and requires less frequent injection as well as monitoring. Potential advantages of LMWHs over other anticoagulants such as warfarin include rapid antithrombotic action and do not require any daily laboratory monitoring. Disadvantages of LMWH include they are more expensive compared to UFH and they are associated with an increased rate of bleeding events when compare to warfarin.[60],[61],[65] LMWH is also associated with complications related to wound drainage, hematomas, thrombocytopenia, and infection.[37] LMWHs are given by subcutaneous route; enoxaparin given either as a 30 mg dose given twice a day or as a 40 mg dose given once a day.

LMWH is found to reduce the incidence of VTE significantly as compared to placebo after TKR [55] and used as an anticoagulant for many years. LMWH has the highest effect regarding preventing and reducing VTE.[37],[56],[57] The ACCP also recommended LMWH over other drugs [5] for patients with a high risk for bleeding or those not cooperative with injections.

Many prospective RCTs have assessed the efficacy of LMWH compared to other thromboprophylactic agents such as UFH [37] and warfarin [60],[61],[62],[63],[64],[65] in post-TKR. Enoxaparin given at a dose of 30 mg twice a day has been found to highly prevent DVT when compared to UFH.[37] Other studies have also demonstrated LMWHs' efficacy superior to warfarin.[63],[65] If started in the morning on the 1st day after surgery, no difference was found between 30 mg of enoxaparin and warfarin in preventing proximal DVT.[63] However, when started 8 h postsurgery, enoxaparin was found to significantly decrease the rates of proximal DVT compared to warfarin.[65] Ardeparin when given either at 35 or 50 units per kilogram twice a day has also higher TP compared to warfarin.[64] Several meta-analyses also compared LMWH with other TP.[56],[57] Howard et al. have shown that LMWH is better than UFH and warfarin in the prevention of DVT and decreasing the number of proximal DVTs.[32] Moreover, also, no increase in bleeding complications was found. In a meta-analysis performed by Westrich et al., the authors found rates of DVT to be 53% with aspirin, 45% with warfarin, and 29% with LMWH.[56] Finally, Brookenthal et al. showed that LMWH prevented DVT significantly higher than warfarin from both distal and proximal DVT.[57] However, No significant difference was found in rates of symptomatic PE, fatal embolism, major hemorrhage, or total mortality between the two groups. LMWH would suggest being more effective than aspirin, UFH, or warfarin in preventing VTE. LMWH continues to be a popular choice of anticoagulant and is efficient and safe in post-TKR patients.

A meta-analysis study including 16 RCTs compared enoxaparin to the newer anticoagulants (rivaroxaban, dabigatran, and apixaban).[67] Moreover, the conclusion is that newer anticoagulants are better in efficacy, but they have a high-risk of bleeding. Results suggest that the risk of symptomatic VTE was found lower to rivaroxaban, while similar to dabigatran as well as to apixaban. Considering the safety, rivaroxaban showed a significant increase in the risk of clinically relevant bleeding, while dabigatran did not associate with a significant increase in bleeding compared to enoxaparin.

Fondaparinux

Fondaparinux is an indirect FXa inhibitor. It is a synthetic pentasaccharide which acts by inhibiting the FXa, by binding to antithrombin, thus limiting thrombus formation. It was mainly developed with a concern to reducing the incidence of DVT after major orthopedic surgery, mainly due to the continued high rates of DVT in post-TKR patients despite the use of LMWH. It is administered as a 2.5 mg once-daily subcutaneous injection as determined after examining different dose-responses.[58] It has been recommended in the United States by the FDA for TP in TKR. Bauer et al. performed a double-blind, RCT comparing fondaparinux 2.5 mg once a day to enoxaparin 30 mg given twice a day in patients who underwent TKR.[59] They showed that those who received fondaparinux had a significantly lower incidence of thromboembolic complications by day 11 of 12.5% compared to 27.8% in the LMWH group. However, those who receive fondaparinux have a higher risk of bleeding; 11 major bleeding episodes compared to only one in enoxaparin group. It did not result in any episodes of fatal bleeding; bleeding occurs in critical organs or leads to reoperation. These findings were further corroborated by a meta-analysis to evaluate the efficacy of fondaparinux compared to enoxaparin in major orthopedic surgery.[59]

Another multicenter RCT from Japan studied the effect of fondaparinux and compared it with placebo as well the dose–response effect (0.75 mg, 1.5 mg, 2.5 mg, and 3.0 mg) in patients with TKA.[68] They found VTE incidence to be 34.2%, 21.3%, 16.2%, and 9.5% in patients who were given fondaparinux 0.75 mg, 1.5 mg, 2.5 mg, and 3.0 mg, respectively, compared to the placebo group which has VTE incidence 65.3%. ACCP recommended [5] fondaparinux as a chemoprophylactic drug for patients having THA or TKA. However, its use requires judgment based on patients' bleeding profile.

Rivaroxaban

Rivaroxaban is a direct FXa inhibitor. It is a FDA-approved oral thromboprophylactic agent. It has an inhibitory effect on thrombin and tissue factor.[69] It also does not require daily monitoring. There are four Phase III RCTs [70],[71],[72],[73] to assess the effectiveness of rivaroxaban as a thromboprophylactic agent for VTE after total joint arthroplasty in patients. Lassen et al.[70] found that 10 mg of rivaroxaban taken as once a day has more efficacy than 40 mg of enoxaparin administered once daily in reducing overall VTE for TKA patients (RR = 9.2%, P < 0.001). No difference found in major bleeding between Rivaroxaban and Enoxaparin groups (0.6% vs. 0.5%; P > 0.05). Turpie et al.[71] compared Rivaroxaban (10 mg, once a day) with Enoxaparin (30 mg, twice a day) in post-TKR patients. They found Rivaroxaban group had overall low incidence of VTE and mortality rate to the Enoxaparin group, with an absolute risk reduction 3.19%, 95% (confidence interval [CI] 0.71–5.67; P = 0.0118). No difference in major bleeding event found between both group (0.7% vs. 0.3%; P = 0.109). In a retrospective review, Jensen et al.[74] found that, however, rivaroxaban had more reoperations than LMWH after TKA (3.94% vs. 1.8%; P = 0.046).

In another study which compared the extended use of Rivaroxaban for 35 days to enoxaparin for 10–14 days post-TKR, Kakkar et al.[73] suggest Rivaroxaban to significantly more effective compared to Enoxaparin for decreasing total VTE as well symptomatic episodes with RR = 7.3%, CI 5.2–9.4; P < 0.0001. However, no significant difference was found in bleeding during the period of treatment (P = 0.25).[73]

RECORD program (Regulation of Coagulation in major Orthopaedic surgery reducing the Risk of DVT and PE) composed of four Phase III clinical prophylaxis studies compared TP effectiveness and safety of rivaroxaban 10 mg taken orally once a day and enoxaparin 40 mg once daily or 30 mg twice daily in patients undergoing TKR. RECORD 3[70],[71],[72],[73] and 4[70],[71],[72],[73] trials mainly included patients scheduled to undergo elective TKR. In the RECORD 3[70],[71],[72],[73] trial, 10 mg of rivaroxaban once daily, started 6–8 h after surgery, was compared with 40 mg of enoxaparin, started in the evening before surgery. The primary efficacy outcome included the composite of any DVT, nonfatal PE, or death from any cause within 13–17 days after surgery. The secondary efficacy outcomes were major VTE and symptomatic VTE. The primary safety outcome was major bleeding. Rivaroxaban was found to have fewer primary and secondary efficacy outcomes (9.6% and 0.7% of patients receiving rivaroxaban vs. 18.9% and 2.0% of patients receiving enoxaparin). The rates of bleeding were similar in the two groups. In the RECORD 4 trial,[70],[71],[72],[73] patients undergoing knee arthroplasty received either oral rivaroxaban 10 mg once daily, beginning 6–8 h after surgery, or subcutaneous enoxaparin 30 mg every 12 h, starting 12–24 h after surgery. The primary efficacy outcome was also DVT, PE, and all-cause mortality up to day 17 after surgery, while the secondary outcome was major VTE (i.e., proximal DVT, nonfatal PE, or death related to VTE). Results of this trial were not as impressive as those seen in the RECORD 3 study. However, there was a significant reduction of the primary efficacy outcome in patients that received rivaroxaban (6.9% vs. 10.1% of patients receiving enoxaparin). Results were similar in the two groups regarding the secondary efficacy outcomes as well as the safety outcomes.

Apixaban

Apixaban is a direct FXa inhibitor. It inhibits both free FXa and prothrombinase activity. It is an oral thromboprophylactic agent. In a study,[75] 1328 patients having TKR were randomized and received apixaban 5–20 mg orally once or twice a day, enoxaparin 30 mg twice a day, or warfarin with target INR 1.8–3. Duration of treatment was 10–14 days, starting 12–24 h after surgery with apixaban or enoxaparin and on the evening of surgery with warfarin. The primary safety outcome includes major bleeding. The study found that the rates of VTE at each dose of apixaban were small compared to enoxaparin or warfarin. A dose related increase in the incidence of total bleeding was also found with the apixaban groups.[75]

Lassen et al.[76],[77],[78] conducted a series of studies to compare the effect of apixaban with different doses of enoxaparin for the prophylaxis for TKA; both agents showed remarkably lower overall VTE rates. However, apixaban result showed relatively less bleeding risk.[76] Another study that compared 2.5 mg of apixaban taken twice a day to 40 mg of enoxaparin given once a day showed overall VTE and mortality rate to be significantly low in the apixaban group.[77] No significant difference was found between the two groups regarding bleeding complication. Studies found that 2.5 mg of apixaban given twice a day has more efficacy than 40 mg of enoxaparin given once a day and has the same efficacy when 30 mg of enoxaparin was given twice a day. A meta-analysis done by Lassen et al. with the purpose of comparing the effectiveness of 2.5 mg of apixaban and 10 mg of rivaroxaban to enoxaparin for prophylaxis in total hip joint and knee joint replacement found that oral FXa inhibitors are superior compared to enoxaparin for preventing DVT, but they found no significant difference for PE, mortality, as well as postoperative wound hematoma and infections.[78]

Dabigatran

Dabigatran is a DTI. It works by binding specifically to the active center of thrombin and inactivates free, fibrin-bound thrombin. This process is reversible leaving a small amount of free and active thrombin to control hemostasis.[79] It is the first oral DTI recommended for chemoprophylaxis after TKR. Advantages of dabigatran include it can be administered orally, is highly specific, has a reversible effect, does not require monitoring, and has a slow onset. Hence, the hemostatic process may take place after procedures and before the effect of anticoagulant commences.[80] Eriksson et al.[81] compared dabigatran with enoxaparin (oral dabigatran 220 mg, oral dabigatran 150 mg, and subcutaneous enoxaparin 40 mg; all once daily). Efficacy outcomes include symptomatic DVT, venographic DVT, and symptomatic PE. Safety outcomes include bleeding events during the study. They found effectiveness outcome as 37.7%, 36.4%, and 40.5%, respectively, for 40 mg enoxaparin; 220 mg dabigatran; and 150 mg dabigatran. They found major bleeding outcome to be 1.3%, 1.5%, and 1.3%, respectively, for 40 mg enoxaparin; 220 mg dabigatran; and 150 mg dabigatran.

Ginsberg et al.[82] also showed that both doses of dabigatran were comparable with 30 mg of enoxaparin taken twice a day regarding bleeding episodes in TKR. Based on the above trials, the ACCP concluded that dabigatran was comparable to enoxaparin/LMWH regarding efficacy and bleeding risks. In RE-MODEL trial,[81] dabigatran etexilate at a dose of 150 mg or 220 mg once daily, starting with a half dose 1–4 h after surgery, was found to be efficient as compared with the European dose of enoxaparin (40 mg once daily) starting the evening before surgery, for 6–10 days. Primary efficacy outcome included total VTE (venographic as well symptomatic) and mortality during treatment, whereas primary safety outcome included incidence of major bleeding events. Results revealed that both doses of dabigatran etexilate were equal to enoxaparin with regard to efficacy and safety profile after 3 months of follow-up. In the RE-MOBILIZE trial,[82] dabigatran (150 or 220 mg once daily) was compared with the North American dose of enoxaparin (30 mg BID). Dabigatran was given as a half dose the day of surgery, and enoxaparin was started 12–24 h postsurgery. The duration of treatment was 12–15 days. Enoxaparin was found to be superior for the primary efficacy endpoint that was a composite of proximal DVT, distal DVT, PE, and all-cause mortality. Bleeding rates were similar between the study groups.

Duration of thromboprophylaxis

The optimal duration of chemical TP for TKR surgery remains a topic of controversy. There should be balance between the benefits of extended TP and risks of bleeding complication as well as socioeconomic considerations.[83],[84] The mean time for VTE to occur after TKR surgery was considered to be 9.7 days.[85] DVT and PE occur, respectively, at a median of 20 and 12 days post-TKR. The ACCP guidelines recommend that a minimum of 10–14 days of prophylaxis be necessary for patients undergoing THA or TKA. The AACP also suggests extending the TP up to 35 days in the outpatient period,[47] while the AAOS does not mention anything about the duration of prophylaxis. The NICE recommended the use of CTP for 10–14 days after TKA and 28–35 days after THA. VTE risk also remains there after discharge from the hospital, so it is better to provide oral prophylaxis even after discharge. LMWH can be administrated by subcutaneous injection, while aspirin, warfarin, dabigatran, and rivaroxaban all can be given orally once a day; further, the latter two require no routine monitoring.


  Guidelines Top


The ACCP, as well as the AAOS, has given guidelines for TP in TKR or THR.[5],[36] The ACCP guidelines recommend the use of antithrombotic prophylaxis over no prophylaxis for TKR or THR. The AAOS suggests that there should be an individual assessment of patients for TKR or THR TP. For average-risk patients, the AAOS does not recommend any specific TP strategy, considering that evidence for comparative effectiveness was found to be inconclusive, whereas, the ACCP make recommendations for specific strategies which include LMWH, fondaparinux, apixaban, dabigatran, rivaroxaban, UFH, warfarin, aspirin, and intermittent pneumatic compression device (IPCD). In the absence of any elevated bleeding risk, LMWH is preferred to the other agents [Table 2].
Table 2: Various guidelines pertaining to the thromboprophylaxis in total knee replacement

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In making guidelines, the ACCP and AAOS both panels considered benefits, as well as a potential complication, but both have a different approach. The ACCP considered asymptomatic DVT which was detected by contrast venography, whereas the AAOS considered only clinical trials on TP, which were symptomatic, or fatal PE, which was considered as the outcome. The ACCP considered a strong correlation between venographically proven DVT to clinically important PE, but the AAOS group believe that this link remains unproven.[36],[86] Further, the AAOS guidelines rely on the ability to stratify patients before TKR based on their risk of PE and major bleeding though the strength of this recommendation is weak. The other main difference between these two guidelines is due to rate of complication (bleeding or death) following aggressive anticoagulation therapy, which is found to be underestimated in the ACCP guidelines.

The NICE of England has also given their guidelines, considering that patients having total joint arthroplasty should receive mechanical prophylaxis and either LMWH or fondaparinux.[87] The NICE has also recommended oral anticoagulants such as dabigatran and rivaroxaban for the primary prevention of VTE after THR or TKR.[87]

American College of Chest Physicians (2012)

The ACCP (in 2012) recommended the use of one of the following prophylactic measure for patients undergoing THR or TKR, for a minimum of 10–14 days (rather than no antithrombotic prophylaxis). These measures included LMWH, fondaparinux, apixaban, dabigatran, rivaroxaban, low-dose unfractionated heparin (LDUH), warfarin, aspirin (all Grade 1B), or an IPCD (Grade 1C). As per their recommendations, irrespective of the concomitant use of an IPCD or length of treatment, the use of LMWH is suggested in preference to the other agents. However, alternative recommendations include the use of fondaparinux, apixaban, dabigatran, rivaroxaban, LDUH (all Grade 1B), adjusted-dose warfarin, and aspirin (all Grade 2C).

In patients undergoing major orthopedic surgery, the following recommendations were made:

  1. To use dual prophylaxis with an antithrombotic agent and an IPCD during the hospital stay (Grade 2C)
  2. To use an IPCD or no prophylaxis rather than pharmacological treatment (Grade 2C) in patients with an increased risk of bleeding
  3. To use apixaban or dabigatran (alternatively, rivaroxaban or adjusted-dose warfarin, if apixaban or dabigatran are unavailable) rather than other forms of prophylaxis (Grade 1B) in those patients who decline or are uncooperative with injections or an IPCD.


Grade 1 recommendations are strong and indicate that the benefits do or do not outweigh risks, burden, and costs, whereas Grade 2 suggestions imply that individual patient values may lead to different choices. Furthermore, Level A indicates consistent results from RCTs or observational studies with very strong association and secure generalization (high), Level B indicates inconsistent results from RCTs or RCTs with methodological limitations (moderate), Level C indicates unbiased observational studies (low), and Level D indicates other observational studies (e.g., case series) (very low).

American Academy of Orthopedic Surgeons (2011)

The AAOS in 2011 suggested the use of pharmacologic agents and mechanical compressive devices for the prevention of VTE in patients undergoing elective THR or TKR and who are not at elevated risk beyond that of the surgery itself for VTE or bleeding (Grade: Moderate). However, these recommendations suggested that the current evidence was unclear about which prophylactic strategy is optimal or suboptimal. Therefore, they were unable to recommend for or against specific prophylactics in these patients (Grade: Inconclusive.) It was suggested, that in the absence of reliable evidence, patients who have had a previous VTE should receive pharmacologic prophylaxis and mechanical compressive devices (Grade: Consensus.)

In the absence of reliable evidence, patients with a known bleeding disorder and active liver disease should use mechanical compressive devices for preventing VTE (Grade: Consensus.)

In the absence of reliable evidence about how long to employ these preventive strategies, it is the opinion of this work group that patients discuss the duration of prophylaxis with their treating physicians (Grade: Consensus.)

Grading was as follows: strong when good-quality evidence, moderate when fair-quality evidence, weak when poor-quality evidence, inconclusive when insufficient or conflicting evidence, or consensus in the absence of reliable evidence.

National Institute for Health and Clinical Excellence (2015)

The NICE offers combined VTE prophylaxis with mechanical and pharmacological methods to patients undergoing elective knee or hip replacement surgery. The recommendations are as follows:

  • Start mechanical VTE prophylaxis at admission. Choose any of the following, based on individual patient factors:


    1. Anti-embolism stockings (thigh or knee length), used with caution
    2. Foot impulse device
    3. IPCDs (thigh or knee length).


  • Continue mechanical VTE prophylaxis until the patient no longer has significantly reduced morbidity.
  • Start pharmacological VTE prophylaxis after surgery, provided there are no contraindications. Choose any of the following, based on individual patient factors:


    1. Dabigatran, starting 1–4 h after surgery
    2. Fondaparinux, starting 6 h after surgical closure, provided hemostasis has been stabilized
    3. Rivaroxaban, starting 6–10 h after surgery
    4. UFH (for patients with renal failure), starting 6–12 h after surgery.


  • Continue pharmacological VTE prophylaxis for 10–14 days.



  Conclusion Top


A number of arthroplasties had been increasingly performed worldwide. VTE remains a clinical concern due to the risk of symptomatic DVT and fatal PE. TP for DVT in elective TKR is constantly evolving. There is no doubt about newly introduced oral anticoagulants as they are found closer to the “ideal” TP drug. They are effective as well as safe, have rapid onset of action and short half-life, have no interactions with food and drugs, have good predictable pharmacokinetics as well as anticoagulant response, do not require daily monitoring, and can be administered by oral route which ensures good patient compliance. Both AAOS and ACCP guidelines are now focusing on significant events as well as high bleeding risks. There should be a good balance between efficacy and safety as inappropriate anticoagulation leads to excessive bleeding. Aspirin (150 mg daily), warfarin (targeting INR of 1.5–2), LMWH (enoxaparin 20–40 mg daily), fondaparinux (2.5 mg daily), dabigatran (110–220 mg daily), and rivaroxaban (10 mg daily) are all appropriate pharmacological agents. The duration of prophylaxis extends from 10 to 14 days extending to 35 days on an individual risk assessment basis. Newer oral anticoagulants are preferred after discharge. There are still many limitations in the published guidelines which represent limitations for the current literature. Further research and studies are needed for identifying patients who are at risk for bleeding. However, the final decision for an ideal TP should be on the treating surgeon's hand who is much familiar with each patient's unique medical history. We recommend that surgeons should use CTP as per individual patient preference. The key to recommending appropriate chemical TP for patients is to maintain balance between safety and efficacy with minimized bleeding.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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