*4.1.2. Chemoprophylaxis*

The AAOS 2011 guidelines suggest pharmacologic agents and/or mechanical device for the prevention of VTE following joint replacement surgery. They did not recommend any specific agent or duration of thromboprophylaxis. Both guidelines support combined methods of chemoprophylaxis with mechanical device. Also, they discourage the regular Doppler screening

Thromboprophylaxis methods can be broadly divided into three—pharmacological, mechanical, and multimodal measures. Pharmacological measures include early active mobilization, intermittent pneumatic compression device (IPCD), compression stockings, and active ankle pumps. Anticoagulants often used are unfractionated and low molecular weight heparins,

The most recent amendments to the AAOS, ACCP, and Surgical Care Improvement Project (SCIP) clinical practice guidelines for VTE prophylaxis after total joint arthroplasty now include mechanical compression devices as modalities for VTE prophylaxis. Mechanical compressive devices increase the local blood flow in the lower extremities, decrease the concentration of the

vitamin K antagonists, and selective factor Xa inhibitor (e.g., fondaparinux).

**Figure 3.** Highlights of the recent AAOS guidelines for thromboprophylaxis.

for DVT postoperatively [7] (**Figure 3**).

**4.1. Methods of thromboprophylaxis**

*4.1.1. Mechanical methods*

46 Primary Total Knee Arthroplasty

*Aspirin*: it is an inhibitor of the cyclooxygenase enzyme system. It is the most simple and commonly used drug for thromboprophylaxis. It is very cheap, patient compliant and with least side effects. Aspirin inhibits COX1 more than COX2. COX1is chiefly expressed on platelets, which helps in platelet aggregation. Meta-analysis showed that aspirin was effective in reducing the rate of DVT to 30.6% from 48.5% [11]. Conflicting literature exists with regard to the efficiency of aspirin in preventing DVT. Aspirin is inferior to warfarin or LMWH in terms of preventing symptomatic PE or proximal DVT [8]. Also, the rate of complications is very low with the use of aspirin. Pulmonary embolism prevention (PEP) trial [12] which concluded that low-dose aspirin, when taken for 35 days, would result in seven times less symptomatic DVT cases, but three bleeding cases and two nonfatal myocardial infarction per 1000 patients. Studies have shown up to 0.13% developing hematoma and bleeding with warfarin in comparison to 0% with aspirin [13]. Studies have been done comparing the incidence of VTE, PE, proximal DVT, and distal DVT in multimodal prophylaxis methods with aspirin and warfarin. They have showed lower incidence of all types of thromboses with aspirin group [14].

*Warfarin*: warfarin is a vitamin K antagonist. It has been used extensively for DVT prophylaxis since decades. It was the first oral anticoagulant. However, the usage is restricted by the bleeding risk, potential drug interaction, and requirement for constant monitoring (INR). Warfarin inhibits the maturation of vitamin k-dependent coagulation factors in the coagulation cascade. Multitude of studies has been carried out comparing the efficacy of warfarin and LMWH. Majority of them showed LMWH was a more effective agent to prevent DVT formation (*P* < 0.05), but no difference to warfarin in preventing symptomatic events including PE [15]. Though regular INR monitoring is needed with warfarin, it significantly reduced the incidence of DVT when compared to aspirin but less effective than LMWH [11].

*Rivaroxaban*: these US FDA-approved drugs were launched after four phase III trials. Studies showed that these groups of drugs showed to be more effective than LMWH in reducing overall VTE incidence and mortality rate in TKA patients with no additional risk of bleeding [19, 20]. But most of the large-scale studies have shown increased risk of bleeding with rivaroxaban when compared to LMWH even though statistically not significant. Apart from the drug reactions and risk of bleeding, these have drug interactions with NSAIDs which the

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*Apixaban*: it is another class of DTI with similar mechanism of action as of dabigatran. It exerts minimal impact on PT, INR, and aPTT. American College of Cardiology (ACC) and American Heart Association (AHA) in 2011 released a focused update recommendation on dabigatran vs. warfarin comparison which stressed its use as an alternative to warfarin in patients with

*Dabigatran*: it is a direct thrombin inhibitor which cleaves both free and fibrin-bound thrombin. FDA investigated the rates of GI bleed and intracranial hemorrhages with dabigatran and warfarin and initially concluded that they both showed similar results. But a similar trial in Europe (RE-ALIGN trial) was stopped as the dabigatran users showed higher incidence of strokes, heart attacks, and thrombosis on prosthetic heart valves. Hence, it is not advised in patients with renal/hepatic impairment or prior history of GI

treating surgeon has to be aware of (**Figure 5**).

increased risk of developing deep vein thrombosis.

**Figure 5.** Figure showing the characteristics of rivaroxaban.

bleeds or recent ulcers.

*Low molecular weight heparins* (*LMWHs*): another widely used drug is low molecular weight heparin (LMWH). LMWHs are fragments of heparin produced by chemical or enzymatic depolymerization. LMWH has the highest efficacy in terms of preventing VTE. Few available ones are enoxaparin, dalteparin, and tinzaparin. Among these three, only two (enoxaparin and dalteparin) are indicated in major orthopedic surgery [16]. The ACCP recommends the use of LMWH in preference to other agents [17]. With the use of LMWH, the rate of fatal PE is reduced to 0.04% (from 0.16%), but the rate of clinically significant bleeding increased from 1.67% to 2.22% [18]. Its advantages are predictability, dose-dependent plasma levels, no need for regular monitoring, a long half-life and less bleeding for a given antithrombotic effect, low risk of immune-mediated thrombocytopenia, and heparin-induced osteoporosis.

*Novel oral anticoagulants*: since 2000, newer oral anticoagulants were introduced, collectively known as novel oral anticoagulants. They inhibit specific steps in the coagulation pathway. New oral anticoagulants include two classes of drugs—direct thrombin inhibitors and factor Xa inhibitors. Factor Xa inhibitors are mainly rivaroxaban and apixaban. They act by binding to the active site of factor Xa, thus inhibiting the interaction with its substrate. Dabigatran is the first FDA-approved direct thrombin inhibitor. Another DTI—Ximelagatran—was introduced but had to be withdrawn from market in 2006 as the FDA-denied approval (**Figure 4**).

The advantages of these agents are rapid onset of action, predictable anticoagulant response, no need for monitoring, wider therapeutic index, fewer drug–drug and drug-food interactions, reduced or comparable rates of thrombosis, bleeding, and other adverse events, and being orally administered, it is convenient and compliant. Many studies have come up with conflicting conclusion regarding these molecules.


**Figure 4.** The new oral anticoagulants and their mode of action.

*Rivaroxaban*: these US FDA-approved drugs were launched after four phase III trials. Studies showed that these groups of drugs showed to be more effective than LMWH in reducing overall VTE incidence and mortality rate in TKA patients with no additional risk of bleeding [19, 20]. But most of the large-scale studies have shown increased risk of bleeding with rivaroxaban when compared to LMWH even though statistically not significant. Apart from the drug reactions and risk of bleeding, these have drug interactions with NSAIDs which the treating surgeon has to be aware of (**Figure 5**).

of studies has been carried out comparing the efficacy of warfarin and LMWH. Majority of them showed LMWH was a more effective agent to prevent DVT formation (*P* < 0.05), but no difference to warfarin in preventing symptomatic events including PE [15]. Though regular INR monitoring is needed with warfarin, it significantly reduced the incidence of DVT when compared to

*Low molecular weight heparins* (*LMWHs*): another widely used drug is low molecular weight heparin (LMWH). LMWHs are fragments of heparin produced by chemical or enzymatic depolymerization. LMWH has the highest efficacy in terms of preventing VTE. Few available ones are enoxaparin, dalteparin, and tinzaparin. Among these three, only two (enoxaparin and dalteparin) are indicated in major orthopedic surgery [16]. The ACCP recommends the use of LMWH in preference to other agents [17]. With the use of LMWH, the rate of fatal PE is reduced to 0.04% (from 0.16%), but the rate of clinically significant bleeding increased from 1.67% to 2.22% [18]. Its advantages are predictability, dose-dependent plasma levels, no need for regular monitoring, a long half-life and less bleeding for a given antithrombotic effect, low

*Novel oral anticoagulants*: since 2000, newer oral anticoagulants were introduced, collectively known as novel oral anticoagulants. They inhibit specific steps in the coagulation pathway. New oral anticoagulants include two classes of drugs—direct thrombin inhibitors and factor Xa inhibitors. Factor Xa inhibitors are mainly rivaroxaban and apixaban. They act by binding to the active site of factor Xa, thus inhibiting the interaction with its substrate. Dabigatran is the first FDA-approved direct thrombin inhibitor. Another DTI—Ximelagatran—was introduced but had to be withdrawn from market in 2006 as the FDA-denied approval (**Figure 4**). The advantages of these agents are rapid onset of action, predictable anticoagulant response, no need for monitoring, wider therapeutic index, fewer drug–drug and drug-food interactions, reduced or comparable rates of thrombosis, bleeding, and other adverse events, and being orally administered, it is convenient and compliant. Many studies have come up with

risk of immune-mediated thrombocytopenia, and heparin-induced osteoporosis.

aspirin but less effective than LMWH [11].

48 Primary Total Knee Arthroplasty

conflicting conclusion regarding these molecules.

**Figure 4.** The new oral anticoagulants and their mode of action.

*Apixaban*: it is another class of DTI with similar mechanism of action as of dabigatran. It exerts minimal impact on PT, INR, and aPTT. American College of Cardiology (ACC) and American Heart Association (AHA) in 2011 released a focused update recommendation on dabigatran vs. warfarin comparison which stressed its use as an alternative to warfarin in patients with increased risk of developing deep vein thrombosis.

*Dabigatran*: it is a direct thrombin inhibitor which cleaves both free and fibrin-bound thrombin. FDA investigated the rates of GI bleed and intracranial hemorrhages with dabigatran and warfarin and initially concluded that they both showed similar results. But a similar trial in Europe (RE-ALIGN trial) was stopped as the dabigatran users showed higher incidence of strokes, heart attacks, and thrombosis on prosthetic heart valves. Hence, it is not advised in patients with renal/hepatic impairment or prior history of GI bleeds or recent ulcers.


**Figure 5.** Figure showing the characteristics of rivaroxaban.

#### *4.1.3. Multimodal methods*

Combining mechanical and pharmacological prophylaxis enables greater reduction of the risk of DTV. It also reduces the dosage of anticoagulants and thus the risk of bleeding, and achieves the same or even better thromboprophylaxis than monotherapy. Classifying patients into low or high risk of developing VTE is advocated. Low-risk patients received aspirin and intermittent calf compression, whereas high-risk patients received LMWH or warfarin and intermittent calf compression. All patients have to be mobilized within 24 h of surgery.

**5. Current trend**

monitoring [30].

able safer approach.

**Author details**

Melvin J. George

**References**

Address all correspondence to: johnirimpenz@yahoo.co.in

American Volume. 2005;**87**:2097-2112

Sree Narayana Institute of Medical Sciences, Kochi, Kerala, India

prophylaxis. The British Journal of Surgery. 2011;**98**:1356-1364

Ideal DVT prophylaxis method still remains an enigma. The choice is based on patient characteristics and surgeon's experience. Aspirin is recognized as a primary chemoprophylactic agent with the adaptation of the recent ACCP guidelines by the Surgical Care Improvement Project (SCIP). They strongly endorse risk stratification for VTE prophylaxis and opined that aspirin will become the mainstay of prevention of VTE for the majority of patients after TJA. Thus, we could optimize outcomes for our patients, by preventing the feared VTE while limiting bleeding complications that can occur with other aggressive anticoagulants [29]. Identifying and stratifying the patients at risk for DVT remains a challenge. As a general consensus, it is taken that patients post TJA can receive aspirin as thromboprophylaxis without much risk. But, those patients at very high risk may need more potent agents and careful

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Further research is needed to identify patients at major risk and probability of VTE and bleeding. The current clinical guidelines provide an orthopedic surgeon with more latitude, and choices of VTE prophylaxis without emphasis on aggressive chemical, and often unneeded prophylaxis. The key to determining the appropriate chemical prophylaxis for patients is to balance safety and efficacy while minimizing bleeding. Modern arthroplasty surgeons advocate early postoperative mobilization and use of mechanical prophylaxis in combination with chemoprophylaxis according to the risk stratification, which of course seems to be a reason-

[1] Liberman JR, Hsu WK. Prevention of venous thromboembolic disease after total hip and knee arthroplasty. Current concepts review. Journal of Bone and Joint Surgery.

[2] Kanchanabat B, Stapanavatr W, Meknavin S, Soorapanth C, Sumanasrethakul C, Kanchanasuttirak P. Systematic review and meta-analysis on the rate of postoperative venous thromboembolism in orthopaedic surgery in Asian patients without thrombo-

Few studies have advocated less potent pharmacological agents for low-risk patients and more potent agents for high-risk patients as the results showed negligible incidence of DVT, PE, and wound hematoma in both the groups [21]. Few recent studies show superior effects for aspirin in multimodal thromboprophylaxis when compared to warfarin [13, 14, 22].

## *4.1.4. Concerns with thromboprophylaxis*

The risks associated with thromboprophylaxis are mainly hemorrhage, wound hematoma, persisting wound drainage, failure of wound healing, risk of infection, and blood loss requiring transfusion. One of the main drawbacks of initiating thromboprophylaxis is the high incidence of major bleeding, reaching up to 4–7.9% [23]. More potent the prophylactic agent, more the incidence. Oral agents hence have lower bleeding rates [15]. A study on 290 patients post-TJA using 10-day course of inj. enoxaparin 30 mg twice daily showed high incidence of 3–5% of readmission, re-exploration, and prolonged hospitalization for wound drainage and bleeding [24]. There were increased rates of return to the operating room for wound complications, wound drainage for more than 7 days, and incidence of symptomatic DVT in 3.8% patients and nonfatal PE in 1.3% patients. Parvizi et al. reviewed 78 septic failure cases that underwent revision and showed a direct correlation between excessive anticoagulation and development of periprosthetic infection [25]. The occurrence of such complications after elective TJA due to the use of prophylactic agents is heartbreaking to most surgeons.

Also, timing of initiation of the prophylaxis is also debated. Two schools of thought are initiation of LMWH 12 h preoperative and 12 h postoperative. Earlier initiation of prophylaxis has shown greater efficacy in preventing DVT but also causes a higher incidence of bleeding. The decision about which agent and when to initiate chemoprophylaxis should be based on the balanced efficacy-bleeding ratio of the prophylactic agents [26].

There is still no consensus on the duration of the use of prophylaxis too. The recently released new AAOS guidelines do not provide a specific duration for prophylaxis [27]. Earlier ACCP guidelines advocated a minimum of 10 days of prophylaxis, with extended prophylaxis up to 35 days. AAOS advised different duration for different agents: LMWH/fondaparinux for 7–12 days and aspirin/warfarin for 6 weeks. Extended prophylaxis with only LMWH was effective post THA, but not TKA [28].
