New Oral Anticoagulants and Outpatient Prophylaxis of Venous Thromboembolism

Abstract

In total hip or total knee arthroplasty, hypercoagulability typically begins on the operating table and a hypercoagulable state persists for up to 3 months after surgery. For that reason, it is critical to begin anticoagulation as soon as possible after wound closure and to continue it beyond the standard time of hospital discharge: current guidelines recommend up to 35 days following total hip arthroplasty and at least 10 days following total knee arthroplasty. Currently, low molecular weight heparin is commonly used for in-hospital prophylaxis, while for post-discharge use, warfarin is the drug most frequently prescribed in the United States. While both are efficacious, both have challenges associated with administration and, in the case of warfarin, a narrow therapeutic window, both food and drug interactions, routine blood monitoring, and an unpredictable dose response. New oral anticoagulants are being developed that will be easier to administer, have minimal or no drug interactions, and do not require coagulation monitoring. These drugs, which include dabigatran, apixaban, and rivaroxaban, should encourage improved compliance with guideline recommendations for optimal duration of thromboprophylaxis and lead to a reduced incidence of venous thrombolic events.

(Am J Manag Care. 2011;17:S15-S21)

Venous thromboembolism (VTE), which comprises deep vein thrombosis (DVT) and pulmonary embolism (PE),¹ is a serious complication after total hip arthroplasty (THA) and total knee arthroplasty (TKA).² In patients undergoing THA or TKA, the formation of blood clots usually starts in the deep vein of the calf,³ and leg scanning and venographic studies have shown that such thrombi often begin during surgery.³ Approximately one-half of such calf DVTs resolve spontaneously within 72 hours, although one-sixth to one-third may extend to involve the proximal veins.^3,4 Although venous thrombi often begin perioperatively, studies have shown that the cumulative risk of VTE may last for up to 3 months after THA and 1 month after TKA.⁵ In addition, the timing of peak incidence of postoperative VTE differs with the type of surgery. Recent data from the Global Orthopaedic Registry (GLORY), a multinational group of 100 centers, suggest that in patients undergoing THA symptomatic VTE occurs approximately 10 days later than in patients undergoing TKA, with a mean time to VTE of 9.7 days for TKA and 21.5 days for THA.⁶

In the past, anticoagulation was given only during the hospital stay, normally 7 to 10 days, and was discontinued on discharge.⁷⁶ Not all orthopedic surgeons are aware that more than half of symptomatic VTEs occur post-discharge (e.g., 75% of patients undergoing THA and 57% of patients undergoing TKA develop VTE after the median time to hospital discharge).⁶ In addition, a marked decrease in the use of thromboprophylaxis is seen at the time of discharge,⁶ although the burden of DVT following hospital discharge after THA or TKA is substantial.^8,9 A meta-analysis of studies in which patients received only short-duration (7-10 days) anticoagulation after THA/TKA found that symptomatic, non-fatal VTE occurred in about 1 in 32 patients and fatal PE in about 1 in 1000 patients within 3 months of surgery.¹⁰ One study found that 10% of patients admitted with a VTE event were discharged without any anticoagulation. Of those, 36% had a malignancy and 26% had had a previous VTE event, both potentiating factors for further VTE.¹¹ Another study found that only 19% of patients older than 65 years received post-discharge thromboprophylaxis after major hip or knee surgery.¹²

However, hospital stays are becoming increasingly shorter. Data from GLORY showed that the median length of hospital stay is 4 days (range, 3-9 days) in patients with TKA and 5 days (range, 3-11 days) in patients with THA.

While continuing thromboprophylaxis as an outpatient may be warranted to prevent late-occurring VTE events,¹³ findings from the Hip and Knee Registry indicated that only two-thirds of patients are given adequate prophylaxis after discharge.¹⁴

Optimal Duration of Prophylaxis After Total Hip and Total Knee Arthroplasty

In patients undergoing joint arthroplasty in the lower limb, the 8th American College of Chest Physicians (ACCP) guidelines recommend at least 10 days of thromboprophylaxis. In patients with THA, ACCP guidelines recommend that thromboprophylaxis be extended up to 35 days, and for the first time, they suggest that in patients with TKA, prophylaxis may also be extended for 35 days, although the evidence is less strong in this group.² The fact that activation of coagulation and venous stasis are present for 5 to 6 weeks,^15-17 along with the prolonged risk of VTE after THA, supports the guideline recommendation of extended thromboprophylaxis. A meta-analysis of data from randomized trials found that extended-duration prophylaxis after THA or TKA significantly reduced the frequency of post-discharge symptomatic VTE compared with placebo or untreated controls.¹⁸ However, the absolute reduction of symptomatic VTE in some studies and meta-analyses may have been overestimated by using venographic DVT to anticipate clinical events.¹⁹ Nevertheless, readmission rates for VTE during the 6 months after THA and TKA were found to be reduced by extended (6 weeks) warfarin administration compared with no outpatient prophylaxis.^20,21

What Prophylaxis Do Patients Currently Receive?

After THA or TKA, the ACCP guidelines recommend thromboprophylaxis with a low molecular weight heparin (LMWH), fondaparinux, or an adjusted-dose vitamin K antagonist, usually warfarin. The guidelines specifically recommend against using acetylsalicylic acid (ASA) alone.² The American Association of Orthopaedic Surgeons (AAOS) guidelines for the prevention of PE recommend the same anticoagulants but also include ASA.²² The AAOS panelists rejected DVT as an outcome because they considered that the link between DVT and PE after THA or TKA was unproven. However, their argument excluded data from important and relevant clinical trials, and they used Level 3 data for support.²³ The AAOS also recommends using ASA for patients at high risk of PE and/or major bleeding.²² This recommendation is largely based on expert opinion, however, and lacks a strong scientific basis.²³

Although almost all patients undergoing TKA and THA receive some form of prophylaxis for VTE, there appears to be considerable variation in the routine practice of orthopedic surgeons. A large proportion of patients do not receive the ACCP guideline-recommended prophylaxis for VTE in terms of type of prophylaxis, start time, and duration of thromboprophylaxis. GLORY investigators assessed the compliance of clinicians from the United States and 12 other countries with the 6th ACCP guidelines (which were released in 2001).^24,25 Warfarin was used more frequently in the United States, while LMWH was used more frequently in other countries.²⁵ Approximately one-third of patients who received LMWH did not receive it at the guidelinerecommended starting time, nor for the appropriate duration.²⁵ Less than one-half of patients with TKA and less than one-third of patients with THA were fully compliant with warfarin use.²⁵ The inadequate use of thromboprophylaxis leaves a significant proportion of patients at risk of developing venous thromboembolic events at a later time.²⁶ While extended thromboprophylaxis with LMWHs^27,28 (specifically enoxaparin²⁹ and dalteparin^30,31) and fondaparinux³² was found to be effective after THA, data to support extended prophylaxis after TKA are less robust.^13,29

Drawbacks of Currently Available Agents for Thromboprophylaxis

LMWHs are the current standard of care for thromboprophylaxis after THA and TKA in many countries, including those in the European Union and Canada.³³ The LMWHs are efficacious, have acceptable bleeding risks, and do not need routine coagulation monitoring.³⁴³⁵ Drawbacks of the LMWHs include a very low potential risk of heparin-induced thrombocytopenia.³⁶ In addition, the current in-hospital length of stay is inadequate for patients who are to be "bridged" from LMWH to warfarin for outpatient thromboprophylaxis, as guidelines recommend concomitant use of both agents for 4 to 5 days and until the international normalized ratio (INR) is in the target range for 2 days.³⁷

However, they are perceived to be more costly compared with warfarin, and need to be administered subcutaneously, making their use as post-discharge prophylaxis problematic, as patients who cannot or are unwilling to self-inject may need to attend daily appointments or receive daily nurse visits to administer their medication. There must also be appropriate and safe disposal facilities for syringes and needles. Nevertheless, LMWHs are safe and effective as outpatient-based therapy. This may result in inadequate post-discharge thromboprophylaxis.

Warfarin is one of the most frequently used pharmacologic thromboprophylaxis agents in the United States, along with the LMWHs.²⁵ While it is efficacious, warfarin has a narrow therapeutic window. Moreover, due to its pharmacokinetics and pharmacodynamics, there is considerable intra- and interpatient variability in the dose response.³⁷ Polymorphisms in the genes encoding for the cytochrome P450 2C9 enzyme, and the vitamin K epoxide reductase, have been shown to contribute to variability in sensitivity to warfarin.³⁸³⁷ Regular coagulation monitoring is required to maintain the INR within the narrow optimal therapeutic range of 2 to 3.^2,39 In fact, many patients' laboratory values are not within the required therapeutic range^40,41 for significant periods during prophylaxis, although 1 study reported that 92% of patients had an INR greater than 1.7 at the time of hospital discharge.⁴²

Warfarin is also associated with multiple drug-drug and food-drug interactions.

The use of fondaparinux after major orthopedic surgery remains limited. Clinical trials have evaluated fondaparinux only up to day 11 after THA and TKA.⁴³ The drawbacks of fondaparinux include its subcutaneous mode of administration, its relatively long half-life, and its perceived association with increased bleeding. In addition, caution is recommended when it is used in the elderly and in patients weighing less than 50 kg, due to an increased risk of bleeding.⁴⁴

Reversal of anticoagulation is fortunately infrequently required in short-term use, as reversal is not easy. Protamine is only partially effective with the LMWHs⁴⁵ and ineffective with fondaparinux.⁴⁴ Warfarin reversal can be achieved by administration of vitamin K, and for serious bleeding, by the use of fresh frozen plasma, prothrombin complex concentrates, or recombinant activated Factor VII.⁴⁶ However, reversal can be slow and difficult. As a result, stopping anticoagulation, supportive therapy, and appropriate treatment, including surgery, are normally used for any emergency until spontaneous reversal is achieved, especially with agents with a short half-life, such as the newer anticoagulants. The use of other modalities, such as recombinant activated Factor VII and prothrombin complex concentrates, may be useful as adjuvants but are as yet relatively unproven.⁴⁷

Strategies to Improve Prophylaxis

As indicated by the GLORY registry,²⁵ physician compliance with guidelines appears to be poor. Management of prophylaxis should obviously begin in the hospital. The guidelines recommend that every hospital have a formal, active strategy that addresses the prevention of VTE. Guidelines also call for a local thromboprophylaxis strategy in the form of a written, institutionwide thromboprophylaxis policy.² (See also the article by Merli in this supplement.⁴⁸) Strategies shown to increase thromboprophylaxis adherence, including computer-based decision support systems, preprinted orders, and periodic audit and feedback, are also recommended, while passive methods are not.² Computerbased decision support systems and reminders have been shown to change physician behavior and increase the use of prophylaxis.^49-51 A further step might be to simplify the prescription process.⁵²⁵³ Multiple strategies are more likely to improve practice.

In addition, the previous ACCP guidelines suggest that resources be devoted to patient-mediated interventions.

While strategies have been developed for patient education about anticoagulation with warfarin,⁵⁴ similar strategies will need to be developed for patient education about anticoagulation with the new oral agents (see below). Poor patient adherence to medication has been well documented,⁵⁵ and this has also been evident with anticoagulation therapy.⁵⁶ There are many reasons for poor adherence, but the drawbacks listed above for the established therapies probably contribute.⁵⁷⁵⁸ Therefore, the advent of new orally active anticoagulants should result in an improvement in the prevention of VTE.⁵⁹ In addition, the adoption of new courses on anticoagulation therapy for pharmacy students should also increase the understanding of issues associated with anticoagulation.⁶⁰

After appropriate patient education, adherence to new oral anticoagulant treatments should be at least as good as that for the established anticoagulants.

Novel Anticoagulants

(Figure)

Several new anticoagulants are in clinical development, with the aim of providing safe, effective, and more convenient alternatives to the currently available agents for the prevention of VTE after THA and TKA. Unlike the current agents, these new anticoagulants have selective targets in the coagulation cascade .^61,62

Apixaban is an oral, direct Factor Xa inhibitor in phase II clinical trials for the prevention and treatment of thromboembolic disorders. A brief overview of the ADVANCE-1 (Apixaban Dosed Orally Versus Anticoagulation with Injectable Enoxaparin to Prevent Venous Thromboembolism 1)⁶³ and ADVANCE-2 (Apixaban Dosed Orally Versus Anticoagulation with Injectable Enoxaparin to Prevent Venous Thromboembolism 2)⁶⁴ studies is given in the article by Merli in this supplement.⁴⁸ Rivaroxaban, another oral, direct Factor Xa inhibitor, has been approved in more than 95 countries for the prevention of VTE after elective THA and TKA. Results of the RECORD (REgulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism) program showed that rivaroxaban 10 mg once daily significantly reduced the incidence of the composite of symptomatic VTE and all-cause mortality compared with enoxaparin regimens of 40 mg once daily, and total VTE when compared with 30 mg enoxaparin twice daily.^65-68 A thorough overview of the RECORD program is given in the article by Kwong in this supplement.⁶⁹

Dabigatran etexilate is an oral, direct thrombin inhibitor that is approved in the European Union and Canada for the prevention of VTE after THA and TKA. RE-NOVATE (Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip arthroplasty) was a double-blind trial in which patients with THA were randomized to dabigatran 220 mg or 150 mg or enoxaparin 40 mg per day for a median of 33 days. The primary efficacy outcome, a composite of venographic or symptomatic VTE and death from all causes, occurred in 6.0% of patients receiving dabigatran 220 mg, 8.6% of those receiving dabigatran 150 mg, and 6.7% of patients receiving enoxaparin, with no significant difference in major bleeding with either dose of dabigatran compared with enoxaparin. However, in 2 trials conducted in patients undergoing TKA, dabigatran met the non-inferiority criteria vs enoxaparin 40 mg sc once daily in reducing total VTE and allcause mortality in 1, RE-MODEL (Oral dabigatran etexilate versus subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee arthroplasty), but failed to do so vs 30 mg enoxaparin twice daily in the other, RE-MOBILIZE (Oral thrombin inhibitor dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total knee arthroplasty).^70-72

Table

The characteristics of these new agents are given in the .^73,74 All of them have the potential to improve adherence to guidelines for extended thromboprophylaxis.⁷⁵

Conclusions

Although the high risk of VTE in patients after THA and TKA is well recognized, understanding the timing of clot formation is essential for the optimal prevention and management of these events. Because they are needed to achieve hemostasis, hypercoagulability and clots may start on the operating table. This suggests that anticoagulation needs to be started in the perioperative period. Most early DVTs after major orthopedic surgery begin in the calf and approximately half of them resolve spontaneously. Thrombi that remain confined to the calf rarely become symptomatic, and some surgeons may doubt the need to actively manage asymptomatic events. However, there is evidence that, in the absence of treatment, approximately one-sixth to one-third of isolated distal DVTs extend to involve the proximal veins, which makes them more likely to be symptomatic and to increase the risk of PE.

Taking into consideration how early clots form after THA and TKA and how long clot formation may continue, both initiation and duration of prophylaxis are suboptimal in current prophylactic practice. As more than half of symptomatic events occur after hospital discharge, continuing thromboprophylaxis post-discharge is vital in preventing late-occurring VTE. This is particularly important in patients undergoing THA, due to the prolonged risk documented in this patient population. Current anticoagulants have characteristics that make them challenging for post-discharge thromboprophylaxis and that may contribute to the observed poor adherence with clinical guidelines. New anticoagulants in development are oral, can be given in a fixed dose, have been found to have a good pharmacokinetic and pharmacodynamic profile, have minimal drug-drug or drug-food interactions, and do not require coagulation monitoring-all features that will make them easier to use in the outpatient setting after THA or TKA.

Author Affiliation: Department of Surgery, McGill University Health Centre, Montreal, Quebec, Canada.

Funding Source: Financial support for this supplement was provided by Ortho-McNeil Janssen Scientific Affairs, LLC and Johnson & Johnson Worldwide Market Access.

Author Disclosure: Dr Fisher received grants/honoraria from Bayer, Portola, sanofi-aventis, and Takeda. He has received lectureship fees from Bayer, Boehringer Ingelheim, Johnson & Johnson, and sanofi-aventis.

Authorship Information: Concept and design; acquisition of data; analysis and interpretation of data; drafting of the manuscript; and critical revision of the manuscript for important intellectual content.

Address correspondence to: William D. Fisher, MD, McGill University Health Centre, 1650 Cedar Ave, Montreal, Quebec, H3G 1A4, Canada. E-mail: wfisher@sympatico.ca.

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