Quick Guide: Anticoagulation Road Map: Deep Venous Thrombosis Prophylaxis

The incidence of deep venous thrombosis (DVT) increases with age and is most common in adults over the age of 60 years.¹ Blood clots, or thrombi, most often form in the lower extremities due to conditions that change the flow of blood or increase levels of hematocrit, thereby increasing the blood’s viscosity.^1,2 The challenge of DVT management is that patients often present asymptomatically; waiting for clinical symptoms to manifest, such as edema, pain, and an increase in skin temperature, may put patients at higher risk of complications and mortality. As such, attention to DVT risk factors in older adults and a thorough understanding of prophylactic measures are vitally important. This resource provides an overview of the burden of DVT in older adults and pharmacologic prophylaxis, with an emphasis on the role of anticoagulation therapy in older adults undergoing knee and hip surgery.

The Risk and Burden of DVT in Older Adults

When DVT is unrecognized and untreated, long-term morbidity from chronic venous stasis may occur and increase the risk of recurrent venous thromboembolism.² Chronic deep vein insufficiency (DVI), a syndrome characterized by destruction of the valves in the communicating leg veins, frequently results after DVT, whether it is symptomatic or asymptomatic.²  Pain in DVI is rare, but other symptoms, such as chronic edema, stasis dermatitis, and hyperemic ulcers may occur, which may lead to additional complications that increase the risks of morbidity and mortality in older adults. DVT becomes a life-threatening condition when part of the thrombus breaks off and travels to the lungs, causing a pulmonary embolism. For example, untreated DVT in the proximal lower extremities has a 50% risk of leading to pulmonary embolism,³ which can lead to death within 30 minutes of onset.²

Among older adults and the elderly, risk factors for DVT include recent hospitalization and prolonged periods of sitting or laying down, obesity, and trauma causing fractures in the pelvis or legs. Additionally, risk is increased due to conditions that increase hematocrit levels, such as dehydration, pulmonary disorders, smoking, and polycythemia.² The risk of DVT is especially high in older adults who undergo major orthopedic procedures, such as elective hip and knee replacement or surgery for fracture.^1,3 DVT is estimated to occur in 20% to 25% of patients over the age of 40 years after routine surgery; when no prophylaxis is given, almost 50% of patients experience DVT after hip surgery.² In patients undergoing elective total hip replacement without prophylaxis, the incidence of DVT ranges from 40% to 60%.⁴

Weighing the Options in DVT Prophylaxis
To reduce the risks associated with DVT morbidity and mortality following hip or knee surgery, anticoagulation therapy is the mainstay of DVT prophylaxis. Subcutaneous injections of low-molecular-weight heparin (LMWH) have been the most widely used prophylactic agent given before surgery.² Compared to its predecessors (standard heparin and warfarin), LMWH demonstrated similar efficacy with the advantages of improved dose-dependent plasma levels, longer half-life, and predictability.⁵ However, the novel oral anticoagulants offer several advantages over LMWH (eg, enoxaparin). Presently, only apixaban and rivaroxaban have indications for DVT prophylaxis in patients undergoing hip or knee replacement surgery as well as reducing the risk recurrent venous thromboembolism. Edoxaban and dabigatran may be used off-label.

Apixaban. Apixaban is indicated in DVT prophylaxis following hip or knee replacement surgery based on the results of the ADVANCE trials.⁶ Compared with enoxaparin, apixaban demonstrated noninferiority or superiority in VTE prevention after total knee or hip replacement, with similar or less major and clinically relevant nonmajor bleeding.^7,8

Edoxaban. Edoxaban is currently approved in the US for treatment of acute VTE, which is beyond the scope of this review. The Hokusai-VTE study found edoxaban to be noninferior to warfarin in preventing recurrent VTE, with significantly lower bleeding.⁹ Edoxaban is not yet indicated in the US for DVT prophylaxis in orthopedic patients, although it has this indication in Japan based on data from the STARS trials, which showed that edoxaban was superior to enoxaparin in VTE prevention after total knee and total hip replacement surgery, without an increased risk of bleeding.⁹

Dabigatran. Dabigatran does not have a specific indication for DVT prophylaxis in patients undergoing orthopedic surgery. But with evidence gleaned from four phase ³ trials and the support of the American College of Chest Physicians evidence-based clinical practice guidelines, dabigatran is being used off-label for thromboprophylaxis in total hip and knee replacement surgeries.5,6 Presently, dabigatran is approved to reduce the risk of recurrent DVT in patients who have previously been treated for DVT and have a creatinine clearance level of >30 mL/min. In the RE-MEDY and RE-SONATE trials, dabigatran was effective in the extended treatment of venous thromboembolism and carried a lower risk of major or clinically relevant bleeding than warfarin but a higher risk than placebo.¹⁰ There are no current dosage recommendations for patients with a creatinine clearance level <30 mL/min.

Rivaroxaban. Rivaroxaban is indicated in DVT prophylaxis following hip or knee replacement surgery based on the results of the RECORD trials.⁶ Compared with enoxaparin, rivaroxaban demonstrated superiority in thromboprophylaxis, with a similar safety profile, in patients undergoing total hip or knee replacement surgery.^11,12

There are numerous advantages to using the novel oral anticoagulants versus LMWH, but there are also numerous prescribing factors to be taken into consideration among older adults. A review of these agents is provided on the reverse side of this handout.

Enoxaparin Versus the Novel Anticoagulants in DVT Prophylaxis Following Hip and Knee Replacement Surgery

Enoxaparin Sodium Injection
Class: Low-molecular-weight heparin 

Dosing: Knee surgery: 30 mg subcutaneous every 12 hours starting 12 to 24 hours after surgery; hip surgery: 30 mg subcutaneous every 12 hours, starting 12 to 24 hours after surgery or 40 mg subcutaneous once-daily starting 9 to 15 hours prior to surgery. Usual treatment duration is 7 to 10 days, but may be used for longer in patients with a slow functional recovery.  

Considerations: Contraindicated in patients with hypersensitivity to pork products; thrombocytopenia; and active major bleeding. In older patients, monitor for increased risk of bleeding.

Apixaban
Class: Direct Factor Xa inhibitor
Dosing for DVT prophylaxis following hip or knee replacement surgery: Oral, 2.5 mg, twice-daily
Compared to enoxaparin:

• Noninferior or superior rate of thromboprophylaxis after total knee or hip replacement surgery
• Similar or less major and clinically relevant nonmajor bleeding

Rivaroxaban
Class: Direct Factor Xa inhibitor
Dosing for DVT prophylaxis following hip or knee replacement surgery: Oral, 10 mg, once-daily, with or without food for 35 days (hip replacement surgery); oral, 10 mg, once-daily with or without food for 12 days (knee replacement surgery)
Compared to enoxaparin:  

•   Superior rate of thromboprophylaxis after total knee and hip replacement surgery
•   Similar safety profile

Off-Label Uses of the Novel Anticoaglants for DVT Prophylaxis Following Knee or Hip Replacement Surgery
The direct thrombin inhibitor dabigatran and the factor Xa inhibitor edoxaban do not have indications for DVT prophylaxis following knee or hip replacement surgery, although healthcare providers may be using them off-label for this purpose based on other sources of safety and efficacy data

Edoxaban
Edoxaban is indicated in the treatment of DVT (60 mg once-daily, or 30 mg once-daily in patients with creatinine clearance level of 15-50 mL/min or body weight less than or equal to 60 mg or who use certain P-gp inhibitors). Edoxaban is currently NOT indicated in patients with creatine clearance>95mL/min because of increased risk of ischemic stroke as compared to warfarin. Edoxaban is indicated for thromboprophylaxis in Japan based on data gleaned from the STARS trials, which showed edoxaban to have a superior rate of thromboprophylaxis after total knee or hip replacement surgery, without increased risk of bleeding, compared to enoxaparin.

Dabigatran
Dabigatran is indicated to reduce the risk of recurrent DVT only in patients with a creatinine clearance level of >30 mL/min (150 mg twice-daily after previous treatment). The use of dabigatran for thromboprophylaxis following hip and knee replacement surgery has been investigated in four phase 3 studies. In the RE-NOVATE trials, dabigatran 150 mg or 220 mg once-daily showed noninferior efficacy and a similar safety profile compared to enoxaparin (40 mg once-daily) for 28 to 35 days after total hip replacement surgery; the RE-MODEL trial found dabigatran to have similar safety and efficacy rates for 6 to 10 days after total knee replacement surgery. In the RE-MOBILIZE trial, dabigatran failed to meet noninferiority criteria for efficacy after total knee replacement surgery compared to enoxaparin for 12 to 15 days.

Pros:

• No routine coagulation monitoring required
• Rapid onset and offset of action
• Predictable profiles
• More convenient dosing and administration

Cons:

• Potentially more expensive, and may not be fully covered by patients’ insurance
• Discontinuation may increase risk of thrombotic events (rivaroxaban)
• With all DVT agents, the use of aspirin and other antiplatelet agents (eg, clopidogrel) has not been adequately studied to advise on the use of any of these agents with the novel oral anticoagulants or enoxaparin; such use may markedly increase bleeding risk from all sites
• No approved antidote for reversal of anticoagulation
• Bleeding risk may be increased in severe renal impairment (creatine clearance 15-29 mL/min)

References:

1. Deep venous thrombosis. Medline Plus. www.nlm.nih.gov/medlineplus/ency/article/000156.htm. Updated February 24, 2014. Accessed April 20, 2015.

2. Peripheral venous disease. In: Merck Manual of Geriatrics. 3rd ed. Whitehouse Station, NJ: Merck Research Laboratories, 2000:923-930.

3. Reyes N, Grosse S, Grant A. Deep vein thrombosis and pulmonary embolism. Centers for Disease Control and Prevention. wwwnc.cdc.gov/travel/yellowbook/2014/chapter-2-the-pre-travel-consultation/deep-vein-thrombosis-and-pulmonary-embolism. Updated August 1, 2013. Accessed April 20, 2015.

4. Agnelli G. Prevention of venous thromboembolism in surgical patients. Circulation. 2004;110:IV-4-IV-12.

5. Comparative effectiveness of pharmacologic and mechanical prophylaxis of venous thromboembolism among special populations. Agency for Healthcare Research and Quality. www.effectivehealthcare.com.ahrq.gov. Published January 12, 2012.

6. Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients. Chest. 2012;141(suppl 2):e278S-e325S.

7. Lassen MR, Gallus A, Raskob GE, et al; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med. 2010;363:2487-2498.

8. Lassen MR, Raskob GE, Gallus A, et al; ADVANCE-2 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement: a randomized double-blind trial. Lancet. 2010;375(9717):p807-p815.

9.   Bounameaux H, Camm AJ. Edoxaban: an update on the new oral direct factor Xa inhibitor. Drugs. 2014;74(11):1209-1231.

10. Schulman S, Kearon C, Kakkar AK, et al; RE-MEDY and RE-SONATE Trials Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Eng J Med.

2013;368:709-718.

11. Eriksson BI, Borris LC, Friedman RJ, et al; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358:2765-2775.

12. Lassen MR, Ageno W, Borris LC, et al; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358:2776-2786.

13. Data and statistics: DVT/PE. Centers for Disease Control and Prevention. www.cdc.gov/ncbddd/dvt/data.html. Updated March 20, 2015. Accessed April 20, 2015.

14. Eliquis (apixaban) [package insert].  Princeton, NJ: Bristol-Myers Squibb; revised 2014.

15. Savaysa (edoxaban) [package insert]. Parsippany, NJ: Daiichi Sankyo, Inc; 2015.

16. Xarelto (rivaroxaban) [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; revised January 2015.

17. Pradaxa (dabigatran) [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; revised January 2015.

18. Lovenox (enoxaparin sodium injection). Bridgewater, NJ: Sanofi-Aventis US, LLC; 2013.

19. Stacy Z. Novel oral anticoagulants for venous thromboembolism prophylaxis after total hip or knee replacement. P.T. 2013;38(1):45-50.