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Featured Clinical Topic: Cardiology/Anticoagulation

16 Sep 2018 11:03 PM | Anonymous

The Role of Extended Thromboprophylaxis in Acutely Ill Medical Patients
Author: Yasmine Zeid, PharmD

Venous thromboembolism (VTE) encompasses two interrelated conditions that are part of the same spectrum: deep vein thrombosis (DVT) and pulmonary embolism (PE).1 A DVT is a venous blood clot that typically forms in the veins of the lower extremities. A PE occurs when part of a DVT breaks off and travels to the lungs, where partial or complete occlusion of blood flow can be fatal.2 VTE affects about 900,000 patients in the United States every year.3 The risk of VTE remains even after diagnosis and treatment, with one-third of patients diagnosed with a VTE having a recurrence within 10 years. It is estimated that over 50% of hospitalized medical patients are at risk for VTE, with VTE being the second most common medical complication that can occur during a patient’s hospital stay. The total annual cost per patient for secondary diagnosis of DVT is $7,594, and the total annual cost per patient for secondary diagnosis of PE is $13,018.3-6 Early recognition of patients who are at an increased risk of developing VTE is imperative to reduce the medical and economic burden of this complication.

Assessing Risk
Virchow’s Triad is a theory that describes three broad factors that are thought to increase the likelihood of VTE formation: alterations in blood flow, hypercoagulability, and vascular endothelial injury.7 Alterations in blood flow can also be referred to as venous stasis, or the slowing or stopping of blood flow.8 One of the most common contributors to venous stasis is immobilization following long-haul traveling or hospitalization. Polycythemia, a disease state that results in hyperviscosity of the blood, can also lead to slowing of blood flow. Hypercoagulability encompasses both hereditary and acquired risk factors. Factor V Leiden disease leads to a hypercoagulable state due a variant in factor V that cannot bind to protein C. Acquired risk factors include pregnancy, oral contraceptive use, obesity, and cancer. Vascular endothelial injury result from physiologic shear stress and disease states such as hypertension.9-10

There are risk assessment tools available to objectively aid in determining a patient’s risk of developing a VTE. The most commonly used one is the Padua Prediction Score Risk Assessment Tool.11 The Padua Prediction Score is comprised of 11 risk factors, both anatomic and hereditary, with each risk factor assigned a point value based on its relative contribution to risk of VTE formation. A total score of <4 means the patient has a low risk of VTE, while a score ≥4 indicates a high risk of VTE.2 Appendix A includes a complete Padua Prediction Score Risk Assessment Tool.

The 2012 American College of Chest Physicians (ACCP) guidelines address VTE prevention in hospitalized medical patients.2 Recommendations for thromboprophylaxis are based upon the calculated risk of VTE using the Padua Prediction Score Risk Assessment Tool while also taking into account a patient’s risk of bleeding. The guidelines recommend against thromboprophylaxis for patients with a low risk of VTE, chemical thromboprophylaxis for patients with a high risk of VTE and low bleeding risk, and mechanical thromboprophylaxis for patients with a high risk of VTE and a high risk of bleeding. Patient-specific factors must be taken into account when caring for high-risk patients so that the risks and benefits of treatment can be adequately weighed.


Chemical Thromboprophylaxis
There are three medications with FDA approval for the chemical prophylaxis of VTE.2 All three medications have shown to be superior to both placebo and mechanical devices used for thromboprophylaxis. Unfractionated heparin (UFH) is administered subcutaneously at a dose of 5000 units three times a day. Low molecular weight heparins (LMWH) include agents such as enoxaparin, which are also administered subcutaneously. Enoxaparin’s traditional dosing is 40 mg once daily, with dose adjustments required for patients with a creatinine clearance less than 30 mL/min, as well as in obese patients. Fondaparinux, a synthetic factor Va inhibitor, is traditionally dosed subcutaneously at 2.5 mg once daily. Dose adjustments are required in patients with renal dysfunction defined as creatinine clearance less than 30 mL/min; use is contraindicated in patients weighing less than 50 kg.

Extended-Duration Thromboprophylaxis
The 2012 ACCP guidelines recommend that VTE prophylaxis be continued throughout a patient’s acute hospital stay for the duration of patient immobilization. The guidelines go further to recommend against extending the duration of treatment beyond this time.2 The question arises as to whether or not the risk of developing a VTE is eliminated at hospital discharge, as patients may have risk factors that persist for weeks or even months after hospital discharge. The concept of extended-duration thromboprophylaxis refers to thromboprophylaxis that continues beyond its initial course.

Evidence to support extended-duration thromboprophylaxis is strongest in hospitalized surgical patients, specifically in patients who have undergone total hip arthroplasty and total knee arthroplasty.12 The 2012 ACCP guidelines recommend a minimum duration of 10-14 days of thromboprophylaxis, with a recommendation for up to 35 days of thromboprophylaxis from the day of surgery.2 Appendix B includes a table with commonly prescribed agents for extended-duration thromboprophylaxis in surgical patients.

The risk of VTE extending beyond hospitalization has been demonstrated in several studies. The MEDENOX study, a randomized-controlled trial that granted enoxaparin its FDA indication for standard-duration thromboprophylaxis, demonstrated that 8% of total VTEs occurred between days 15 and 110.13 In an observational study in 2011, data from over 15,000 patients in the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) study was analyzed to determine the incidence of VTE for 3 months after admission. The risk of VTE post-discharge was 45%.5 Moreover, an observational study published in 2012 examining the risk of VTE following hospitalization found that 56.6% of all VTE events occurred after discharge.14

To date, there are four large randomized controlled trials that have evaluated short-term versus extended-duration thromboprophylaxis in the acutely ill medical population. A table summarizing these four trials is included in Appendix C. The EXCLAIM trial, published in 2010, evaluated extended-duration thromboprophylaxis versus standard-duration with enoxaparin. All enrolled patients initially received open-label subcutaneous enoxaparin (40 mg once daily) for 10±4 days. Upon successfully completing open-label prophylaxis, patients were randomized in a 1:1 ratio to receive either subcutaneous enoxaparin (40 mg once daily) or placebo for an additional 28±4 days. The primary efficacy outcome was a composite of VTE events during the double-blind treatment period, and the primary safety outcome was major hemorrhagic complications. The EXCLAIM trial found that extended-duration enoxaparin did reduce the frequency of VTE events while also increasing the incidence of major bleeding. A subgroup analysis for two endpoints of the study, VTE at day 28 and major bleeding events, was completed looking specifically at three factors: age, sex, and immobility levels. In female patients age >75 years with level 1 immobility (defined as total bed rest without bathroom privileges), the risk of VTE at day 28 was significantly lower in the extended-duration thromboprophylaxis group.15

The ADOPT trial, published in 2011, evaluated extended-duration thromboprophylaxis with apixaban following standard-duration prophylaxis with enoxaparin. Patients were randomly assigned in a 1:1 ratio to receive apixaban, administered orally at a dose of 2.5 mg twice daily, or enoxaparin, administered subcutaneously at a dose of 40 mg once daily, during their stay in the hospital, for a minimum of 6 days. After 6 days, the decision to discontinue the parenteral study drug was made at the discretion of the investigators, and patients continued treatment up to 30 days with either apixaban 2.5 mg twice daily or an oral placebo. Notably, the dose of apixaban that was utilized in the ADOPT study was 2.5 mg twice daily, which is FDA-approved dose for extended-duration thromboprophylaxis in patients undergoing total hip and total knee arthroplasty. The primary efficacy outcome was a composite of VTE events during the 30-day treatment period, and the primary safety outcome was major bleeding. Extended-duration apixaban was not found to be superior to standard-duration thromboprophylaxis with enoxaparin, and a significant increase in major bleeding events was observed.16

The MAGELLAN study, published in 2013, evaluated extended-duration thromboprophylaxis with rivaroxaban versus standard-duration prophylaxis with enoxaparin. Patients were assigned in a 1:1 ratio to one of the following therapies: rivaroxaban 10 mg once daily orally for 35±4 days plus subcutaneous placebo for 10±4 days; or, enoxaparin 40 mg once daily subcutaneously for 10±4 days plus an oral placebo for 35±4 days. Similarly to the dose of apixaban in the ADOPT study, this 10 mg once daily dose of rivaroxaban was based upon the FDA-approved dose of the medication for extended-duration prophylaxis in total hip and total knee arthroplasty patients. The primary efficacy outcome was a composite of VTE events, with a non-inferiority analysis up to day 10 (compared standard-duration prophylaxis with rivaroxaban to standard-duration enoxaparin) and a superiority analysis up to day 35 (compared extended-duration rivaroxaban to standard-duration enoxaparin). The primary efficacy outcome was a composite of major bleeding or clinically relevant nonmajor bleeding events. Rivaroxaban was found to be noninferior to enoxaparin for the standard duration of therapy; additionally, extended-duration rivaroxaban was superior to standard enoxaparin prophylaxis. A significantly higher risk of major bleeding and clinically relevant nonmajor bleeding was observed in the rivaroxaban group versus the enoxaparin group.17

The APEX trial, published in 2016, is the most recent study examining extended-duration thromboprophylaxis in the acutely ill medical population. It evaluated extended-duration thromboprophylaxis with the newest FDA-approved factor Xa inhibitor, betrixaban, versus standard-duration prophylaxis with enoxaparin. Patients were divided into three patient cohorts: cohort 1 included patients with elevated baseline D-dimer level greater than 2x upper limit of normal; cohort 2 included patients in cohort 1 plus patients ≥75 years of age; and cohort 3 included the overall study population. Patients were then randomized in a 1:1 ratio to receive either enoxaparin 40 mg once daily subcutaneously for 10±4 days plus placebo once daily for 35 to 42 days; or, subcutaneous placebo for 10±4 days plus oral betrixaban. Betrixaban was administered as a 160 mg loading dose followed by 80 mg once daily for 35-42 days. The primary efficacy outcome was a composite of VTE events, and the primary safety outcome was the occurrence of major bleeding. Extended-duration prophylaxis with betrixaban reduced overall VTE events compared to standard-duration enoxaparin in cohort 1, but this finding was not found to be statistically significant. While cohorts 2 and 3 did demonstrate a statistically significant reduction in VTE events, because the first cohort failed to show statistical significance, all subsequent analyses were considered to be exploratory. The efficacy results of the APEX trial were later analyzed using a modified intent-to-treat analysis (mITT) for patients who took at least 1 dose of study drug and had a follow-up assessment of VTE. Major bleeding was not significantly increased in any of the patient cohorts; however, major or clinically relevant nonmajor bleeding was significantly increased in all three patient cohorts.18-19

Betrixaban was granted FDA-approval in June 2017, and it is the first and only anticoagulant with approval for both hospital and extended thromboprophylaxis of VTE in acutely ill medical patients. The recommended dosing is 160 mg on day 1 of therapy, following by 80 mg daily for 35-42 additional days. In patients with a creatinine clearance of 15-30 mL/min and/or receiving concurrent treatment with P-glycoprotein inhibitors, the dose is reduced to 80 mg on day 1, followed by 40 mg daily for 35-42 additional days. Betrixaban must be taken at the same time every day with food to avoid high concentrations.19 The average wholesale price (AWP) for 35 days of therapy with betrixaban is about $650, compared to about $260 dollars for standard-duration enoxaparin.20

Based on the evidence available at this time, as well as current guideline recommendations, extended-duration thromboprophylaxis in the acutely ill medical population should not be routinely practiced until the potential risks and benefits have been evaluated on an individual patient-case basis. Although betrixaban is now approved for this indication, its efficacy has not yet been well established. Even though its use did not demonstrate an increase in major bleeding in the APEX trial, an increase in major or clinically relevant nonmajor bleeding was still observed. Extended-duration thromboprophylaxis may be beneficial in a niche patient population (female, age ≥75, immobilized, elevated D-dimer), and more studies are needed to better characterize this population.


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2.       Kahn SR, Lim W, Dunn AS, et al. Prevention of VTE in nonsurgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e195S.

3.       Fernandez MM, Hogue S, Preblick R, Kwong WJ. Review of the cost of venous thromboembolism. Clinicoecon Outcomes Res. 2015;7:451–62.

4.       Spyropoulos AC, Lin J. Direct medical costs of venous thromboembolism and subsequent hospital readmission rates: an administrative claims analysis from 30 managed care organizations. J Manag Care Pharm. 2007; 13: 475-486.

5.       Spyropoulos AC, Anderson FA Jr, Fitzgerald G, et al. Predictive and associative models to identify hospitalized medical patients at risk for VTE. Chest 2011; 140:706.

6.       Hull RD, Hirsh J, Sackett DL, Stoddart GL. Cost-effectiveness of primary and secondary prevention of fatal pulmonary embolism in high-risk surgical patients. Can Med Assoc J 1982; 127:990.

7.       Dickson, B.C. (2004a) Venous thrombosis: on the history of Virchow’s triad. University of Toronto Medical Journal; 81, 166–171.

8.       Goldhaber SZ. Risk factors for venous thromboembolism. J Am Coll Cardiol 2010; 56:1.

9.       Anderson FA, Spencer FA. Risk factors for venous thromboembolism. Circulation 2003; 107: 19-116

10.   Martinelli I, Cattaneo M, Taioli E, et al. Genetic risk factors for superficial vein thrombosis. Thromb Haemost 1999; 82:1215.

11.   Barbar S, Noventa F, Rossetto V, et al. A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score. J Thromb Haemost 2010; 8:2450.

12.   Falck-Ytter Y, Francis CW, Johanson NA et al (2012) Prevention of VTE in orthopedic surgery patients: antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 141(2 Suppl):e278S–e325S.

13.   Samama MM, Cohen AT, Darmon JY, Desjardins L, Eldor A, Janbon C, Leizorovicz A, Nguyen H, Olsson CG, Turpie AG, Weisslinger N (1999) A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patient. N Engl J Med 341:793–800.

14.   Amin AN, Varker H, Princic N, Lin J, Thompson S, Johnston S. Duration of venous thromboembolism risk across a continuum in medically ill hospitalized patients. J Hosp Med. 2012;7(3):231-8.

15.   Hull RD, et al. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients with recently reduced mobility: a randomized trial. Ann Intern Med. 2010 Jul 6;153(1):8-18.

16.   Goldhaber SZ, Leizorovicz A, Kakkar AK, et al. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med; 365: 2167-77.

17.   Cohen AT, et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med. 2013. 368(6): 513-523.

18.   Cohen AT, Harrington RA, Goldhaber SZ, et al. Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients. N Engl J Med 2016; 375:534.

19.   Bevyxxa(betrixaban) [package insert]. San Francisco, CA: Portola Pharmaceuticals, Inc.; June 2017.

20.   Micromedex Solutions. Ann Arbor (MI): Truven Health Analytics; publication year [5 January 2018]. Available from: www.micromedexsolutions.com

21.   Lovenox® (enoxaparin) [package insert]. Bridgewater, NJ. Sanofi-Aventis; October 2017.

22.   Xarleto® (rivaroxaban) [package insert]. Titusville, NJ. Janssen Pharmaceuticals, Inc. October 2017.

23.   Eliquis® (apixaban) [package insert]. Princeton, NJ. Bristol-Myers Squibb. November 2017.

24.   Pradaxa® (dabigatran) [package insert]. Ridgefield, CT. Boehringer Ingelheim Pharmaceuticals, Inc. July 2017.

Additional supporting tables are below and as a PDF file.

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