Currently Viewing:
Supplements Extended Prophylaxis for Venous Thromboembolism in Acute Medically Ill Patients
Currently Reading
Venous Thromboembolism in Acute Medically Ill Patients: Identifying Unmet Needs and Weighing the Value of Prophylaxis
Paul P. Dobesh, PharmD; Tania Ahuja, PharmD; George A. Davis, PharmD; Hugh Fatodu, MBA, RPh; William H. Francis, MBA, RPh; Frank P. Hull, MD; Gary L. Johnson, MD, MS, MBA; Joshua D. Lenchus, DO, BSPharm; Jacqueline Glee Lenoir, PharmD; Claudette McPherson, RN, BSN; Jeffrey Nemeth, PharmD, MPA; and Ralph J. Riello III, PharmD
Best Practices for Implementing Venous Thromboembolism Prophylaxis Across the Continuum of Care
Paul P. Dobesh, PharmD; Tania Ahuja, PharmD; George A. Davis, PharmD; Hugh Fatodu, MBA, RPh; William H. Francis, MBA, RPh; Frank P. Hull, MD; Gary L. Johnson, MD, MS, MBA; Joshua D. Lenchus, DO, BSPharm; Jacqueline Glee Lenoir, PharmD; Claudette McPherson, RN, BSN; Jeffrey Nemeth, PharmD, MPA; and Ralph J. Riello III, PharmD
Participating Faculty

Venous Thromboembolism in Acute Medically Ill Patients: Identifying Unmet Needs and Weighing the Value of Prophylaxis

Paul P. Dobesh, PharmD; Tania Ahuja, PharmD; George A. Davis, PharmD; Hugh Fatodu, MBA, RPh; William H. Francis, MBA, RPh; Frank P. Hull, MD; Gary L. Johnson, MD, MS, MBA; Joshua D. Lenchus, DO, BSPharm; Jacqueline Glee Lenoir, PharmD; Claudette McPherson, RN, BSN; Jeffrey Nemeth, PharmD, MPA; and Ralph J. Riello III, PharmD
EXCLAIM. The randomized, parallel, placebo-controlled Extended Prophylaxis for Venous Thromboembolism in Acutely Ill Medical Patients with Prolonged Immobilization (EXCLAIM) trial compared extended-duration enoxaparin (28±4 days) with standard-duration VTE prophylaxis with enoxaparin (10±4 days).32 A total of 5963 patients aged ≥40 years (mean age of 67.9 years), having an acute medical illness (eg, heart failure, respiratory disease, or infection), experiencing decreased mobility for ≥3 days before enrollment, and likely to have decreased mobility for ≥3 days after enrollment, were randomized to prophylaxis. Patients were randomized 1:1 to enoxaparin 40 mg per day subcutaneously or placebo for 28±4 days after receiving open-label enoxaparin for an initial 10±4 days. Compared with standard-duration VTE prophylaxis with enoxaparin, extended-duration enoxaparin significantly decreased the occurrence of VTE events (2.5% vs 4%, respectively; P <.04). However, major bleeding was significantly increased with extended-duration enoxaparin (0.8% vs 0.3%, respectively; P <.05).32

ADOPT. The randomized, double-blind, double-dummy, placebo-controlled Apixaban Dosing to Optimize Protection from Thrombosis (ADOPT) trial compared extended-duration apixaban (30 days) with standard-regimen enoxaparin (6 -14 days).33 A total of 6528 acutely ill patients aged ≥40 years (mean age for apixaban and enoxaparin is 66.8±12.0 years and 66.7±12.0 years, respectively) who had congestive heart failure, respiratory failure, other medical disorders, ≥1 other risk factor for VTE, and who were hospitalized with an expected inpatient stay of ≥3 days were randomized to prophylaxis. Patients were randomized 1:1 to apixaban 2.5 mg orally twice daily for 30 days, or enoxaparin 40 mg per day subcutaneously for 6 to 14 days. Of the patients who could be evaluated, there were no differences between extended-duration apixaban and standard-duration VTE prophylaxis with enoxaparin regarding a 30-day composite total mortality related to VTE, PE, symptomatic DVT, or asymptomatic proximal-leg DVT. Out of all of the test subjects, 4495 (2211 in the apixaban group and 2284 in the enoxaparin group) could be evaluated for the primary efficacy outcome. Sixty patients (2.71%) in the apixaban group and 70 patients (3.06%) in the enoxaparin group met the primary efficacy outcome criteria (relative risk with apixaban, 0.87; 95% CI, 0.62 to 1.23; P = .44). By day 30, major bleeding was found to have occurred in 0.47% with extended-duration apixaban, compared with 0.19% of those receiving standard-duration VTE prophylaxis with enoxaparin.33

MAGELLAN. The randomized, double-blind, placebo-controlled Efficacy and Safety Study for the Prevention of Venous Thromboembolism in Hospitalized Acutely Ill Medical Patients Comparing Rivaroxaban With Enoxaparin (MAGELLAN) trial compared extended-duration rivaroxaban 10 mg daily (35±4 days) with standard-duration VTE prophylaxis with enoxaparin (10±4 days).34 A total of 8101 patients aged ≥40 years (mean age 71.0 years) who were hospitalized for an acute medical illness were randomized to prophylaxis. A primary efficacy outcome event occurred in 6.6% of patients in the rivaroxaban group and in 4.6% of those in the enoxaparin group. At day 35, an event of efficacy outcome occurred in 9.4% of those receiving extended-duration rivaroxaban and 7.8% of patients receiving enoxaparin followed by placebo.34 The rate of clinically relevant bleeding was significantly higher in the rivaroxaban group than the enoxaparin group (4.1% vs 1.7%, respectively). Fatal bleeding occurred in 7 patients in the extended-duration rivaroxaban group and in 1 patient in the group receiving enoxaparin followed by placebo.

MARINER. The randomized, double-blind, placebo-controlled MARINER trial evaluated the efficacy and safety of thromboprophylaxis with rivaroxaban for the prevention of symptomatic VTE events in high-risk medical patients.35 Investigators used a modified version of the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE VTE) risk score, combined with laboratory testing, to identify eligible patients, 12,019 of which were included in the intention-to-treat analysis. The population was generally a lower risk population than other extended VTE prophylaxis studies. Upon hospital discharge, rivaroxaban was administered as 10 mg once daily for patients with creatinine clearance (CrCl) ≥ 50 ml/min; for patients having CrCl ≥30 ml/min and <50 ml/min, the dose is decreased to 7.5 mg once daily. Prophylaxis continued for 45 days, with the primary efficacy end point being the composite of symptomatic VTE (lower extremity DVT and nonfatal PE) and VTE-related deaths.

Among patients receiving rivaroxaban, 0.83% achieved the primary efficacy outcome, as compared with 1.1% of patients who were given placebo (P = .14). Symptomatic nonfatal VTE were identified in 0.18% of patients in the rivaroxaban group, as compared with 0.42% of patients in the placebo group (HR, 0.44; 95% CI, 0.22-0.89). Additionally, major bleeding occurred in 0.28% and 0.15% of patients in the rivaroxaban and placebo groups, respectively. The investigators concluded that, although the risk for major bleeding was low in this post-discharge population, rivaroxaban treatment was not associated with a significantly lower risk of symptomatic VTE and death, possibly due to overall low event rates. 

Findings from the MARINER trial and others revealed that net clinical benefit with extended-duration thromboprophylaxis (ie, enoxaparin, apixaban, and rivaroxaban) was not observed when compared with standard-duration VTE prophylaxis with enoxaparin, mostly due to increased major bleeding events. According to the stakeholders, an unmet medical need exists for an agent in this space that is both safe and effective.

A New Option

In 2017, betrixaban was approved for the prophylaxis of VTE events in adult patients hospitalized for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE.36 The betrixaban approval was based on data from the Acute Medically Ill VTE Prevention with Extended Duration Betrixaban Study (APEX) trial, which enrolled only hospitalized, acute medically ill patients who had risk factors for VTE events.36,37 Betrixaban is currently the only approved agent indicated for VTE prophylaxis over periods of 35 to 42 days.36

In the APEX study, patients hospitalized for acute medical illness, were randomly assigned to 2 regimens. One group received subcutaneous placebo ‘enoxaparin’ for 10±4 days, plus oral betrixaban (160 mg loading dose, followed by 80 mg once daily) for 35 to 42 days. Patients having severe renal impairment or those receiving P-glycoprotein inhibitors received half dose betrixaban (80 mg loading dose, followed by 40 mg once daily). The other group received subcutaneous enoxaparin (40 mg once daily for 10±4 days) plus oral placebo ‘betrixaban’ for 35 to 42 days.37 Patients with severe renal insufficiency randomized to enoxaparin received 20 mg instead of 40 mg daily. Paul P. Dobesh, PharmD, explained that the APEX study design was informed by previous studies and focused on defining acute medically ill patients at high-risk for experiencing VTE events, who would most likely benefit from extended prophylaxis. The stakeholders also noted that APEX was designed specifically for extended prophylaxis in this patient population.

Stakeholders were encouraged by the availability of an agent that can be administered over a longer time. However, they acknowledged that the issue of post-discharge risk and extended-duration therapy has yet to be addressed, and that VTE prophylaxis of any kind remains underutilized.

See the second article in this publication (page S475) for extensive analysis of the APEX trial and the role of betrixaban in the VTE prophylaxis landscape.

Treatment Guidelines for Prophylaxis

Many thromboembolic disease guidelines from major medical organizations are available:
  • American College of Cardiology
  • American Heart Association
  • American Academy of Neurology
  • American College of Chest Physicians (ACCP)
  • North American Spine Society
  • American Society of Clinical Oncology
  • Endoscopic Surgeons
  • American College of Physicians
  • American Academy of Family Physicians
  • Institute for Clinical Systems Improvement
  • American Academy of Orthopaedic Surgeons
  • Michigan Quality Improvement Consortium
  • Society of American Gastrointestinal and Endoscopic Surgeons
Of these, the stakeholders report generally defaulting to the ACCP guidelines, also known as the CHEST guidelines, for VTE prophylaxis recommendations. For acutely ill hospitalized patients, the CHEST guidelines suggest anticoagulant prophylaxis with low molecular weight heparin, low-dose unfractionated heparin (twice daily or 3 times daily), or fondaparinux.7 According to the guidelines, thromboprophylaxis should continue for 6 to 21 days until full mobility is restored or discharge from the hospital, whichever comes first.7 Importantly, all current guidelines were published before data from the APEX trial became available.

Because no current guidelines recommend use of VTE prophylaxis following standard-duration therapy, its use has become complicated. According to Riello and other stakeholders, the 2012 ACCP guidelines recommend against extending thromboprophylaxis beyond the period of patient immobilization or acute hospital stay in acute medically ill patients who received an initial course of thromboprophylaxis. Additionally, duration of hospital stays has broadly shortened since the results from the original studies were published. Davis went on to explain that lack of guidelines complicates International Classification of Diseases (ICD) coding. “I have read thousands of discharge summaries over the years. I have never seen on the discharge lists ‘high-risk for VTE events,’ because it is not a recognized code.” Dobesh reiterated that the APEX trial sought to provide guidance on identifying high-risk patients. This is further discussed in the subsequent articles in this supplement.

Challenges and Complications Associated With the Use of Thromboprophylaxis

Beyond the challenges associated with guidelines for treatment, other clinical issues that complicate the use of extended VTE prophylaxis in the population under discussion include renal impairment, drug interactions, knowledge gaps, and continuity of care.

Of the currently approved direct-oral anticoagulants (DOACs), betrixaban is the least renally excreted, at <18% of absorbed drug dose (or 11% of the administered dose).38,39 Renal excretion among other DOACs ranges from 25% to 80%.42 Concomitant medication use with DOACs may increase the risk of major bleeding, although trials have not yet included betrixaban.40

 
Copyright AJMC 2006-2019 Clinical Care Targeted Communications Group, LLC. All Rights Reserved.
x
Welcome the the new and improved AJMC.com, the premier managed market network. Tell us about yourself so that we can serve you better.
Sign Up