Bridging anticoagulation when treating venous thromboemboli

Given the rising number of options for treating venous thromboemboli (VTE), questions occasionally arise on what is the standard for initiating and continuing anticoagulation.  Questions such as, "How long do we need to overlap parenteral anticoagulation for?" and "Can we begin monotherapy with a new oral anticoagulant?" will be discussed below.

Options for treating VTE now include (in no particular order):

• IV or subcutaneous unfractionated heparin
• Low-molecular-weight heparins (LMWH - enoxaparin, dalteparin, tinzaparin, nadroparin)
• Fondaparinux
• Warfarin
• Dabigatran, rivaroxaban, apixaban, and possibly edoxaban soon (collectively often referred to as NOAs - New Oral Anticoagulants)

Determining which treatment is best for each patient depends on a variety of factors such as the location or extent of the VTE, whether symptoms are present, and the presence of comorbidities (renal dysfunction, valve replacements or disease, cancer, bleeding diatheses).  The most recent recommendations of the ACCP CHEST guidelines were updated in 2012 but do not include the latest evidence regarding the NOAs.1

If deciding to use warfarin as the long-term VTE treatment option:

• A "bridge" or "overlap" of parenteral anticoagulation and warfarin therapy is necessary
• Early initiation of warfarin (ie. same day) is recommended
• Both are to be continued for a minimum of 5 days and until the INR is 2.0 or above for at least 24 hours.¹

Why is it important to bridge patients?

Bridging patients when intending to use warfarin as your long-term treatment is necessary not solely from a pharmacologic (where it makes sense2) or guideline perspective (where it's recommended1).  Appropriate overlap therapy is one of the core measures of The Joint Commission's VTE Core Measure Set (VTE-3) which are aligned with the Centers for Medicare and Medicaid Services Clinical Quality Measures (CQM).  The rates that institutions meet these measures is reported nationally, is publicly available, and is tied to CMS incentive payments.  If overlap therapy is being held due to excessive anticoagulation (ie. the INR increased to supratherapeutic levels), documentation that therapy is being held due to increased risk of bleeding should be clear.

Certain patients are excluded from the VTE Core Measure Set.  These include patients:3 ·        Less than 18 years old ·        Who have a length of stay >120 days ·        With Comfort Measures Only documented ·        Enrolled in clinical trials ·        Discharged to a healthcare facility for hospice care ·        Discharged to home for hospice care ·        Who left against medical advice ·        Discharged to another hospital ·        Without warfarin therapy during hospitalization ·        Without VTE confirmed by diagnostic testing

If deciding to use dabigatran as the long-term VTE treatment:

• Parenteral anticoagulation needs to be given first for a minimum of 5 days before starting dabigatran (these medications should not be overlapped)
• In the large phase 3 studies, RECOVER and RECOVER-II, the parenteral phase (usually LMWH) lasted for a median of 9 days but the labeling only indicates that 5 are necessary
• Edoxaban, if it gets approved, has also followed this dosing strategy

If deciding to use rivaroxaban or apixaban as the long-term VTE treatment:

• Either of these can be started right away as monotherapy as no bridging was used in their large, phase 3 studies
• A higher dose is used initially (3 weeks for rivaroxaban, 1 week for apixaban) and is then lowered for the bulk of the treatment duration

So which strategy is best?

Two systematic reviews and meta-analyses were recently published addressing the efficacy and safety of the various treatment strategies now available for treating acute VTE.  These two analyses generally concluded that the new oral anticoagulants and vitamin K antagonists have similar efficacy in the treatment of acute VTE.  Though there are many details and caveats in the recent NOA phase 3 studies which are a favorite to debate (where in some cases, statistically significant differences were found) the clinical differences are all within a very small margin.  The meta-analyses' equivocal findings persisted across a variety of subgroups including those with DVT versus PE, weight ≥100kg, moderate renal insufficiency (creatinine clearance 30-49 mL/minute), age ≥75 years old, and cancer.  As far as adverse events, the NOAs, rivaroxaban and apixaban in particular, are associated with less bleeding compared to a LMWH-VKA combination.4,5

Take home points:

• Anticoagulation strategies using new oral anticoagulants or traditional parenteral - vitamin K antagonist overlap are relatively comparable in efficacy
• When using a vitamin K antagonist treatment strategy, appropriate overlap of a minimum of 5 days and an INR above 2 for >24 hours has clinical and financial ramifications
• Document when overlap therapy is not acceptable (ie. increased risk for bleeding)

References:
1.  Kearon C, Akl EA, Comerota AJ, et al.  Antibiotic therapy for VTE disease: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.  CHEST  2012;141(2)(Suppl):e419s-94s.

2.  Weitz JI. Chapter 30. Blood Coagulation and Anticoagulant, Fibrinolytic, and Antiplatelet Drugs. In: Brunton LL, Chabner BA, Knollmann BC. eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e. New York, NY: McGraw-Hill; 2011.  Accessed October, 2014.
3.  Specifications Manual for National Hospital Inpatient Quality Measures.  The Joint Commission.  Available at: http://www.jointcommission.org/specifications_manual_for_national_hospital_inpatient_quality_measures.aspx.  Accessed October, 2014.
4.  Castellucci LA, Cameron C, Le Gal G, et al.  Clinical and safety outcomes associated with treatment of acute venous thromboembolism.  JAMA  2014;312(11):1122-35.

5.  van Es N, Coppens M, Schulman S, et al.  Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials.  Blood  2014;124(12):1968-75.

photo by Tim Drivas