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A 34-year-old woman presents for follow-up after completion of six months of therapeutic anticoagulation for a deep venous thrombosis (DVT) of the right lower extremity complicated by pulmonary embolism (PE). She initially presented six months prior to urgent care with severe right lower extremity swelling and pain following immobilization and casting for a right ankle fracture. She was promptly diagnosed with a large proximal DVT of the right lower extremity via lower extremity doppler ultrasound and, given shortness of breath and tachycardia at the time of presentation, PE protocol computerized tomography (CT) was performed that demonstrated multiple bilateral pulmonary emboli. She was initiated on therapeutic anticoagulation with rivaroxaban (Xarelto). She has no other known medical problems and no prior personal or family history of venous thromboembolism (VTE). She takes no medications aside from rivaroxaban, does not use exogenous hormonal birth control, and takes no nutritional supplements. Her body mass index (BMI) is 22. She had no complications whatsoever from the rivaroxaban and is interested in any evidence-based intervention to minimize her risk of recurrent VTE, given the size of her first clot and the negative impact it has had on her life.

Based on the results of the EINSTEIN CHOICE study, which of the following is the most appropriate next step in management?

1. Obtain thrombophilia workup (antiphospholipid antibody testing and testing for factor V Leiden, prothrombin gene mutation, protein C deficiency, protein S deficiency, and antithrombin deficiency)
2. Discontinue rivaroxaban and initiate aspirin 81 mg daily for one year
3. Reduce rivaroxaban dose to 10 mg daily and continue indefinitely
4. Reduce rivaroxaban dose to 10 mg daily and continue this dose for one year
5. Continue rivaroxaban 20 mg daily indefinitely

Answer

4. Reduce rivaroxaban dose to 10 mg daily and continue this dose for one year

The patient is an otherwise young, healthy woman who suffered a provoked VTE following immobilization of her leg in a cast. She has a normal weight, does not use exogenous hormones for birth control, and has no known underlying thrombophilia. She was appropriately treated with therapeutic anticoagulation for six months, and now presents for the next step in her management. Continuation of rivaroxaban for one year at a dose of either 10 mg daily or 20 mg daily for one year is the most appropriate evidence-based risk reduction strategy, making reducing rivaroxaban dose to 10 mg daily and continuing this dose for one year, the correct answer. This is based on the results of the EINSTEIN CHOICE study, published in the New England Journal of Medicine in March 2017. In this randomized, double-blind, phase III trial, 3,365 patients 18 years of age or older who had either provoked or unprovoked, objectively confirmed, symptomatic proximal DVT or PE who were treated for six to 12 months with therapeutic anticoagulation, were randomized in a 1:1:1 ratio to either rivaroxaban 20 mg daily, rivaroxaban 10 mg once daily, or aspirin 100 mg daily for an additional six to 12 months. 60 percent of patients in the trial had an index VTE that was classified as provoked, like the patient in the vignette. The primary endpoint was a composite of symptomatic, recurrent fatal or nonfatal VTE or unexplained death: 1.5 percent for the rivaroxaban 20 mg group, 1.2 percent for the rivaroxaban 10 mg group, and 4.4 percent for the aspirin group, a statistically significant difference for both rivaroxaban groups when either was compared to the aspirin group (no difference between the two rivaroxaban groups). There was no significant difference in major or clinically relevant non-major bleeding between the two groups. Therefore, the results of this major trial indicate that extension of anticoagulation with either prophylactic or therapeutic doses of rivaroxaban for a year is superior to aspirin for a year in the reduction of recurrent VTE without an increase in the risk of bleeding (why answer choice B is incorrect). Answer choice A is incorrect, as thrombophilia testing is not recommended for patients with provoked VTE (see ASH Choosing Wisely guidelines).

Further study is required to know if longer durations (beyond one year) of prophylactic dose rivaroxaban offers benefit in these patients, but we have no evidence to suggest that continuation of 10 mg daily rivaroxaban offers benefit over one year (the EINSTEIN CHOICE trial did not continue anticoagulation for longer than one year after completion of the initial course of therapeutic anticoagulation). Continuation of therapeutic anticoagulation indefinitely in a young, healthy woman with no underlying major thrombophilia who suffered a provoked VTE (answer choice E) would not be appropriate, as we do not have evidence to support this management strategy at this time.

Case study submitted by Hanny Al-Samkari, MD, of Massachusetts General Hospital, Dana-Farber Cancer Institute/Brigham & Women’s Hospital, Partners CancerCare, Boston, MA.

Resources 

1. Weitz JI, Lensing AWA, Prins MH, et al. . N Engl J Med. 2017; 376:1211-1222.