A 75-year-old woman presents to the emergency department after experiencing sudden onset, progressive dyspnea over the past 24 hours. She had a right-sided open reduction internal fixation of a stress ankle fracture without complication three days ago. On presentation she is afebrile with blood pressure 110/84 mm Hg, heart rate 123 bpm, respiratory rate 26 bpm, and oxygen saturation is 86% on ambient air, which improves to 96% with three liters of supplemental oxygen via nasal cannula. Troponin T is 0.16 ng/mL (normal <0.04 mg/mL), N-terminal prohormone brain natriuretic peptide (NT-proBNP) is 2,155 pg/mL, and creatinine is 0.8. Her weight is 150 lbs and creatinine clearance is 65 mL/min. Computed tomography angiography (CTA) of the chest reveals large filling defects in the proximal right and left pulmonary arteries and a right to left ventricular ratio of 1.2. Transthoracic echocardiography is remarkable for acute right ventricular strain.
She is placed on an intravenous heparin infusion, and taken to the cardiac catheterization lab for placement of two ultrasound-facilitated infusion catheters in the bilateral pulmonary arteries for low-dose catheter-directed thrombolysis. The procedure is uncomplicated and she receives a total of 24 mg of tPA over 12 hours. The catheters are then removed.
After five more days of parenteral anticoagulation, which of the following long-term anticoagulation strategies would be preferred for this patient?
Show Answer
The correct answer is: B. Edoxaban 60 mg once-daily.
This patient is presenting with high-risk submassive pulmonary embolism (PE) after recent orthopedic surgery. Elevated cardiac biomarkers, acute right ventricular strain on echocardiography, and increased right to left ventricular ratio are all negative prognostic indicators in this case. There are several options for the acute management of submassive PE, and these are described elsewhere on ACC.org.1
Options for long-term anticoagulation to prevent recurrent venous thromboembolism (VTE) for patients with submassive PE include vitamin K antagonists (e.g. warfarin), factor Xa inhibitors (e.g. edoxaban), low molecular weight heparins (LMWHs; e.g. enoxaparin), and direct thrombin inhibitors (e.g. dabigatran). Of these options, only edoxaban has been shown to have superior efficacy to warfarin in patients with submassive PE, as such, answer B is correct and answer A is not the best answer. In the Comparative Investigation of Low Molecular Weight (LMW) Heparin/Edoxaban Tosylate (DU176b) Versus (LMW) Heparin/Warfarin in the Treatment of Symptomatic Deep-Vein Blood Clots and/or Lung Blood Clots (Hokusai-VTE) trial,2 the rate of recurrent VTE in patients with submassive PE was 3.3% in the edoxaban arm, and 6.2% in the warfarin arm. Other factor Xa inhibitors, namely rivaroxaban and apixaban, were found to be non-inferior to warfarin for preventing recurrent VTE in the Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Pulmonary Embolism (EINSTEIN) and Efficacy and Safety Study of Apixaban for the Treatment of Deep Vein Thrombosis or Pulmonary Embolism (AMPLIFY) trials.3-5 Results with rivaroxaban as compared to warfarin did not demonstrate any heterogeneity across the severity of PE.
LMWHs have been shown to be non-inferior to warfarin in many randomized clinical trials,6 but there are no data to indicate that they are superior to warfarin in patients with submassive PE, therefore, answer C is not the best answer. Notably, LMWHs were shown to decrease the rate of recurrent VTE compared to warfarin in patients with malignancy in the Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) trial,7 but the patient presenting in this case has no cancer history. Similarly, the Efficacy and Safety of Dabigatran Compared to Warfarin for 6 Month Treatment of Acute Symptomatic Venous Thromboembolism (RE-COVER) trial demonstrated that dabigatran is non-inferior, but not superior, to warfarin for the treatment of VTE,8 as such, answer D is not the best answer.
Therefore, the best answer choice is edoxaban 60 mg once-daily. Although this treatment strategy has not yet been incorporated into guidelines (edoxaban was approved for use in the U.S. and Europe in 2015), edoxaban is the only long-term anticoagulant that has been shown to be superior to warfarin in the treatment of submassive PE, and is non-inferior or superior to warfarin with regard to safety outcomes. Of note, in the treatment of patients with acute VTE (including PE), the dose of edoxaban should be adjusted for weight and renal function if indicated (30 mg once-daily if weight ≤60 kg, CrCl 15-50 mL/min, or concomitant potent P-glycoprotein inhibitor; 60 mg once-daily otherwise). Since our patient has normal CrCl, weight is >60 kg, and no potent P-glycoprotein inhibitor is being administered, no dose adjustment is necessary and the patient should receive edoxaban 60 mg once-daily.
Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013;369:1406-15.
The EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363:2499-510.
The EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287-97.
Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013;369:799-808.
Andras A, Sala Tenna A, Crawford F. Vitamin K antagonists or low-molecular-weight heparin for the long term treatment of symptomatic venous thromboembolism. Cochrane Database Syst Rev 2012;10:CD002001.
Lee AY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003;349:146-53.
Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361:2342-52.
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