Treatment options, management approach, and bleeding risks for the outpatient handling of pulmonary embolism
CASE: Your patient is a 33-year old female with newly diagnosed left segmental PE. She was initially tachycardic, which has since improved with acetaminophen. Her ECG and biomarkers are unremarkable. She appears well and scores 0 on sPESI and Hestia Criteria. You think she is appropriate for treatment as an outpatient. The patient asks about a recent commercial she just saw for Xarelto® or rivaroxaban. Is this an option?
Anticoagulation is the primary therapy for PE. Heparin bridging with warfarin is effective and well validated, but this process requires close monitoring over many days.[1-8] Novel oral anticoagulants (NOACs) have fewer drug and dietary interactions and no need for monitoring. [1,9-11] However, to avoid the risk of clot extension, patients must not miss a single NOAC dose due to short medication half-life.
How do NOACS compare with each other and prior anticoagulation regimens (heparin/warfarin) in terms of efficacy and bleeding? Rates of recurrent venous thromboembolism (VTE), all-cause mortality, and major bleeding are similar in studies evaluating rivaroxaban, apixaban, edoxaban, and dabigatran versus standard heparin/warfarin—about 2.5% or less. Major bleeding and mortality rates for these drugs is about 2% or less. In general, NOACS performed as well or slightly better than the traditional vitamin K antagonists (VKA) in all studies. [12-18] Table 1 provides a deeper dive into the outcomes of these studies.
In summary, NOACs are safe and can be used, though the pharmacokinetics of each drug should be considered when making a therapeutic choice.  The 2016 ACCP guidelines support NOAC therapy in outpatients for three months in VTE patients without cancer. For the ED, we like rivaroxaban or apixaban for outpatient therapy. Edoxaban and dabigatran require initial parenteral anticoagulation while rivaroxaban and apixaban do not. [11,18-24] No routine monitoring is needed for any of the NOACS, but dosing routines can differ between agents. Once-a-day drugs are likelier than twice-a-day drugs to promote adherence. Further details are shown in Table .
WHEN ARE NOACS NOT THE BEST OPTION?
NOACs can be expensive, and cost may prohibit their use. However, rivaroxaban and apixaban may be free for the first 30 days (check out the Xarelto and Eliquis websites for details). Patients with active malignancy, large or massive PE, thrombophilia, renal or hepatic disease, thrombocytopenia, risk for bleeding, and pregnancy should be treated initially with heparin. [1,11,18,24] Patients must be able to adhere to the regular dosing regimen due to the short medication half-life.
HOW CAN YOU ASSESS BLEEDING RISK?
When considering anticoagulation and outpatient therapy in patients with acute PE, another factor is the risk of bleeding. Major bleeding can occur in 3% of patients with up to a 10-fold increase in risk in those on anticoagulation (though this risk is mainly associated with heparin and warfarin). [11,18,24-26] NOACs demonstrate a significantly lower risk of bleeding, [12-18] but there are factors that increase risk of major hemorrhage—particularly age, comorbidities, and other medications.
The HAS-BLED score is shown in Table 3. [26,27] It was originally derived from the Euro Heart survey evaluating risk of hemorrhage in patients with atrial fibrillation.  MDCalc provides a great summary on mdcalc.com. A score of one or less is low risk for bleeding, two warrants consideration of anticoagulation with moderate risk of bleeding, and three or greater is high risk (consider alternative to anticoagulation). [26,27] A score of one predicts approximately a 3.4% chance of major hemorrhage, which increases to greater than 5% with those scoring higher than three. [26,27] However, this score has primarily been studied for use in atrial fibrillation and older anticoagulants, not VTE or NOACs. The score is easy to use and does demonstrate ability to predict major hemorrhage.
Another score used in patients with VTE is the Outpatient Bleeding Risk Index (again assessed in heparin and warfarin), shown in Table 4. [28-30] Zero points is low risk, 1-2 is moderate, and > 3 is high. Patients in the low risk group demonstrate 3% risk of bleeding, though patients categorized as high risk may demonstrate bleeding in 30% of cases. [28-30] These scores should be used for those with significant comorbidities when determining the safety of outpatient therapy. The higher the points on each score, the more consideration is needed regarding whether the patient should be started on anticoagulation, and as we will see in the next section, bleeding risk is a component on assessing the need for admission.
We’ve discussed several key factors in the evaluation and management of PE as an outpatient, along with NOACs. With all this information, here is an easy, step-by-step process to evaluate whether the patient in front of you is safe for home therapy. [10,31,32]
1. Does the patient have confirmed PE? If yes, continue down this approach.
2. Is the patient hemodynamically stable? If not, the patient needs admission.
3. Is there evidence of end-organ dysfunction or RV strain, whether by biomarker and/or US? If the patient does have signs of end-organ dysfunction, admission is needed, as this suggests submassive PE.*
4. Does the patient have unstable comorbidities requiring O2, IV medications, or social reasons for admission? If yes, then admission is recommended.
5. Is the patient at high risk for bleeding (HASBLED or Outpatient Bleeding Risk Index)? If yes, admission may be needed.
6. If outpatient treatment is appropriate, consider NOAC therapy versus standard heparin and VKA therapy. Comorbidities (renal disease, liver disease, thrombocytopenia, malignancy) and pregnancy are potentially prohibitive for NOAC therapy.  Importantly, follow up is essential for these patients with PE. The best approach is a clinical pathway developed with hospital services, such as hematology, primary care, hospitalist, and internal medicine.
8. Ensure the patient agrees with the plan and discuss with the patient the need to return to the ED for worsening shortness of breath (at rest or with exertion), syncope, worsening chest pain, or any other concern.
*Ultrasound may provide further risk stratification, but it is not absolutely necessary for risk stratification. It allows physicians to evaluate for RV strain, which suggests submassive PE. The ESC incorporates US and biomarkers in risk stratification. 
You come back to the patient after going through your steps, and the patient again states she wants to go home. She is low risk for bleeding and has no other red flags on the Outpatient Bleeding Risk Index or the HAS-BLED score. The patient’s insurance will cover rivaroxaban, and fortunately her primary care physician is still in his office when you contact him. He agrees to see the patient in two days and agrees with your plan.
You write for her NOAC, carefully go over the dosing regimen, and discharge her home with strict return precautions. Note: For a more in-depth discussion of the controversies associated with outpatient PE therapy, risk scores, NOACs, and an algorithm, please see the Journal of Emergency Medicine’s article-in-press: Long B, Koyfman A. Best Clinical Practice: Controversies in Outpatient Management of Acute Pulmonary Embolism. JEM 2017; article in press. DOI: dx.doi.org/10.1016/j.jemermed.2016.11.020
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