Determining the best therapy options for patients with lower extremity issues.
Case: A 43-year-old female presents with right lower extremity swelling one week after an overseas plane flight. She has normal vital signs and her right lower extremity displays significant edema and redness. An ultrasound displays a DVT. Does she need admission for anticoagulation? What options do you have for therapy?
Look back a couple years into our therapy for deep venous thrombosis (DVT) and you see almost everyone treated with subcutaneous low molecular weight heparin (LMWH) with bridging with an oral vitamin K antagonist (VKA) until therapeutic. This isn’t always completed in the hospital, and outpatient therapy with LMWH and outpatient VKA bridging is safe.(1,2) Unfortunately, starting this treatment regimen requires extensive patient education, access to medications for home, regular subcutaneous injections and routine follow up for laboratory monitoring.(3,4) It also significantly affects patient diet and the administration of other medications due to interactions with warfarin.(3,4)
What about direct oral anticoagulants, DOACs, otherwise known as NOACs? There are two types: direct thrombin inhibitors (dabigatran) and factor Xa inhibitors (apixaban, edoxaban and rivaroxaban).(5,6) The new ACEP Clinical Policy on evaluation and management of patients with suspected acute venous thromboembolic disease (VTE) directly address DOACs for treatment of DVT.(6)
The next question of the policy asks: In adult patients diagnosed with acute lower extremity DVT who are discharged from the ED, is treatment with a NOAC safe and effective compared with treatment with LMWH and VKA?
ACEP and the American College of Chest Physicians (ACCP) 2016 guidelines support use of DOACs in the outpatient setting.(6,7) These guidelines recommend that in patients with proximal DVT or PE with no malignancy, treatment with a DOAC for three months over VKA therapy is recommended.(7) They also recommend treatment for three months in patients with a nonsurgical, transient risk factor or if in association with surgery. If the DVT is unprovoked, at least three months of therapy is recommended.(7)
How can DOACs change our management? Using these medications can reduce in-hospital admissions (and inpatient complications such as infection), costs and crowding. They can decrease need for follow up, improve patient satisfaction (no need for those pesky LMWH injections) and better use of resources.(5,6) DOACs can be expensive and anticoagulation reversal was previously a potentially difficult venture.(5,6)
Fortunately, several agents have demonstrated promise, and JAMA released a clinical guidelines synopsis in May 2018 detailing reversal of oral anticoagulants.(8) For patients taking apixaban, edoxaban or rivaroxaban who require reversal, intravenous (IV) 4 factor PCC (4F-PCC) or activated PCC is recommended. For dabigatran, IV idarucizumab or IV 4F-PCC/activated PCC is recommended.(8) Andexanet alfa has been approved by the FDA for urgent reversal of rivaroxaban and apixaban.(9)
With this potential for benefit, are DOACs safe and efficacious? On what literature does the ACEP clinical policy base its recommendations? Fortunately, a significant number of studies have suggested efficacy for treatment of DVT. One multicenter study evaluated patients with VTE (both pulmonary embolism and DVT) undergoing treatment with rivaroxaban.
Seventy-one patients (68%) had DVT, while five patients (3%) had both PE and DVT.(10) Of the 271 patients, 39% were low risk and discharged from the ED, which represented over half of new DVT cases. No patients experienced a recurrent VTE over six months, and no patients experienced a significant bleeding event.(10) Three patients experienced a recurrent DVT after stopping therapy, and unfortunately, patients did not undergo randomization (increasing risk of bias).(10)
The EINSTEIN study was one of the first evaluating DOAC therapy for DVTs.(11) This noninferiority study randomized patients to oral rivaroxaban versus traditional therapy, finding rivaroxaban therapy was noninferior for recurrent VTE (2.1% versus 3% when compared to traditional therapy) and a major bleeding event (8.1% versus 8.1%).(11) The AMPLIFY study evaluated 5,395 patients randomized to apixaban or standard therapy, with 65% of patients having an isolated DVT.(12) Again, patients receiving apixaban had a 2.3% recurrent rate, versus 2.7% in standard therapy, with reduced rate of bleeding in the apixaban group (0.6% vs. 1.8%).(12)
The Hokusai-VTE study evaluated edoxaban versus VKA therapy, with 8,292 enrolled patients.(13) This study differs in that all patients received parenteral anticoagulation for five days. Patients receiving edoxaban demonstrated similar rate of recurrent VTE to warfarin (3.4% vs. 3.3%), but the edoxaban group demonstrated fewer bleeding events (8.5% vs. 10.3%).(13) The RE-COVER trial evaluated dabigatran against warfarin for six months, with 69% of patients with isolated DVT.(14) Dabigatran was noninferior for recurrent VTE and bleeding.(14)
Finally, there are a number of meta-analyses evaluating DOAC therapy.(15-18) These have found no difference in rate of recurrent VTE in DOACs versus traditional therapy, but there may be reduced risk of bleeding, including both direct thrombin inhibitors and oral factor Xa inhibitors, when compared with standard therapy.(15-18)
So, it appears DOACs are safe and efficacious. However, what do you need to know when using these medications? Outpatient therapy is possible in patients who can follow up, do not possess any of the contraindications for therapy, are at low risk of bleeding and can obtain their medications.(5,7) Treatment for at least three months is recommended in patients with unprovoked DVT.(5,7) Rivaroxaban and apixaban do not require bridging with parenteral anticoagulation such as heparin. These medications can be expensive, which may prohibit their use.
Rivaroxaban and apixaban can be free for the first 30 days (see https://www.xarelto-us.com/carepath/savings-program and https://www.eliquis.com/eliquis/hcp/patient-offers-resources). Patients with active malignancy, thrombophilia, renal or hepatic disease, thrombocytopenia, risk for bleeding and pregnancy should be treated initially with heparin.(5,7,19,20) It is also important for patients to take the medication as prescribed and not miss a dose, as these medications are rapidly metabolized.(5,7,20) Rivaroxaban should be taken with food.
Table – DOAC Summary
|Medication||Rivaroxaban (Xarelto®)||Apixaban (Eliquis®)||Edoxaban (Savaysa®)||Dabigatran (Pradaxa®)
|Mechanism||Factor Xa inhibitor||Factor IIa inhibitor|
|Dose||15 mg twice daily for 21 days, then 20 mg once daily||10 mg twice daily for 7 days, then 5 mg twice daily||60 mg once daily||150 mg twice daily|
|Notes||– Caution warranted in those on medications affecting cytochrome P450 3A4 or p-glycoprotein.
– NOACs should be avoided in patients with severe renal or liver disease, those who cannot comply with consistent dosing, recent bleeding and platelets < 70,000/mm3.
– Cost may be prohibitive for long-term therapy, though there are options for a free 30-day supply.
– Patients with cancer should be provided heparin over NOACs (ACCP Grade 2B recommendation).
Case Conclusion: The patient has an isolated proximal DVT and normal renal function. She desires discharge home and she states she is able to follow up with her primary physician. You prescribe rivaroxaban, which does not require parenteral anticoagulation.
– DOACs are safe and efficacious for DVT therapy, even in the outpatient setting.
– ACEP and ACCP guidelines support DOAC use in the outpatient setting.
– DOACs include oral factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) and direct thrombin inhibitors (dabigatran).
– DOACs demonstrate similar efficacy and reduced risk of bleeding compared to standard therapy including LMWH and VKA.
- Lozano F, Trujillo-Santos J, Barrón M, et al. Home versus in-hospital treatment of outpatients with acute deep venous thrombosis of the lower limbs. J Vasc Surg. 2014;59:1362-1367.e1.
- Othieno R, Abu Affan M, Okpo E. Home versus in-patient treatment for deep vein thrombosis. Cochrane Database Syst Rev. 2007;(3):CD003076.
- Akinwunmi F. Common concerns of warfarin patients. Pharmaceutical Journal. Published 1 Sep 2011. Available at https://www.pharmaceutical-journal.com/learning/learning-article/common-concerns-of-warfarin-patients/11083381.article?firstPass=false
- Pirmohamed M. Warfarin: almost 60 years old and still causing problems. British Journal of Clinical Pharmacology. 2006;62(5):509-511.
- Pollack C. New oral anticoagulants in the ED setting: a review. Am J Emerg Med. 2012;30:2046–54.
- Clinical Policy: Critical Issues in the Evaluation and Management of Adult Patients Presenting to the Emergency Department With Suspected Acute Venous Thromboembolic Disease. Ann Emerg Med. 2018;71:e59-e109.
- Kearon C, Akl EA, Ornelas J, Blaivas A, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016;149:315–52.
- Anderson I, Cifu AS. Management of bleeding in patients taking oral anticoagulants. JAMA 2018 May;319(19):232-3.
- From The Medical Letter on Drugs and Therapeutics. Andexxa—An Antidote for Apixaban and Rivaroxaban. JAMA.2018;320(4):399-400.
- Beam DM, Kahler ZP, Kline JA. Immediate discharge and home treatment with rivaroxaban of low-risk venous thromboembolism diagnosed in two US emergency departments: a one-year preplanned analysis. Acad Emerg Med. 2015;22:789-795.
- Bauersachs R, Berkowitz SD, Brenner B, et al; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499-2510.
- Agnelli G, Buller HR, Cohen A, et al; for the AMPLIFY investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369:799-808.
- Büller HR, Décousus H, Grosso MA, et al; the Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369:1406-1415.
- Schulman S, Kearon C, Kakkar AK, et al; for the RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361: 2342-2352.
- Robertson L, Kesteven P, McCaslin JE. Oral direct thrombin inhibitors or oral factor Xa inhibitors for the treatment of deep vein thrombosis. Cochrane Database Syst Rev. 2015;(6):CD010956.
- Cohen AT, Hamilton M, Mitchell SA, et al. Comparison of the novel oral anticoagulants apixaban, dabigatran, edoxaban, and rivaroxaban in the initial and long-term treatment and prevention of venous thromboembolism: systematic review and network meta-analysis. PLoS One. 2015;10:e0144856.
- Kang N, Sobieraj DM. Indirect treatment comparison of new oral anticoagulants for the treatment of acute venous thromboembolism. Thromb Res. 2014;133:1145-1151.
- Di Minno MN, Lupoli R, Di Minno A, et al. Effect of body weight on efficacy and safety of direct oral anticoagulants in the treatment of patients with acute venous thromboembolism: a meta-analysis of randomized controlled trials. Ann Med. 2015;47:61-68.
- Loffredo L, Perri L, Del Ben M, et al. New oral anticoagulants for the treatment of acute venous thromboembolism: are they safer than vitamin K antagonists? A meta-analysis of the interventional trials. Intern Emerg Med. 2015;10:499–506.
- Hayes B. Pharmacology of Venous Thromboembolism. ALIEM U Capsules. February 2017. https://www.aliemu.com/modules/pharmacology-of-venous-thromboembolism/. Accessed June 2018.