COMPARISON OF NEW TO AND LOW-MOLECULAR-WEIGHT

A resource guide provided by Symbria Rx Services 7125 Janes Avenue Woodridge, Illinois

July 2014

Copyright © 2014 by Symbria, Inc.

Three new oral anticoagulants have been marketed recently that will compete with the traditional anticoagulants of warfarin and low-molecular-weight heparin (LMWH). Medications included as LMWH are enoxaparin and dalteparin. The new agents are apixaban (Eliquis), (Pradaxa), and (Xarelto). Their mechanisms of action involve direct inhibition of clotting factors (factor-Xa with apixaban and rivaroxaban, with dabigatran). In terms of efficacy and safety, the new agents are comparable to warfarin and LMWH. Therefore, selection of the most appropriate medication will be guided by other considerations as outlined below. • Indications for use: 1) For prophylaxis of thromboembolism post-hip/knee surgery, both apixaban and rivaroxaban can be used in place of LMWH. They are typically administered for 12 days post-knee, or 35 days post-hip. Dosing/conversion for this indication: apixaban 2.5mg twice daily (BID) (if converting from LMWH start at the time the next dose of LMWH is due); rivaroxaban 10mg daily (if converting from LMWH start at the time the next dose of LMWH is due). 2) To prevent thromboembolic in non-valvular patients, apixaban, dabigatran, and rivaroxaban can be used instead of warfarin therapy. For this indication, they are typically administered long term. Dosing/conversion for this indication: apixaban 5mg BID (if converting to apixaban from existing warfarin therapy, start when international normalized ratio (INR) is below 2); dabigatran 150mg BID (if converting to dabigatran from existing warfarin therapy, start when the INR is below 2); rivaroxaban 20mg daily with food (if converting to rivaroxaban from existing warfarin therapy, start when the INR is below 3). 3) For treatment/prevention of or pulmonary (DVT/PE), dabigatran or rivaroxaban or can be used as an alternative to LMWH therapy followed by warfarin. For this indication treatment would typically extend 3 months or longer. Dosing/conversion for this indication: dabigatran 150mg BID started after 5-10 days of LMWH (if converting to dabigatran from existing warfarin therapy, start when the INR is below 2); rivaroxaban 15mg BID with food x21 days, followed by 20mg once daily with food

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thereafter (if converting to rivaroxaban from existing warfarin therapy, start 20mg daily with food when the INR is below 3). Note: The new agents are not recommended for use in patients with prosthetic heart valves.

• Route of administration: All the new agents are given orally like warfarin, whereas LMWH must be given by subcutaneous injection. • Frequency of administration: Apixaban and dabigatran are given twice daily (BID). Rivaroxaban, like warfarin, is approved for once-daily administration (though rivaroxaban can be given BID for initial treatment of DVT/PE). LMWH injections can be either once or twice daily, depending on the clinical situation. • Renal dosing: For patients with renal dysfunction, all of the new agents have precautions for use. Depending on the degree of renal impairment, the new agents require either dosage reductions or are contraindicated. Warfarin therapy is minimally impacted by renal disease. LMWH agents require dosage modifications for renal impairment. • Lab monitoring: Warfarin requires regular INR monitoring (at least monthly, if stable). The new agents do not require INR monitoring, or any other anticoagulation test. Initial renal evaluation (serum creatinine), with periodic follow up, is all that is needed for the new agents. LMWH also needs renal monitoring, but no INRs. • : None of the new anticoagulants has an antidote for rapid reversal of anticoagulation. For warfarin, vitamin-K can be used to reduce INR. Protamine will partially reverse the effects of LMWH. • Diet: The new agents have no dietary restrictions. Warfarin therapy is sensitive to vitamin-K intake, and so dietary changes can result in INR fluctuations. LMWH is not impacted by diet. • Drug interactions: Though the new agents are involved in some drug- drug interactions, they generally have less to consider than warfarin (for which there are many interactions). The LWMH agents have a low incidence of drug interactions. • Cost: The new agents are more expensive than warfarin, but are similar in cost to LMWH. Generally, the monthly cost of the new anticoagulants is about $300 to $350, as compared to $50 per month for warfarin (including one INR per month). If the INR is not stable, lab costs will

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increase warfarin’s cost accordingly. The LMWH agents remain expensive, with cost varying widely depending on the dosage required. Based upon these factors, the patient’s physician will select which is best for the individual’s clinical situation. Some patients will benefit from the newer agents, while others will be better suited to the more traditional options of warfarin and LMWH.

Jeff Schrier, Pharm D/CGP

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