Dabigatran is an oral factor IIa inhibitor approved for reducing the risk of stroke and systemic embolism in patients with nonvalvular AF. This evidence is based on the Randomized Evaluation of Long-term Anticoagulant Therapy (RE-LY) trial, which was a multicenter, randomized, noninferiority trial evaluating the efficacy of 2 blinded fixed-dosage dabigatran regimens (150 or 110 mg administered orally twice daily) in comparison with open-label adjusted-dose warfarin (goal international normalized ratio, 2–3) in patients with the presence of > 1 risk factor for stroke (previous stroke or transient ischemic attack, a left ventricular ejection fraction of < 40%, New York Heart Association class II or higher heart failure symptoms within 6 months before screening, and an age of ≥ 75 years or an age of 65 to 74 years plus diabetes mellitus, hypertension, or coronary artery disease), and a diagnosis of nonvalvular AF within the past 6 months.1
Dabigatran is available in 75- and 150-mg capsules that contain pellets in a tartaric acid formulation. The capsules should not be opened or chewed because the bioavailability of dabigatran would be elevated approximately 75%, increasing the risk for dabigatran-associated bleeding. Therefore, dabigatran should not be administered to patients via nasogastric or other enteral feeding tubes.
The dose of dabigatran for patients with nonvalvular AF with a creatinine clearance (CrCl) > 30 mL/min is 150 mg orally twice daily. For patients with a CrCl of 15 to 30 mL/min, the dose is 75 mg orally twice daily. At our institution, we recommend not administering dabigatran to patients with a CrCl < 30 mL/min or if they have unstable renal function.
Rivaroxaban is an oral factor Xa inhibitor approved for reducing the risk of stroke and systemic embolism based on the Rivaroxaban-Once Daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF trial), which was a multicenter, randomized, double-blind, double-dummy, noninferiority trial.2 It compared the efficacy of rivaroxaban administered as a once-daily, 20-mg oral dose with warfarin (dose titrated to a goal international normalized ratio of 2–3) in patients with nonvalvular AF who were determined to be at moderate to high risk of stroke (CHADS2 score ≥ 2). The Regulation of Coagulation in Orthopaedic Surgery to Prevent Deep Vein Thrombosis and Pulmonary Embolism (RECORD) trials were randomized, double-blind, noninferiority trials comparing rivaroxaban with enoxaparin in patients undergoing total hip or knee arthroplasty.3-6 These studies served as the basis for the approval of rivaroxaban.
Rivaroxaban is available in 10-, 15-, and 20-mg tablets. Patients with nonvalvular AF and a CrCl > 50 mL/min should receive 20 mg orally once daily. However, patients with a CrCl of 15 to 50 mL/min are treated with 15 mg orally once daily. This agent should not be used in patients with a CrCl < 15 mL/min.
Patients undergoing total hip or knee arthroplasty received prophylaxis with rivaroxaban 10 mg beginning 6 to 10 hours postoperatively. Patients with a CrCl < 30 mL/min should not receive rivaroxaban for VTE prevention because of the risk for major bleeding. The treatment duration for total hip arthroplasty is 35 days, while in total knee arthroplasty, only 12 days are recommended. Rivaroxaban has a black box warning for an increased risk of stroke with discontinuation, and reported spinal hematomas occurring in patients receiving neuraxial anesthesia or spinal puncture in joint replacement surgery.
I believe that hospitals will have all of these agents on formulary because of the indications in clinical practice, especially AF, which can be treated with a number of these FDA-approved drugs. In addition, rivaroxaban will be added to low-molecular-weight heparins, unfractionated heparin, warfarin, and aspirin for VTE prophylaxis for joint replacement surgery. This agent will be followed by all of the other oral anticoagulants as they are FDA approved for this indication. Dabigatran and rivaroxaban will soon be approved by the FDA for the treatment of deep vein thrombosis and pulmonary embolism. This will add another indication for these new oral agents. It is now easy to understand the challenges facing hospital formularies across the country.
We decided that these new oral anticoagulants will be high-risk medications; therefore, additional processes will be in place to guide the use of these agents to improve therapeutic outcomes and minimize the potential for adverse events. The following are a few strategies that we have adopted at Thomas Jefferson University Hospitals.7
The new oral anticoagulants are restricted to particular hospital services that have in-depth knowledge of the medications and disease states, such as the hematology, cardiology, and vascular medicine departments.
A multidisciplinary team of clinicians and pharmacists have developed standards that serve as inclusion and exclusion criteria for appropriate patient selection for use of the new oral anticoagulants. At Thomas Jefferson University Hospitals, an algorithm is used once an order is placed for dabigatran or rivaroxaban (Figure 1). This approach ensures appropriate patient selection and medication dosing, as well as a verification of medication use. Institutions that use computerized physician order entry have the luxury of using information systems (ie, flags, alerts, algorithms) to facilitate proper usage.
Antithrombotic therapy stewardship algorithm.
After the new anticoagulants have been added to the formulary and restriction strategies have been identified, it is necessary to provide periodic reporting to the Pharmacy and Therapeutics Committee or relevant subcommittees. Reporting should include both quality and safety data. A drug utilization review may be performed as an assessment for the appropriate use of the new drugs as defined per institutional guidelines and inclusion/exclusion criteria. Adverse event reporting and management in terms of both minor and major bleeding are important safety measures that must be reported on a periodic basis.
Traditional anticoagulants, which require laboratory monitoring, force physicians to ensure appropriate hand-off from the inpatient to outpatient setting. Due to the complexities of managing warfarin and other agents, anticoagulation clinics have been established to safely manage patients who are taking these drugs. Despite the benefits of the new oral anticoagulants, a management program should be designed to ensure the appropriate care transition for patients receiving either dabigatran or rivaroxaban, and eventually the other agents from the inpatient to outpatient setting.
There are 3 major elements for establishing this care-transition program: education, follow-up care, and communication. Education, including written, oral, and electronic media explaining the new oral anticoagulants, is provided for the patient, family, and staff involved in the patient’s care. The second critical anchor is follow-up care. This step requires a phone call to the patient 48 hours following discharge and scheduling an appointment with the patient’s primary care physician or subspecialist in a 7- to 10-day timeframe after leaving the hospital. The final step is communication with the receiving physician through phone contact and written communication, which includes patient discharge instructions and a discharge summary.
The system for assessing the effectiveness of the care-transition program for patients receiving antithrombotic therapy must include the evaluation of the education program, confirmation of follow-up appointments and phone contact, and oral as well as written communication with the receiving physician. Therefore, documentation that education is provided and the effectiveness of the process are measured.
Clinics must confirm that the patient was contacted within 48 hours of discharge and scripted information was collected on the patient’s symptoms, including any new developments and medications. Follow-up appointments with the primary care physician or subspecialist are documented within the 7-day timeframe. Finally, the patient will receive verbal and written discharge instructions, which will include medication, testing during the hospitalization, and follow-up with the primary care physician or subspecialist. This communication will be documented both by phone record and discharge summary provided within 24 hours of leaving the hospital.
As clinical trials in multiple areas of thrombotic disease are completed and more oral anticoagulants are approved by the FDA, hospital formularies will expand the number of anticoagulants with different dosing schedules and no evidence of interchangeability; this proposes a risk for hospitals. Therefore, a well-designed, systematic team approach to formulary management will be mandatory.