Comparison of Oral Anticoagulants for Extended VEnous Thromboembolism (COVET)

1. Request for PCORnet Collaborators:Comparison of Oral Anticoagulants for extended VEnousThromboembolism (COVET) Lana Castellucci, David Garcia, and Thomas L. Ortel

2. Background • LOI/Application Due Date • Accepting site requests at this time; planned date for enrollment of first patient is 1 October 2017 • Seeking interest from investigators at CDRNs for participation in a research study to answer the following questions: • In patients who have completed 3-12 months of anticoagulation for acute venous thromboembolism (VTE) and need prolonged therapy, are the direct oral anticoagulants rivaroxaban and/or apixaban superior to warfarin?

3. Background • The minimal duration of anticoagulant therapy for an acute, unprovoked VTE is 3-6 months • Recurrent VTE occurs in up to 10% of patients in the first year after stopping anticoagulant therapy • The annual risk of major bleeding in patients who continue anticoagulant therapy is ~2% • Guidelines recommend continuing anticoagulation long-term if the risk for bleeding is “low” • Next crucial question: which anticoagulant is best?

4. Study Objectives • For patients who have completed an initial 3-12 months of oral anticoagulant therapy for an acute, symptomatic VTE, who are continuing anticoagulant therapy, this study will: • Determine if apixaban is superior to warfarin in the reduction of clinically relevant bleeding • Determine if rivaroxaban is superior to warfarin in the reduction of clinically relevant bleeding • Determine if apixaban is non-inferior to warfarin in the prevention of recurrent VTE • Determine if rivaroxabanis non-inferior to warfarin in the prevention of recurrent VTE • A secondary objective is the comparison of apixaban vs rivaroxaban for the prevention of clinically relevant bleeding and recurrent VTE

5. Additional Aims • To engage patient groups and stakeholders to evaluate the burden of warfarin use (laboratory monitoring, drug/food interactions, frequency of dose adjustment, etc), and DOAC use (once vs. twice daily) • To assess adherence to medication

6. Study Design: Patient Population • Inclusion criteria: • Adult patients, age 18 years or older • Confirmed symptomatic and unprovoked DVT/PE • Initial treatment with 3-12 months of oral anticoagulant • Considered by their primary provider to be at high risk of recurrent VTE • Exclusion criteria: • CrCl < 30 mL/min • Liver disease • Strong P-glycoprotein or CYP3A4 inducers/inhibitors • Life expectancy < 3 months

7. Study Design: Treatment Regimens & Follow-up • Patients are randomized to one of three treatment options: • Warfarin, INR 2-3 • Rivaroxaban, 20 mg daily • Apixaban, 2.5 mg twice daily • Initial Encounter (site activities) • Obtain consent and release of information form for any potential outcome events during the study period • Obtain demographic information and patient history • Obtain medication history and review for any contraindicated medications at baseline • Initial physical examination

8. COVET Trial Design • Follow-Up • Study participants will be followed for 12 months via structured telephone interviews at 1, 6, and 12 months • Follow-up calls will be conducted through a centralized Call Center • PROBE (Prospective Randomized Open Blinded End-point) • All outcome events centrally adjudicated by a blinded adjudication committee

9. Collected Information & Outcome Measures • Primary Safety Endpoint • Clinically relevant bleeding • Major bleeding • Clinically relevant non-major bleeding • Primary Efficacy Endpoint • Recurrent VTE

10. Collaboration with PCORnet Investigators and Sites • Explain your need from each collaborating site • Identification and screening of potentially eligible patients for study participation • Obtain informed consent on eligible patients who agree to participate and contact information for follow-up • Collect initial visit data (Call Center will take care of all follow-up data collection) • Specify short term and long term expectations from the collaborating investigator/sites. • We are asking each site to enroll a total of ~50 patients during the study enrollment period (~3 years)

11. Benefits for Participating Sites • Participation in a clinical trial that will address a question that is important to patients on indefinite anticoagulant therapy following an unprovoked venous thromboembolic event • The site investigator at each participating institution that enrolls patients into the study will be included as a co-author on the primary manuscript as the COVET Investigators

12. Questions?