XARELTO®: Clinical trials for initial treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE)
Proven clinical outcomes in dedicated DVT/PE trials1-4
EINSTEIN DVT/PE trial design: Randomized, phase 3, multicenter, open-label, parallel-group, active-controlled, event-driven, noninferiority studies (EINSTEIN DVT and EINSTEIN PE) with patients receiving XARELTO® at an initial dose of 15 mg twice daily with food for the first 3 weeks, followed by XARELTO® 20 mg once daily with food or enoxaparin 1 mg/kg twice daily for at least 5 days with VKA, then VKA only after target INR (2.0-3.0) was reached. Patients were included with a DVT if they had acute, symptomatic, objectively confirmed proximal DVT, without symptomatic PE and were included with a PE if they had acute, symptomatic PE with objective confirmation, with or without symptomatic DVT. Patients were treated for 3, 6, or 12 months at HCP discretion.
Primary outcomes: The primary efficacy outcome was symptomatic, recurrent fatal or nonfatal PE or DVT and the principal safety outcome was clinically relevant bleeding, defined as a composite of major and clinically relevant nonmajor bleeding. Bleeding was defined as major if it was clinically overt and associated with a decrease in hemoglobin level of ≥2 g/dL; if bleeding led to the transfusion of ≥2 units of red cells; or if bleeding was intracranial or retroperitoneal, occurred in another critical site, or contributed to death. Clinically relevant nonmajor bleeding was defined as overt bleeding that did not meet the criteria for major bleeding but was associated with medical intervention, unscheduled contact with the physician, interruption or discontinuation of the study drug, or discomfort or impairment of activities of daily life.
Trial design: A prospective, multicenter, single-arm, investigator-initiated, and academically sponsored management trial to investigate the efficacy and safety of early transition from hospital to ambulatory treatment in low-risk acute PE (identified through a modified Hestia criteria) in patients taking XARELTO® (15 mg twice daily for the first 3 weeks, followed by 20 mg once daily for at least 3 months). At the discretion of the treating physician for patients with CrCl >50 mL/min, a reduced maintenance dose (15 mg once daily) was prescribed if the individual risk for bleeding was deemed to outweigh the risk for recurrent VTE. A total of 4 patients received the reduced dose.
Primary outcomes: The primary outcome was symptomatic recurrent VTE or PE-related death within 3 months of enrollment. Safety outcomes were major bleeding (defined by ISTH criteria), clinically relevant nonmajor bleeding, and serious adverse events.
Trial design: Randomized, multicenter, open-label, parallel-group study of patients with low-risk PE admitted to the ED. Low-risk PE was determined by the absence of Hestia criteria, and is not meant to replace clinical judgment. Patients were randomized in a 1:1 ratio at early discharge to open-label XARELTO® (15 mg twice daily for 21 days and then 20 mg once daily to study completion) or SOC (per local protocol, which could include hospitalization and any FDA-approved anticoagulant strategy, including XARELTO®). Patients taking XARELTO® who were discharged early were discharged within 24 hours of ED triage. Patients receiving SOC were treated per protocol, which could include hospitalization or any FDA-approved anticoagulant therapy, including XARELTO®.
Primary efficacy outcome: Total time spent in the hospital for DVT/PE or bleeding events 30 days post randomization.
Limitations: The sample size was decreased due to slower than anticipated enrollment and unanticipated funding limitations, though the primary endpoint was met. The unexpectedly large effect size is most likely the result of practice differences in the rates of ED PE discharge in the United States compared with European studies used for its prediction. Also, ED physicians could exclude patients based on a subjective evaluation of hemodynamic stability and their impression of the patient’s ability to adhere to the protocol. Additionally, the use of an endpoint committee did not eliminate potential bias because a patient would know their admission status and could not be blinded to their assigned cohort. Though some may consider the fact that 75% of the control group were discharged on a DOAC as a limitation, and that randomization alone may have contributed to group differences, this reflects current ED practice patterns. Finally, the pragmatic nature of the trial called for the physician to define SOC, which may have contributed to bias to the null.
*The decision regarding initiation setting should be based on the prescriber's clinical judgment.
CrCl = creatinine clearance; DOAC = direct oral anticoagulant; DVT = deep vein thrombosis; ED = emergency department; HCP = healthcare professional; INR = international normalized ratio; ISTH = International Society on Thrombosis and Haemostasis; PE = pulmonary embolism; SOC = standard of care; VKA = vitamin K antagonist; VTE = venous thromboembolism.