Rivaroxaban for the Treatment of Venous Thromboembolism

Student thesis: Doctoral ThesisDoctor of Philosophy


For many years, the standard treatment for acute venous thromboembolism (VTE) was vitamin K antagonists. In 2012, there was a paradigm shift in the treatment of acute VTE with the licensing of rivaroxaban, the first direct oral anticoagulant (DOAC) to become available for this indication. In the phase III studies, rivaroxaban was found to be as safe and effective as traditional therapies. This thesis, divided into two parts, investigates the use of rivaroxaban in routine care in an unselected population.

I) The aim of the FIRST registry was to report on the safety and efficacy of rivaroxaban in routine clinical care in the UK as well as to describe the extent of, and determinants of nonadherence to rivaroxaban in this population.
The primary outcomes were treatment emergent recurrent VTE and bleeding complications as well as all-cause mortality. In total 1262 patients were recruited from 22 different hospitals. The median duration of exposure was 135 days [IQR 84 – 307]. There were seven episodes of VTE recurrence (0.6%). A first major or clinically relevant bleeding event (MB or CRNMB) was reported by 79/1239 (6.4%), 8.66/100 pt. years (95% CI; 6.90 to 10.73). A higher incidence rate of MB or CRNMB was reported by women <50, compared with ≥50 relative risk 5.44 (95% CI; 2.97 to 9.97). Nonadherence was reported by 155/1030 (15%) of participants at least once during their treatment on rivaroxaban.

II) The aim of the second component was to derive a population (PK) model for rivaroxaban using data from routine clinical practice to evaluate which factors influence rivaroxaban exposure. A population PK model was developed using a non-linear mixed effects approach and then used to simulate rivaroxaban concentrations at the extremes of bodyweight. In total 913 patients contributed data to the final model developed (weight range 39kg-172kg). A one-compartment model with between-subject variability on clearance and a proportional error model best described the data. Creatinine clearance calculated by Cockcroft Gault, with lean body weight as the weight descriptor in this equation, was the most significant covariate influencing rivaroxaban exposure.

Overall this thesis demonstrates that, for the majority, rivaroxaban is safe and effective for the treatment of VTE. Women of childbearing age are at a greater risk of significant bleeding associated with rivaroxaban than older women and male patients and importantly, rivaroxaban can be prescribed at extremes of bodyweight.
Date of Award1 Mar 2022
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorJignesh Patel (Supervisor) & R. Ayra (Supervisor)

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