Lead Investigator: Stefano Barco, University Medical Center Mainz
Title of Proposal Research: Differential effects of long-term treatment with warfarin vs. edoxaban on blood count parameters. A parallel posthoc analysis of the Hokusai VTE and Engage AF-TIMI-48 trials
Vivli Data Request: 4352
Funding Source: None
Potential Conflicts of Interest: None
Summary of the Proposed Research:
Approximately 1% of the general population receives a vitamin K antagonist (VKA) anticoagulant, warfarin, for the prevention and treatment of thromboembolic events, including venous thromboembolism and peripheral arterial embolism or stroke. Specifically, warfarin is able to reduce blood clotting by reducing the production of some clotting proteins, which is dependent on vitamin K. Beyond the effects on coagulation factors, it has been described that warfarin may influence the functioning of several systems and organs. For example, warfarin may be harmful to bone health and increase the risk of fractures if administered over the long-term (Lutsey et al., JAMA Internal Medicine, 2019). Moreover, warfarin may influence the expression of some proteins of the vascular wall (endothelium) and promote vascular calcification and atherosclerosis (Siltari A, Basic Clin Pharmacol Toxicol, 2018).
For the first time, the results of a recent study (Verma et al., Blood, 2019) suggested that VKA treatment may impair the function of the bone marrow. These experiments were conducted in animal models and provisionally confirmed in a case-control study in humans. In this study (Verma et al., Blood, 2019), it appeared that the proportion of individuals using VKA was higher among patients with versus without myelodysplastic syndrome, a group of conditions that are characterized by disturbances of the bone marrow function with reduction of one or more types of blood cells. Moreover, VKA use seemed to be associated with a modest reduction in some types of blood cells, such as leukocytes, monocytes and lymphocytes, even in the absence of myelodysplastic syndrome.
A possible negative effect of VKA on blood count parameters may affect treatment strategies, especially in patients who are supposed to receive VKA for several years. Therefore, this finding requires confirmation in the setting of longitudinal studies comparing the effects of a long-term administration of VKA warfarin therapy with that of one of the new direct non-VKA oral anticoagulant drugs, which are characterized by a completely different mechanism of action and, therefore, may not exert any influence on bone marrow function.
In the Hokusai VTE and Engage AF-TIMI-48 randomized controlled trials, more than 30,000 patients had been randomized to receive either warfarin or the new direct non-VKA oral anticoagulant edoxaban for periods of 3-12 months following a diagnosis of acute deep vein thrombosis or pulmonary embolism (Hokusai VTE) and up to 3 years for atrial fibrillation (Engage AF-TIMI-48). All patients underwent routine blood tests at predefined time points. Therefore, these studies would represent the optimal setting to study the effects of long-term treatment with warfarin vs. edoxaban on blood count parameters.
Requested Studies:
A Phase 3, Randomized, Double-Blind, Double-Dummy, Parallel Group, Multi-Center, Multi-National Study for Evaluation of Efficacy and Safety of Edoxaban (DU-176b) Versus Warfarin In Subjects With Atrial Fibrillation – Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation (ENGAGE – AF TIMI – 48) (EngageAFTIMI48)
Sponsor: Daiichi Sankyo
Study ID: NCT00781391
Sponsor ID: DU176b-C-U301
A Phase 3, Randomized, Parallel-Group, Multi-Center, Multi-National Study for the Evaluation of Efficacy and Safety of (LMW) Heparin/Edoxaban Versus (LMW) Heparin/Warfarin in Subjects With Symptomatic Deep-Vein Thrombosis (DVT) and or Pulmonary Embolism (PE).
Sponsor: Daiichi Sankyo
Study ID: NCT00986154
Sponsor ID: DU176b-D-U305