AntiCoagulants and COGnition (ACCOG)

AntiCoagulants and COGnition (ACCOG Trial): a Single-blind Randomized Controlled Trial Comparing the Neurocognitive Effects of Rivaroxaban Versus Vitamin K Antagonist

The purpose of this study is to compare the change of global cognitive performance after 52 weeks of intervention among participants with nonvalvular atrial fibrillation (NVAF) receiving rivaroxaban versus a vitamin K antagonist (warfarin).

The secondary objectives are to compare, among participants with NVFA receiving rivaroxaban versus warfarin :

• the changes of global cognitive performance after 26 weeks of intervention
• the changes of executive functions after 26 and 52 weeks of intervention
• the changes of episodic memory after 26 and 52 weeks of intervention
• the changes of independence and autonomy after 26 and 52 weeks of intervention

Study Overview

• Status: Recruiting
• Conditions: Nonvalvular Atrial Fibrillation
• Intervention / Treatment: Drug: Rivaroxaban 20 MG; Drug: Warfarin

Detailed Description

Detailed Description:

Vitamin K antagonists (VKAs) are commonly used for their role in hemostasis by interfering with vitamin K cycle decreasing the bioavailability of the vitamin K active form. In addition to a role in blood coagulation, vitamin K participates in brain health and function by regulating the synthesis of sphingolipids, a constituent of the myelins sheath and the neurons membrane, and through the biological activation of vitamin K-dependent proteins (VKDPs) involved in neuron survival. Epidemiological studies have reported a positive association between higher serum vitamin K concentration and better verbal episodic memory performance in older adults, and an inverse association between dietary vitamin K intakes and behavioural disorders and cognitive complaint. The clinical implication is that the use of VKAs, which deplete the active form of vitamin K, may be responsible for Central Nervous System (CNS) disorders.

CNS abnormalities were observed in newborns exposed in utero to VKA. Similarly, the investigators and other researchers reported that the use of VKAs (especially fluindione) was directly associated with cognitive decline (notably executive dysfunction) and hippocampal atrophy in older adults, even while taking into account the history of atrial fibrillation, stroke and vascular brain changes. These cross-sectional and longitudinal studies were yet limited by their observational design. Clinical trials are now warranted to explore the effect on cognition of VKAs against direct oral anticoagulants (DOACs), whose indications are similar but whose mechanism does not interfere with vitamin K. The favorable impact of the use of DOACs compared to VKA in the incidence of dementia was also observed in a US retrospective population-based study of patients managed per routine clinical care.

The investigators hypothesize that VKAs have a deleterious impact on cognition and brain morphology compared to DOACs, due to the decrease in vitamin K bioavailability. A review of the published clinical trials comparing the effects of VKAs and DOACs, especially rivaroxaban, shows that cognition and brain volume were not assessed as outcomes in these trials.

• Study Type: Interventional
• Enrollment (Anticipated): 48
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Cédric ANNWEILER, MD, PhD; Phone Number: +33 2 41 35 54 86; Email: cedric.annweiler@chu-angers.fr

Study Locations

• France
  • Angers, France, 49933 cedex 9
    • Recruiting
    • Angers University Hospital
    • Contact: Cédric ANNWEILER, MD, PhD; Phone Number: +33 2 41 35 47 25; Email: cedric.annweiler@chu-angers.fr
    • Principal Investigator: Cédric ANNWEILER, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 70 years and older (Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Men or women ≥ 70 years old
• Newly diagnosed hemodynamically stable NVAF longer than 52 hours or of unknown duration, and CHA2DS2-VASc score according to ESC 2016 guidelines for anticoagulation treatment indications
• MMSE score ≥ 20
• Subjects who can give written consent to participate in the study
• Affiliation to a social security scheme.

Exclusion Criteria:

• Known history of stroke and/or a diagnosed condition of dementia (DSM-IV criteria) and/or severe depressive symptomatology (score on the 4-item Geriatric Depression Scale > 3)
• Moderate or severe mitral stenosis
• Conditions other than NVAF that require anticoagulation
• Use of anticoagulant more than 3 days at inclusion or more than 15 days in the preceding 12 months
• Regular use of antiplatelet medications and/or nonsteroidal anti-inflammatory agents and/or azole class of antifungal agents and/or inhibitor of HIV protease
• Acute thromboembolic events or thrombosis (venous/arterial) within the last 14 days prior to randomization
• Known presence of cardiac thombus or myxoma or valvular atrial fibrillation
• Any contraindication to anticoagulation, high risk of bleeding, and any other contraindication listed in the local labeling for the experimental treatment and comparator treatment
• Unstable health, severe hepatic failure, or severe and moderate renal failure (creatinine clearance <50 mL/min), acute coronary syndromes
• Participation in another simultaneous clinical trial
• Inability to understand and speak French
• Refusal to participate from the participant
• Persons deprived of their liberty by administrative or judicial decision, persons under psychiatric care under duress, adults subject to a legal protection measure or unable to express their consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Supportive Care
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: "Intervention" group	Drug: Rivaroxaban 20 MG; Rivaroxaban intake, 20mg/day
Active Comparator: "Control" group	Drug: Warfarin; Warfarin intake, with target INR range between 2 and 3

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in global cognitive performance	Global cognitive performance is assessed with Alzheimer's Disease Assessment Scale-cognition score (ADAS-cog). Total scores range from 0-70, with higher scores (≥ 18) indicating greater cognitive impairment.	This outcome is assessed at baseline, 26 and 52 weeks after inclusion.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in executive functions	Executive functions are assessed with Frontal Assessment Battery score (FAB).	This outcome is assessed at baseline, 26 and 52 weeks after inclusion.
Change in executive functions	Executive functions are assessed with digit spans.	This outcome is assessed at baseline, 26 and 52 weeks after inclusion.
Change in executive functions	Executive functions are assessed with Trail Making Tests (TMT) parts A and B.	This outcome is assessed at baseline, 26 and 52 weeks after inclusion.
Change in executive functions	Executive functions are assessed with Stroop test.	This outcome is assessed at baseline, 26 and 52 weeks after inclusion.
Change in executive functions	Executive functions are assessed with the Processing Speed Index.	This outcome is assessed at baseline, 26 and 52 weeks after inclusion.
Change in episodic memory	Episodic memory is assessed with Five-word test. The 5-word test studies the recall of a short list. The score of the first immediate recall and the score of the delayed recall should normally be equal to 10.	This outcome is assessed at baseline, 26 and 52 weeks after inclusion.
Change in independence and autonomy	Independence and autonomy are assessed with Activities of Daily Living (ADL) score. ADL is an autonomy assessment grid (from 0 to 6) for basic activities of daily living (ADL). The lower the score, the more dependent the patient is.	This outcome is assessed at baseline, 26 and 52 weeks after inclusion.
Change in independence and autonomy	Independence and autonomy are assessed with the 4-item Instrumental Activities of Daily Living (IADL-PAQUID) score. This test is used to assess the level of dependence in instrumental activities of daily living. The scale ranges from 0 to 4, with 0 indicating total dysautonomy and 4 indicating a totally autonomous person.	This outcome is assessed at baseline, 26 and 52 weeks after inclusion.

Collaborators and Investigators

• Sponsor: University Hospital, Angers
• Collaborators: Bayer

Study record dates

Study Major Dates

• Study Start (Actual): February 13, 2020
• Primary Completion (Anticipated): February 1, 2023
• Study Completion (Anticipated): February 1, 2023

Study Registration Dates

• First Submitted: August 26, 2019
• First Submitted That Met QC Criteria: August 27, 2019
• First Posted (Actual): August 29, 2019

Study Record Updates

• Last Update Posted (Actual): July 27, 2022
• Last Update Submitted That Met QC Criteria: July 25, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Rivaroxaban; Warfarin
• Other Study ID Numbers: 2019-000794-23

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No