Vitamin K antagonist (VKA) therapy versus New Oral Anticoagulants (NOACs) therapy in patients with currently well controlled VKA therapy for non-valvular atrial fibrillation: a pilot study

Rationale:
Life-long anticoagulation is indicated for many patients with atrial
fibrillation (AF) to prevent embolic stroke. In the Netherlands in 2010,
225,000 patients received vitamin K antagonists (VKA) for this indication. This
number has been increasing by about 5% per year for the last
view years.
Yet, VKA therapy is challenging due to inter- and intra-individual variations,
which require frequent monitoring and dose adjustments. The efficacy and safety
of VKA therapy are strongly dependent on the achieved quality of
anticoagulation (i.e. the proportion of time that
a given patient is within the predefined therapeutic range, or *individual Time
in Therapeutic Range* (iTTR).
Recently, anticoagulant treatments have become available that are easier to
use. These NewOral Anticoagulants (NOACs; dabigatran and rivaroxaban) showed
non-inferiority for prevention of embolic stroke or systemic embolism and major
bleeding compared to warfarin.
A disadvantage of the NOACs is the higher costs. Introduction for all patients
would result in an increase of 78-156 million Euro in the Dutch pharmaceutical
budget annually. Before the general introduction of the NOACs, the advantages
must be weighed against the limitations.
This balance might be different for different categories of patients.
In the large registration trials, concerns were raised focusing on a low
achieved quality of anticoagulation in the control VKA group, and a possible
heterogeneity of the risk-benefit ratio in patients with different VKA control.
This means that the observed non-inferiority of
NOACs versus VKA might not be applicable to patients whom VKA is well
controlled. This has triggered concerns, as expressed in reports from the
Health Care Council and the Health Care Insurance Board of the Netherlands
(1,2). This is in particular relevant for the Dutch setting, in which VKA
treatment is managed by a well organized nation-wide network of Thrombosis
Services. As a result, in a large cohort of
Dutch patients, three quarter of AF patients achieved an iTTR that was
associated with good clinical outcome, both in terms of efficacy and safety.
Bad quality of VKA treatment was restricted to a subgroup of patients and not
randomly distributed over time. Presently, the relevant guidelines do not
endorse switching patients who are already on anticoagulants from VKA to NOACs.
However, it is anticipated that many providers and patients will switch to a
NOACs because of the ease of use, without taking quality of VKA treatment into
account. The three quarters of patients with adequate controlled VKA might not
benefit from such a switch to NOACs. We hypothesize that, in patients in whom
adequate quality of anticoagulation is achieved, VKA therapy is superior to
NOACs, in terms of net clinical benefit as well as cost-effectiveness

Objectives:
To collect data on effect size for, and determine the feasibility of, a full
scale multicentre RCT
(Randomized Controlled Trial) that
1. compares the efficacy and safety of NOACs with VKA treatment according to
Dutch
standards, in VKA-experienced patients with currently well controlled VKA
therapy, in
the Dutch real-life setting
2. compares differences in treatment satisfaction, compliance and quality of
life between
NOACs and VKA treatment.

A randomized (1:1) controlled open-label two-center study comparing VKA versus
NOACs in 240 patients with currently well controlled VKA therapy for
non-valvular AF.

Intervention:
Patients randomized to receive VKA will continue their treatment according to
usual care, managed by the Thrombosis Service using a therapeutic range of INR
2.0-3.5. Patients randomized to NOACs will be instructed on the use of NOACs,
and followed as per usual care

We will compare two registered treatment modalities; therefore we expect no
extra risks associated with participation in this study compared to regular
treatment. A data safety monitoring board will review the study after every 20
clinical events that qualify as study endpoints. The study will include 3 extra
visits (randomization, 6 months and 12 months). During these visits patients
will be asked to report on events and other
relevant medical information and to fill in 2 questionnaires. Patients will be
asked to keep a diary during the whole study period.