Switching anticoagulant management from a VKA to a NOAC-based tratment strategy in frail elderly patients with atrial fibrillation

For long, vitamin K antagonists (VKAs) were the only therapeutic strategy to
reduce stroke risk in patients with atrial fibrillation (AF). Recently, an
alternative has entered the clinical domain: non-VKA oral anticoagulants
(NOACs). Large randomized controlled trials (RCTs) demonstrated that NOACs are
at least as effective as VKAs to reduce the risk of ischaemic stroke, yet with
a better safety profile (notably fewer intracranial bleeds). Based upon these
trial results, the recent guidelines from the European Society of Cardiology
(ESC) have a strong preference of NOACs over VKAs when starting oral
anticoagulant treatment in AF patients. Moreover, the ESC guideline considers
switching VKA-treatment to a NOAC appropriate, in particular when the time in
therapeutic INR range is low while on a VKA, although this latter
recommendation is less strong than the preference of NOACs over VKAs when newly
initiating oral anticoagulant treatment. However, frail elderly patients were
under-represented in the landmark NOAC RCTs, leaving a knowledge gap on the
optimal anticoagulant treatment strategy (VKA or NOAC) in this increasing group
of frail AF patients. Both may have advantages as well as risks, and it is yet
unknown which type of oral anticoagulant (VKAs or NOACs) should be preferred in
this specific population. In particular, it is unknown if switching (chronic)
VKA treatment to a NOAC yields fewer bleeding complications in frail elderly AF
patients, as may be expected given the current results from RCTs and
observational studies that were performed with non-frail AF patients.

The primary objective is to evaluate whether the impact of a strategy aimed at
switching INR-guided VKA management to a NOAC-based treatment strategy is
superior in terms of the occurrence of major or clinically relevant non-major
bleeding complications in frail elderly patients with AF. Hereto we will assess
the relative risk (hazard ratio) of the randomised groups with respect to the
time to first occurrence of a major or clinically relevant non-major bleeding
complication (whichever comes first). The total of the two components of this
composite outcome, (major or clinically relevant non-major bleeding
complications), will also be analysed as separate outcomes secondarily. Other
secondary objectives include a comparison of both treatment strategies on the
occurrence of all-cause thrombo-embolic events, the composite of ischaemic and
haemorrhagic stroke, quality of life and cost-effectiveness, as well as an
identification of risk factors for bleeding in frail elderly AF patients
treated with either a VKA or a NOAC.

Multi-centre pragmatic open label registry-based randomized controlled clinical
trial.

In the index group, the treating physician (general practitioners (GPs) or
cardiologists) will be encouraged to switch oral anticoagulant management from
INR-guided VKA-management to a NOAC-based management with prescription of one
of the available NOACs (dabigatran 150mg twice a day, rivaroxaban 20mg once
daily, apixaban 5mg twice a day or edoxaban 60mg once daily) based upon
physician and patient preference. Dose adjustments for NOAC treatment will be
conform guidelines. The control group continues with current routine-care VKA
treatment (either acenocoumarol 1mg or fenprocoumon 3mg), with dose tailoring
based upon regular INR measurements.

Both VKAs and NOACs are guideline-recommended treatment options for stroke
prevention in AF, and inherently carry a risk of bleeding with possibly an
overall lower risk of (notably intracranial) bleeding on NOACs. Nevertheless,
the risk of these bleeding complications is not directly related to study
participation or study procedures, yet part of routine practice as current
guidelines clearly indicate the need to prescribe anticoagulants for stroke
prevention in elderly AF patients. Patients in the index group are not being
visited at home anymore by the thrombosis service for regular INR measurements
and dismissal of these regular home visits could lead to change in quality of
life, both in a positive and negative way. Patients in both the index group and
the control group are asked baseline characteristics and follow-up questions at
respectively 0 and 1, 3, 6, 9 and 12 months. Moreover, patients are asked to
fill in quality of life questionnaires at 0, 6 and 12 months.