Prospective registry of management and outcome of bleeding complications in patients treated with non-vitamin K antagonist oral anticoagulants (NOACs)

Oral anticoagulants (OAC) are indicated for patients with atrial fibrillation
(AF) and for treatment and prevention of venous thromboembolism (VTE). For six
decades vitamin K antagonists (VKA) were the only available OAC. Although VKA
are highly effective in prevention of thromboembolism, their use is limited by
a narrow therapeutic index and huge inter- and intra-individual variability
that necessitates frequent monitoring and dose adjustments. An important side
effect of VKA is an increased risk of bleeding. The incidence of VKA associated
bleeding is estimated at 16.5% per year and the incidence of major bleeding is
2.7% per year.
Recently a new class of oral anticoagulants has been developed. These
non-vitamin K antagonist oral anticoagulants (NOACs) have a predictable
pharmacokinetic and -dynamic profile allowing a fixed dose regimen. This offers
major simplification of coagulant treatment. Currently three NOACs are
registered, namely rivaroxaban, apixaban and dabigatran etexilate (after here
referred to as dabigatran). Procedures for registration of edoxaban are ongoing
with the European Medicine Agency. Approval is expected in 2014.
As with VKA, the most important adverse event of NOACs is the occurrence of
bleeding. NOACs are evaluated in large phase III clinical trials. These studies
showed that NOACs reduced the risk of major bleeding in comparison to VKA. Also
the risk of intracranial bleeding was reduced with 30-70% in patients on NOACs.
No data on post-marketing surveillance in patients with long-term exposure are
available yet.

A potential drawback of NOACs is the lack of a (specific) antidote that
neutralizes the anticoagulant effect. Such an antidote can be useful in
patients that need to undergo emergency invasive surgery or in case of bleeding
complications. For VKA reversal can be reached through administration of
vitamin K or prothrombin complex concentrate (PCC). Studies in animals and
healthy volunteers have indicated that PCC may have a role in reversing the
anticoagulant effect of NOACs and can reduce the bleeding. Based on these
studies, the Dutch Leidraad Begeleide Introductie Nieuwe Orale
Antistollingsmiddelen advises treatment with PCC in case of a severe NOAC
associated bleeding. However, the efficacy of PCC for immediate reversal of
NOACs has not been tested in patients on NOACs.

Primary objective
To assess the outcome of NOAC associated bleeds and emergency invasive surgery
or procedures.

Secondary objectives
1) To describe the treatment of patients presenting with NOAC associated
bleeding
2) To evaluate the current perioperative strategies for patients on NOAC*s who
require emergency invasive procedures
3) In the subgroup of patients who receive PCC as a prohaemostatic agent (as
indicated by the treating physician), the goal is to determine the effect of
administration of PCC on 1) the outcome of the bleed (or invasive procedure)
and 2) coagulation assays.

This is an investigator initiated prospective multi-center cohort study. The
currently participating hospitals are the academic hospitals of the
Universities of Amsterdam, Rotterdam, Maastricht and Groningen. Further
participation with community hospitals around Amsterdam will be sought.

Main study
Patients will be eligible for participation in this study if they are treated
with a NOAC and present themselves with a NOAC associated bleed or the need to
undergo an immediate invasive surgery or procedure within 8 hours. The
treatment of a NOAC related emergency situation is the responsibility of the
treating physician. The interventions to control bleeding and the perioperative
strategies are not part of the study protocol.
Information about history, concomitant medication, laboratory assays, applied
treatment regimens and outcomes will be collected from patient charts and
letters. In addition, we will collect citrated blood at two different time
points, at presentation and 4-8 hours after presentation (total 2x 9.0 mL).

Substudy
In the subgroup of patients that are treated with PCC, two additional blood
draws (9 mL each) will be performed in the first 24 hours (just after PCC
administration and 24 hours after administration).

The tubes of all patients will be double spun to produce platelet poor plasma
and will be stored to later on assess the effect of PCC on coagulation assays.

Historic control group
The subgroup of patients receiving PCC for a NOAC related emergency will be
compared to a historical control cohort of age-matched patients treated with
PCC because of VKA associated bleeding or the need for immediate invasive
procedures whilst on VKA treatment. The patients for this retrospective group
will be identified through PCC distribution and administration files from the
blood bank in the AMC. Clinical data from the patients will be retrieved form
charts and letters.

Because this is not an intervention study, we will not administer a specific
investigational product or treatment. Patient management is left to the
treating physician, including the decision to administer PCC.
The only executed intervention is the collection of additional blood. We will
collect citrated blood at two times in the first 24 hours in all patients
(total 2x 9.0 mL). In the subgroup of patients treated with PCC, citrated blood
will be collected at two additional time points in the first 24 hours (total 2x
9.0 mL). The extra samples will be drawn adjacent to regular blood drawings or
additional venepunctures will be performed when this is not attainable (maximum
of four drawings). The risks of a venepuncture are hematoma formation or
tromboflebitis.
This study does not include additional visits to the hospital, nor will
patients be asked to fill out questionnaires.
Based on the small risks of venepunctures and the fact that we will not impose
an intervention or change a patients behaviour, we think the burden for
patients participating in this study is minimal.