This document discusses direct oral anticoagulants (DOACs), including their mechanism of action, pharmacological properties, and comparisons to standard anticoagulants. It addresses the use of DOACs in special situations, reversal of their effects, preoperative use, and combinations with antiplatelet drugs. Guidance is provided on switching between anticoagulants and managing DOACs in various clinical scenarios.

1. DR. Sameh Attia Ali Basha
MBBCh,MSc,MRCS A,Egyptian Board of
Vascular Surgery

2.  1. Introduction
 2. Mechanism of action
 3. Pharmacological properties
 4. DOAC versus standard anticoagulant
 5. DOAC in special situation
 6. Reversal of DOAC effect
 7. Preoperative use of DOAC
 8. Combination with antiplatelet
 9. Switching between anticoagulant

3.  New oral anticoagulant (NOACs) FDA
approved since 2009, so it is better to be
named as direct oral anticoagulant (DOAC), or
non vitamin K antagonist oral anticoagulant.

4.  Unlike VKAs, which block the formation of
multiple active vitamin K-dependent coagulation
factors (factors II, VII, IX, and X), these drugs
block the activity of single step in coagulation
pathway.
 Two classes of direct oral anticoagulant are
currently available:
1. The oral direct thrombin inhibitors (DTIs; e.g.
Dabigatran).
2. Oral direct factor Xa inhibitors (e.g.
Rivaroxaban, Apixaban, Edoxaban, and
betrixaban).

10.  The use of DOACs in the initial and long-term
management of patients with VTE was
demonstrated in large, randomized studies.
 These trials demonstrated non-inferior
efficacy and safety of DOACs compared with
standard anticoagulant treatment.

11.  Recent studies suggest that factor X inhibitor
exerts an anti inflammatory property in
addition to their anticoagulant effects
through Protease-Activated Receptors (PARs)
in many cell types such as endothelial cells.
 Katoh conducted a study on the Anti-
inflammatory effect of factor-Xa inhibitors in
Japanese patients with atrial fibrillation.

12.  concluded that plasma concentrations of
pentraxin 3 (PTX 3) , FDP and D-dimer
decreased and thrombomodulin increased
after the initiation of treatment with FXa
inhibitors hence supporting the anti
inflammatory effects.
 Major CD, Santulli RJ, Derian CK, Andrade-Gordon P. Extracellular mediators in
atherosclerosis and thrombosis: lessons from thrombin receptor knockout mice.
Arterioscler Thromb Vasc Biol. 2003;23(6):931-9. Borissoff JI, Spronk HM, ten Cate H.
The hemostatic system as a modulator of atherosclerosis. N Engl J Med.
2011;364(18):1746-60.
 Katoh H, Nozue T, Michishita I. Anti-inflammatory effect of factorXa inhibitors in
Japanese patients with atrial fibrillation. Heart Vessels. 2017;32(9):1130-6.

18.  Two specific DOAC reversal agents have been
approved by the US FDA:
1. idarucizumab for reversal of dabigatran.
2. andexanet alfa for reversal of apixaban and
rivaroxaban.
 Non-specific prohemostatic agents have also
been used off-label for DOAC reversal
including prothrombin complex concentrate
(PCC) (multiple brands) and activated
prothrombin complex concentrate (APCC)

21.  In all patients with DOAC-associated major
bleeding, treatment with supportive measures
is recommended.
 Administration of a reversal agent only if
bleeding is life-threatening, or is not
controlled with maximal supportive
measures, or reasonable expectation that the
patient has clinically relevant plasma DOAC
levels

22.  In patients with dabigatran-associated major
bleeding in whom a reversal agent is warranted,
idarucizumab 5 g IV.
 If idarucizumab is not available, we suggest
treatment with APCC 50 units/kg IV.
 In patients with rivaroxaban-associated or
apixaban-associated major bleeding in whom a
reversal agent is warranted, we suggest
treatment with andexanet alfa dosed according
to the USA FDA label.
 If andexanet alfa is not available, we suggest
treatment with four-factor PCC 2000 units.

24.  In patients with DOAC overdose without
bleeding, we suggest against the routine use
of reversal agents.
 In DOAC-treated patients who present with
trauma without bleeding, we suggest against
the routine use of reversal agents.

26.  The management needs to take into consideration of the
thromboembolic risk balanced against the bleeding risk.
 Guidance on when to discontinue the DOAC can only be
provided based on the elimination half-life of the drugs to
ensure that procedures are undertaken at the time when there
is minor or no anticoagulant effect.
 Dabigatran clearance is depended on renal function, therefore
patient’s renal function, timing of surgery and risk of
bleeding should be carefully considered.
 Apixaban, edoxaban and rivaroxaban must be discontinued
24 hours before surgery regardless of the patient’s renal
function. Where the surgical procedure carries a high risk of
bleeding they should be stopped 48hours prior to the
procedure.

29.  If an emergency invasive procedure or surgical
intervention is required the anticoagulant should
be temporarily discontinued.
 The procedure should be delayed if possible by
at least 12-24 hours after the last dose was
taken. If surgery cannot be delayed the risk of
bleeding may be increased.
 The risk of bleeding should be weighed against
the urgency of the intervention.
 Where urgent life-saving surgery cannot be
delayed contact the haematologist on call in
relation to measures that can be taken to control
bleeding prior to and during surgery.

31.  DOACs should NOT be used in combination with
antiplatelets such as aspirin, clopidogrel, prasugrel,
ticagrelor or dipyridamole as currently there is no
data to support this.
 There is an increased risk of bleeding if aspirin is
used in combination with dabigatran or rivaroxaban.
 The risk has only been well evaluated with aspirin
combined with dabigatran compared to aspirin
combined with warfarin.
 Aspirin should only be used in combination with
dabigatran only where you would normally use
aspirin with warfarin, and consider dose reduction to
110mg bd.
 Aspirin and Rivaroxaban combination is not
recommended.

32.  Dabigatran is not recommended in patients with
unstable ischemic heart disease as it increases
the rate of myocardial infarction relative to
warfarin.
 On the other hand, rivaroxaban was associated
with reduced risk of MI compared to warfarin.
 A significant increase in bleeding risk was
reported with the triple combination of apixaban,
aspirin and clopidogrel in a clinical study in
patients with acute coronary syndrome.

33.  Do not administer parenteral anticoagulant
and DOACs simultaneously.
 For Low Molecular Weight Heparin (LMWH)
this can be done at the next scheduled dose
 Unfractionated Heparin start DOAC at the
time of discontinuation of infusion or 4 hour
after for edoxaban.
 Stop warfarin and start DOAC based on INR.

34.  Usually, DOACs can continue alongside
warfarin until desired INR reached
 DOACs can affect INR values. Seek
Haematology advice to interpret INR and
timing of blood sample taking.