This document discusses direct oral anticoagulants (DOACs), including their mechanisms of action, pharmacological properties, clinical trials comparing them to standard anticoagulants, and special considerations for their use. It provides details on specific DOACs like dabigatran, rivaroxaban, apixaban, and edoxaban. It also addresses DOAC dosing adjustments for patients with renal or liver impairment, use in pregnancy and lactation, reversal agents, and periprocedural management.

1. Dr. Samiaa Hamdy
Assiut University, Chest departement

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:
 The oral direct thrombin inhibitors
(DTIs; e.g. Dabigatran) and
 Oral direct factor Xa inhibitors (e.g.
Rivaroxaban, Apixaban, Edoxaban, and
betrixaban).

5. EdoxabanApixabanRivaroxabanDabigatr
an
Drug
Direct factor
Xa inhibitor
Direct factor
Xa inhibitor
Direct factor
Xa inhibitor
Direct
thrombin
inhibitor
Mechanism
NoNoNoYesPro-drug
9-11h12h5–9 h (young)
11–13 h
(elderly
12-17Half-life,h
1–2 h1–4 h2–4 h0.5–2Time to maximum
plasma
concentration
50%25%35%80%Renal excretion
50%YesYes20%Liver metabolism

6. EdoxabanApixabanRivaroxabanDabigatranDrug
No problemNo problemNo problemDyspepsiaGastrointestinal
tolerability
6–22%moreNo effect+39%moreNo effectAbsorption with
food
Official
recommendation
NoMandatoryNoIntake with food
Once dailyTwice dailyOnce dailyTwice dailyDosing
60 mg QD5 mg BID20 mg QD
In acute VTE
15mg BID
for 21 days
then 20mg
OD
150 mg
BID
Usual dose
regimen

7. 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.

8. 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.

9. concluded that plasma concentrations of
pentraxin 3 and FDP 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.

10. Safety
Outcome
(bleeding)
Efficacy outcome
(VTE recurence or death)
TreatmentTrial Name
5.6% dabigatran
8.8% warfarin
2.4%enoxa/dabigatra
2.1% enoxa/warfrin
Enoxa/dabigatran (150
mg BD) •
Enoxa/warfarin
RE-COVER,
2009
5.0% dabigatran
7.9% warfarin
2.3% enoxa/dabigatran
2.2% enoxa/warfrin
Enoxa/dabigatran (150
mg BD) •
Enoxa/warfarin
RE-COVER II
2011
8.1% rivaroxaban •
8.1% enoxa/VKA
2.1% rivaroxaban;
3.0% enoxa/VKA
Rivaroxaban (15 mg
BD for 3/52 then 20
mg OD)
Enoxa/VKA
EINSTEIN-DVT
2010
10.3% rivaroxaban •
11.4% enoxa/VKA
2.1% rivaroxaban
1.8% enoxa/VKA
Rivaroxaban (15 mg
BD for 3/52 then 20
mg OD)
Enoxa/VKA
EINSTEIN-PE
2012

11. Safety
Outcome
(bleeding)
Efficacy outcome
(VTE recurence or
death)
TreatmentTrial Name
0.6% apixaban
1.8% enoxa/VKA
2.3% apixaban
2.7% enoxa/VKA
Apixaban (10 mg BD for
7 days then 5 mg BD)
Enoxa/warfarin
AMPLIFY,
2013
8.5% enoxa/edoxaban
10.3% enoxa/warfarin
3.2% enoxa/edoxaba
3.5% enoxa/warfarin
LMWH/edoxaban (60
mg OD or 30 mg OD)
UFH or LMWH/Warfarin
Hokusai,
2013

12. Route of elimination of DOACSs:
Renal eliminationLiver eliminationDOAC
25%75%Apixaban
35%65%Rivaroxaban
50%50%Edoxaban
80%20%Dabigatran

13. Child-Pugh class CChild-Pugh class BChild-Pugh class A
Not recommendedUse with caution (no
dose adjustment)
Dabigatran (no dose
adjustment)
Not recommendedUse with caution (no
dose adjustment)
Apixaban (no dose
adjustment)
Not recommendedNot recommendedEdoxaban (no dose
adjustment)
Not recommendedNot recommendedRivaroxaban (no dose
adjustment)

14. USA
CrCl 15–29 ml/min
Europe
CrCl 15–29 ml/min
DOAC
AF: 5 mg bd, unless two of serum
creatinine >133 mmol/l, <60 kg or >80
years, when dose is 2.5 mg bd
DVT/PE: 10 mg bd for 7 days then 5 mg bd
THR/TKR: 2.5 mg bd
AF: 2.5 mg bd
DVT/PE: 10 mg bd for
7 days then 5 mg bd
THR/TKR: 2.5 mg bd
Apixaban
AF: 75 mg bd
DVT/PE: Not recommended
THR/TKR: Not recommended
Not recommendedDabigatran
AF: 30 mg od
DVT/PE: Parenteral anticoagulation for 5
days
then 30 mg od
AF: 30 mg od
DVT/PE: Parenteral
anticoagulation for
5 days then 30 mg od
Edoxaban
AF: 15 mg od
DVT/PE: Avoid use
TKR/THR: Avoid
AF: 15 mg od
DVT/PE: 15 mg bd for
3 weeks then 20 mg od,
consider reduction to
15 mg od*
TKR/THR:10 mg od
Rivaroxaban
Dose adjustment in CKDs:
NB:
All DOAC not recommended for CKDs patients with Cr Cl less than 15 ml/min

15. USA
CrCl 30-50ml/min
Europe
CrCl 30-50ml/min
DOAC
AF: 5 mg bd, unless two of serum
creatinine >133 mmol/l, <60 kg or >80
years,
when dose is 2.5 mg bd
DVT/PE: 10 mg bd for 7 days then 5 mg
bd
THR/TKR: 2.5 mg bd
AF: 5 mg bd, unless two of
serum
creatinine >133 mmol/l, <60
kg or >80
years, when dose is 2.5 mg
bd
DVT/PE: 10 mg bd for 7 days
then 5 mg bd
THR/TKR: 2.5 mg bd
Apixaban
AF:150 mg bd
DVT/PE: Parenteral anticoagulation for
5 days then 150 mg bd
THR/TKR: 150 mg od
AF: 150 mg bd or 110 mg bd*
DVT/PE: Parenteral
anticoagulation for
5 days then 150 mg bd or 110
mg bd*
THR/TKR: 75 mg day 1 then
150 mg per day
Dabigatran
AF: 30 mg od
DVT/PE: Parenteral anticoagulation for
5 days then 30 mg od
AF: 30 mg od
DVT/PE: Parenteral
anticoagulation for
5 days then 30 mg od
Edoxaban
AF:15 mg od
DVT/PE: 15 mg bd for 3 weeks then
20 mg od
THR/TKR:10 mg od
AF: 15 mg od
DVT/PE: 15 mg bd for 3
weeks then 20 mg od
THR/TKR: 10 mg od
Rivaroxaban

16. Dabigatran, rivaroxaban, and edoxaban are
classified by the Food and Drug
Administration as a pregnancy class C:
“risk cannot be ruled out.”
Apixaban is classified as a pregnancy
class B:“animal reproduction studies have
failed to demonstrate a risk to the fetus
and, there are no adequate and
well-controlled studies in pregnant
women.”

17. Until evidence on the safety of NOACs
in pregnancy is available, LMWH
should be the anticoagulant of choice
in pregnancy.
It is uncertain whether NOACs are
excreted in breast milk and thus all
NOACs should be avoided during
lactation”

18. several concerns related to the use of
NOACs for VTE prophylaxis or
treatment in patients with cancer:
First, the exact mechanism of cancer-
associated VTE is not entirely understood,
but it is likely multifactorial (eg, increased
expression of tissue factor, apoptosis,
formation of microparticles, and deleterious
effects of chemotherapy on vascular
endothelium). NOACs target single
coagulation factors and may not be able to
adequately block the upregulation of the
coagulation system that occurs in many
types of cancer

19. Second, cancer cells may alter the efficacy of the
antithrombotic agents.
Third, NOACs interfere with the CYP3A4 (rivaroxaban and
apixaban) and the P-glycoprotein system (dabigatran,
rivaroxaban, apixaban, edoxaban, and betrixaban), which
play an integral role in the metabolism of several
chemotherapeutic agents.
Fourth, overexpression of P-glycoprotein on the surface of
cancer cells has been associated with multidrug
resistance, since P-glycoprotein functions as an efflux
pump and its inhibition has been proposed as a therapeutic
strategy to overcome resistance to chemotherapy drugs, It
is unknown whether NOACs, through their interference
with the P-glycoprotein pathway, affect the efflux-mediated
chemotherapy resistance.

20. Fifth, nausea and vomiting are highly
prevalent in patients with cancer, reaching
20% to 30% in patients with advanced
cancer, and this might result in inadequate
adherence to oral medication administration.
Given the short half-life of NOACs
Last, renal dysfunction is highly prevalent in
patients with cancer, and many
chemotherapy regimens are also nephrotoxic

21.  Two specific DOAC reversal agents have been
approved by the US FDA: idarucizumab for
reversal of dabigatran, and 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)

22.  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

23. 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 US FDA label.
If andexanet alfa is not available, we suggest
treatment with four-factor PCC 2000 units

25. In patients with edoxaban-associated or betrixaban-
associated major bleeding in whom a reversal agent
is warranted, off-label treatment with either high
dose andexanet alfa (800 mg bolus given at 30
mg/min followed by a continuous infusion of 8
mg/min for up to 120 min) or four-factor PCC 2000
units.
In DOAC-treated patients who require an invasive
procedure, a reversal agent administered only if the
procedure cannot be safely performed while the
patient is anticoagulated, cannot be delayed, and
there is demonstration or reasonable expectation
that the patient has clinically relevant plasma DOAC
levels.

26. patients who require an urgent procedure
and in whom a reversal agent is
warranted, we suggest treatment with
reversal agents at the same dosing used
for major bleeding.
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.

28. 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.

30.  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.

33. When neuraxial anaesthesia (spinal/epidural
anaesthesia) or spinal/epidural puncture is
employed, patients treated with
antithrombotic agents for prevention of
thromboembolic complications are at risk of
developing an epidural or spinal haematoma
which can result in long-term or permanent
paralysis.

35. 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.

36. 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..

37. 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.

38. Stop warfarin/sinthrome and start
DOAC based on INR

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

40. This work is dedicated to the spirit of my mother