Oral anticoagulation in AF

 Atrial fibrillation (AF) is the most common sustained
cardiac arrhythmia.
 The estimated number of individuals with AF globally
in 2010 was 33∙5 million 20∙9 million males and
12∙6 million females .
 Prevalence: 596.7/100000 in males
373.1/100000 in females
 Incidence: 77.5/100000 in males
59.5/100000 in females
Sumeet S.Chugh etal CIRCULATIONAHA.113.005119
December 17, 2013,

 AF is associated with a 5-fold increased risk of
stroke
 AF is also associated with a 3-fold risk of HF
 2-fold increased risk of both dementia and mortality
HF : Heart Failure

First diagnosed episode of AF
Paroxysmal
(<7 days)
Persistent (>7
days to 12m)
Long standing
persistent
(>1year)
Permanent
(accepted)

Atrial fibrillation
Anticoagulation Assess TE risk
NOAC
OAC
Aspirin or none
Rate and rhythm
control
AF type symptoms
Rate control
+/- Rhythm control
Ablation

CHADS2
C
congestive
cardiac
failure
H
Hypertension
A
Age more
than 75
D
Diabetes
S2
Previous
Stroke or TIA
Gage BF, Waterman AD et. al. JAMA 2001;285:2864–2870

Risk Profile Class / Level
CHA2DS2-VASc = 0
No antithrombotic therapy
Class IIa
CHA2DS2-VASc = 1
No antithrombotic therapy
Or
Asprin
Or
Oral anticoagulation
Class IIb
CHA2DS2-VASc ≥ 2
Oral anticoagulation
Class I

INR . international normalized ratio

Kinetics
Absorption Oral: Rapid, complete
Distribution 0.14 L/kg
Metabolism Hepatic, primarily via CYP2C9;
minor pathways include CYP2C8,
2C18, 2C19, 1A2, and 3A4
Excretion Urine (92%, primarily as
metabolites)
Half-life 20-60 hours

 Onset of action:
◦ 5-7 days
◦ May requiring bridging
 Antidote:
◦ Vitamin K, FFP, PRBC
 Interactions:
◦ Foods with high vitamin K content

 Medications
◦ Amiodarone
◦ Antiplatelets
◦ Azole antifungals
(fluconazole)
◦ 2nd/3rd-gen Cephalosporins
◦ Fluoroquinolones
(ciprofloxacin)
◦ Griseofulvin
◦ Isoniazid
◦ Macrolides (clarithromycin)
◦ Metronidazole
◦ NSAIDs
◦ Penicillins (nafcillin)
◦ Prednisone
◦ Rifampin
◦ SSRIs
◦ Sulfonamides (Bactrim)
◦ Tetracyclines (Doxycycline )
 Herbals
◦ Ginger
◦ Gingko
◦ Fenugreek
◦ Chamomile
◦ St. John’s Wort

 ADRs
◦ Bleeding/Hemorrhage/Hematuria
◦ Vasculitis
◦ Dermatitis, pruritus, urticaria
◦ Abdominal pain, N/V/D
◦ Anemia
◦ Skin necrosis, gangrene, “purple toes” syndrome

Hart R, et al. Ann Intern Med 1999;131:4
Warfarin
Better
Control
Better
AFASAK
SPAF
BAATAF
CAFA
SPINAF
EAFT
100% 50% 0 -50% -100%
Aggregate

 VKA
 Similar to Warfarin
 Lesser pharmacogenimic interaction (VKORC1
and CYP2C9)
 Lesser food and drug interactions
 Higher potency and longer half life

 Requires monitoring
 Numerous drug and diet interactions
 Narrow therapeutic range
 Difficult to control – takes time to get in or out of
the system
Role for new anticoagulants?

 Ideal anticoagulant:
◦ Equally efficacious
◦ Equally safe
◦ No monitoring
◦ Fewer interactions
◦ Oral
◦ Reversible

 Direct thrombin inhibitors
◦ Dabigatran
 Factor Xa inhibitors
◦ Rivaroxaban
◦ Apixaban
◦ Edoxaban

Dabigatran Apixaban Rivaroxaban
Bioavailability 3-7% 50%
66% (w/o food)
~100% with food
Prodrug yes no no
Clearance:
non-renal/renal of adsorbed
dose if normal renal function
20%/80% 73%/27% 65%/35%
Liver metabolism: CYP3A4 no
yes (elimination;
minor CYP3A4)
yes (elimination)
Absorption with food no effect no effect +39%
Intake with food? no no mandatory
Absorption with H2B/PPI plasma level -12 to -30% no effect no effect
Asian ethnicity plasma level +25% no effect no effect
GI tolerability dyspepsia 5-10% no problem no problem
Elimination half-life 12-17h 12h 5-9h (young)/11-13h (elderly)
16
www.escardio.org/EHRA

 P-glycoprotein transporter involved in absorption and renal
clearance – plasma levels may be affected by P-gp inducers
or inhibitors1
 Cytochrome P450 CYP3A4 involved in hepatic clearance of
rivaroxaban and apixaban – plasma levels may be affected
by CYP3A4 inducers of inhibitors2
17
1. Gnoth et al, J Pharmacol Exp Ther 2011;338:372-80 2. Mueck et al, Br J Clin Pharmacol 2013

Three levels of alert:
 Red – contraindicated/not recommended for use
 Orange – adapt NOAC dose
◦ dabigatran: 150 mg to 110 mg BID
◦ rivaroxaban: 20 mg to 15 mg QD
◦ apixaban: 5 mg to 2.5 mg BID
 Yellow – consider dose reduction if two concomitant yellow
interactions
 Where no data available, NOACs not recommended yet
18

Dabigatran Apixaban Edoxaban Rivaroxaban
Atorvastatin P-gp/ CYP3A4 +18% no data yet no effect no effect
Digoxin P-gp no effect no data yet no effect no effect
Verapamil P-gp/ wk CYP3A4
+12–180%
no data yet
+ 53% (slow release)
minor effect
Diltiazem P-gp/ wk CYP3A4 no effect +40% No data minor effect
Quinidine P-gp +50% no data yet +80% +50%
Amiodarone P-gp +12–60% no data yet no effect minor effect
Dronedarone P-gp/CYP3A4 +70–100% no data yet +85% no data yet
Ketoconazole;
itraconazole;
voriconazole;
posaconazole;
P-gp and BCRP/
CYP3A4
+140–150% +100% no data yet up to +160%
19
Red – contraindicated; orange – reduce dose; yellow – consider dose reduction if another yellow factor present;
hatching – no data available; recommendation made from pharmacokinetic considerations

Interaction Dabigatran Apixaban Rivaroxaban
Fluconazole CYP3A4 no data no data +42%
Cyclosporin; tacrolimus P-gp no data no data +50%
Clarithromycin;
erythromycin
P-gp/ CYP3A4 +15–20% no data +30–54%
HIV protease inhibitors
P-gp and BCRP/
CYP3A4
no data strong increase up to +153%
Rifampicin;
St John’s wort;
carbamezepine;
phenytoin;
phenobarbital
P-gp and BCRP/
CYP3A4/CYP2J2
-66% -54% up to -50%
Antacids GI absorption -12-30% no data no effect
20
Red – contraindicated; orange – reduce dose; yellow – consider dose reduction if another yellow factor present;

Aged ≥ 80 years Increased plasma level
Aged ≥ 75 years Increased plasma level
Weight ≤ 60 kg Increased plasma level
Renal function Increased plasma level
21
Other increased
bleeding risk
Pharmacodynamic interactions – antiplatelet drugs, NSAIDs
Systemic steroid therapy
Other anticoagulants
Recent surgery on critical organ (brain, eye)
Thrombocytopenia (e.g. chemotherapy)
HAS-BLED ≥ 3
Orange – reduce dose; yellow – consider dose reduction if another yellow factor present;

RE-LY ROCKET-AF ARISTOTLE
Dabigatran 150mg BID
vs. warfarin
Rivaroxaban 20mg daily
vs. warfarin
Apixaban5mg BID
vs. warfarin
Study Design
Trial design
RCT Open blinded
assessment
RCT DB DD RCT DB DD
Sample size (n) 18,000+ 14,000+ 18,000+
Inclusion criteria
AF and selected risk
factor(s) for embolization
AF and CHADS2 ≥2 AF or flutter and CHADS2 ≥1
Key exclusion
criteria
Valvular AF
Use of ASA ≥100 mg/day
CrCl <30 ml/min
Valvular AF;
Use of ASA >100 mg/day
CrCl <30 ml/min
Valvular AF
Need for ASA >165 mg/day
SCr >2.5mg/dL or CrCl
<25ml/min
Follow-up (mean) 2 yr 1.9 yr 1.8 yr
Outcome Definitions
Primary Efficacy Composite of systemic embolism and stroke (ischemic or hemorrhagic)
Major Bleeding ISTH: fatal/critical organ bleed; decrease ≥2g/dL Hbg or transfusion of ≥2U blood
Mortality All causes
Baseline Characteristics
Age (years) 71 (mean) 73 (median) 70 (median)
Female (%) 36.4% 39.7% 35.2 %
CHADS2 (mean) 2.1 3.5 2.1
Previous embolic
episode (%)
20%
(stroke or TIA only)
55%
(stroke,TIA, systemic
embolism)
19%
(stroke, TIA, systemic embolism)
TTR (%)
(Standard 60-65%)
64% 55% 62%

Comparison of Efficacy Results
RE-LY ROCKETAF ARISTOTLE
Outcome (%/year)
Dabigatran
150mg BID
vs. warfarin
p Value
Rivaroxaba
n 20mg
daily
vs. warfarin
p Value
Apixaban
5mg BID
vs. warfarin
p Value
Primary Outcome
Stroke or systemic
embolism
1.1 vs. 1.7%
p<0.001
NNT 88
2.1 vs. 2.4% p=0.12 1.3 vs. 1.6%
p=0.01
NNT
167
Stroke 1.0 vs. 1.6%
p<0.001
NNT 88
1.65 vs.
1.96%
p=0.09 1.2 vs. 1.5%
p=0.01
NNT
175
Ischemic stroke 0.9 vs. 1.3%
p=0.03
NNT 132
1.3 vs. 1.4 p=0.58
0.97 vs.
1.05%
p=0.42
Hemorrhagic
stroke
0.1vs0.4%
p<0.001
NNT 182
0.26 vs.
0.44%
p=0.02
NNT 333
0.24 vs.
0.47%
p<0.00
1
NNT
238
All cause death 3.6 vs. 4.1% p=0.051 4.5 vs. 4.9% p=0.15 3.5 vs. 3.9
p=0.04
7
NNT
132
MI/ACS 0.7 vs. 0.5%
p=0.048
NNH 0.9 vs. 1.1% p=0.12 0.5 vs. 0.6% p=0.37

Comparison of Safety Results
RE-LY ROCKETAF ARISTOTLE
Major bleed
3.1 vs.
3.36%
p=0.31
3.6 vs.
3.4%
p=0.58
2.1 vs.
3.1%
p<0.001
NNT 67
Intracranial
bleed
0.3 vs.
0.74%
p<0.00
1
NNT
116
0.5 vs.
0.7%
p=0.02
NNT 250
0.3 vs.
0.8%
p<0.001
NNT 128
GI bleed
1.5 vs.
1.0%
p<0.00
1
NNH
100
3.2 vs.
2.2%**
p=0.001
NNH 100
0.76 vs.
0.86%
0.37

 Factor Xa inhibitor
 Doses 60mg and 30mg OD
 Engage AF trial(November 2013, NEJM)
◦ Versus Warfarin, RCT DD
◦ More than 20000 subjects
◦ Non inferior
◦ Less major bleed

 Boxed warning: Less effective in pateints with
CrCl >95ml/min, as it was associated with more
thromboembolic complications compared to
warfarin. Also contraindicated if CrCl <
15ml/mim
 Was FDA approved in January 2015
 Approved by European union in June 2015
 Savaysa (USA), Lixiana(Europe)

 All major trials excluded Valvular AF
 Re-Align AF
◦ RCT, Nejm 2013
◦ Dabigatran vs Warfarin in prosthetic heart valve
◦ Significantly increased bleeding
◦ Significantly increased thromboembolism
◦ Stopped prematurely

Advantages Disadvantages
 Cheap: 2rs/5mg
 Antidote available
 Robust data(Class IA)
 Time tested
 Narrow TI/Non target
INR
 Frequent INR
monitoring
 Numerous drug-drug
and drug-food
interactions
 Slow onset and offset
of action/ Requires
bridging

Advantages Disadvantages
 Quick onset/offset of
action
 Few drug-drug and
drug-food interactions
 No need of monitoring
 Cost
◦ Dabigatran
(Pradaxa:71.8rs/150 or
110mg)
◦ Apixaban (Equilis:
72.5 rs)
◦ Rivaroxaban (Xarelto:
240rs)
 No antidote
 Less robust data (Class
IB)

 Patient not willing for regular INR
 Patient preferance
 Target INR not achieved with warfarin

1In patients with AF, antithrombotic therapy should be individualized
based on shared decision making after discussion of the absolute and RRs
of stroke and bleeding, and the patient’s values and preferences. IC
2. Selection of antithrombotic therapy should be based on the risk of
thromboembolism irrespective of whether the AF pattern is paroxysmal,
persistent, or permanent IB.
Among patients treated with warfarin, the INR should be
determined at least weekly during initiation of antithrombotic
therapy and at least monthly when anticoagulation (INR in
range) is stable IABridging therapy with unfractionated heparin (UFH) or low-molecular-
weight heparin (LMWH) is recommended for patients with AF and a
mechanical heart valve undergoing procedures that require
interruption of warfarin. Decisions regarding bridging therapy should
balance the risks of stroke and bleeding. IC
The direct thrombin inhibitor, dabigatran, should not be
used in patients with AF and a mechanical heart valve
IIIB

Renal function should be evaluated prior to
initiation of direct thrombin or factor Xa
inhibitorsand should be re-evaluated when
clinically indicated and at least annually IB
For patients with nonvalvular AF unable to maintain a
therapeutic INR level with warfarin, use of a direct thrombin
or factor Xa inhibitor (dabigatran, rivaroxaban, or apixaban)
is recommended. IC
For patientwith a CHA2DS2-VASc score of 2 and who have
endstage CKD (creatinine clearance [CrCl] <15 mL/min) or
are on hemodialysis, it is reasonable to prescribe warfarin
(INR 2.0 to 3.0) for oral anticoagulation IIaB
The direct thrombin inhibitor, dabigatran, and the factor Xa
inhibitor, rivaroxaban, are not recommended in patients with
AF and end-stage CKD or on hemodialysis because of the lack
of evidence from clinical trials regarding the balance of risks
and benefits IIIC

 Warfarin
◦ Give vitamin K 5-10 mg
◦ Fresh frozen plasma
◦ Octaplex
 Prothrombin complex concentrate
 Works within 1 hour
 More effective than plasma at reversing INR
 Small volume
 40 ml usually enough for most patients
 $$$$$

 No specific monitoring test available
 No reversal agents for new anticoagulants

Plasma peak 2h after ingestion 1-4h post ingestion 2-4h after ingestion
Plasma trough 12-24h after ingestion 12-24h after ingestion 16-24h after ingestion
PT cannot be used cannot be used prolonged: may indicate
excess bleeding risk but local
calibration required
INR cannot be used cannot be used cannot be used
aPTT at trough >2x ULN suggests
excess bleeding risk
cannot be used cannot be used
dTT At trough >200ng/ml ≥ 65s: excess
bleeding risk
cannot be used cannot be used
Anti-FXa assays n/a no data yet quantitative; no data on
threshold values for bleeding
or thrombosis
Ecarin clotting time at trough >2x ULN: excess
bleeding risk
not affected; cannot be used not affected; cannot be used12

 Randomized, double-blind, placebo controlled
study
 12 healthy male volunteers received rivaroxaban
20mg BID or dabigatran 150 mg BID for 2.5 days
 Followed by bolus of 50IU/kg PCC (Cofact) or
saline
 Procedure then repeated with the other
anticoagulant treatment

 Rivaroxaban:
◦ Prolonged the PT
◦ Immediately reversed by PCC completely
◦ Endogenous thrombin potential inhibited
◦ Also completely normalized with PC
 Dabigatran:
◦ Affected PTT, ecarin clotting time, and thrombin time
◦ Not reversed by PCC

 Antidote to Dabigatran
 NEJM 6th august 2015 (REVERSE AD TRIAL)
 IV 5g dose
 Rapidly reversed anticoagulant effecs in
minutes
 Pending approval

37
Van Ryn et al Am J Med 2012;125:417

VKA to NOAC INR <2.0: immediate
INR 2.0–2.5: immediate or next day
INR >2.5: use INR and VKA half-life to estimate time to INR <2.5
Parenteral anticoagulant to NOAC:
Intravenous unfractioned heparin
(UFH)
Low molecular weight heparin (LMWH)
Start once UFH discontinued (t½=2h). May be longer in patients with renal impairment
Start when next dose would have been given
NOAC to VKA Administer concomitantly until INR in appropriate range
Measure INR just before next intake of NOAC
Re-test 24h after last dose of NOAC
Monitor INR in first month until stable values (2.0–3.0) achieved
NOAC to parenteral anticoagulant Initiate when next dose of NOAC is due
NOAC to NOAC Initiate when next dose is due except where higher plasma concentrations
expected (e.g. renal impairment)
Aspirin or clodiprogel to NOAC Switch immediately, unless combination therapy needed22

Missed dose: BID: take missed dose up to 6 h after scheduled intake. If not possible skip dose and
take next scheduled dose.
QD: take missed dose up to 12 h after scheduled intake. If not possible skip dose and
take next scheduled dose.
Double dose: BID: skip next planned dose and restart BID after 24 h.
QD: continue normal regimen.
Uncertainty about intake: BID: continue normal regimen.
QD: take another dose then continue normal regimen.
Overdose: Hospitalization advised.
25

Dabigatran Apixaban Edoxaban * Rivaroxaban
No important bleeding risk and/or local haemostasis possible: perform at trough level
(i.e. ≥12h or 24h after last intake)
Low risk High risk Low risk High risk
Low
risk
High risk Low risk High risk
CrCl ≥80 ml/min ≥24h ≥48h ≥24h ≥48h
no data
yet
no data
yet
≥24h ≥48h
CrCl 50–80 ml/min ≥36h ≥72h ≥24h ≥48h
no data
yet
no data
yet
≥24h ≥48h
CrCl 30–50 ml/min
§
≥48h ≥96h ≥24h ≥48h
no data
yet
no data
yet
≥24h ≥48h
CrCl 15–30 ml/min
§
not
indicated
not
indicated
≥36h ≥48h
no data
yet
no data
yet
≥36h ≥48h
CrCl <15 ml/min no official indication for use
40
www.escardio.org/EHR
A
Last intake of drug before elective surgical intervention
*no EMA approval yet.; Low risk: surgery with low risk of bleeding. High risk: surgery with high risk of bleeding § many of these patients may be
on the lower dose of dabigatran (i.e. 2x110 mg/d) or apixaban (i.e. 2x2.5 mg/d), or have to be on the lower dose of rivaroxaban (15 mg/d).

Procedures with immediate and complete
haemostasis:
Atraumatic spinal/epidural anethesia
Clean lumbar puncture
Resume 6–8 h after surgery
Procedures associated with immobilization:
Procedures with post-operative risk of bleeding:
Initiate reduced venous or intermediate dose of LMWH 6–8
h after surgery if haemostasis achieved.
Restart NOACs 48–72h after surgery upon complete
haemostasis
Thromboprophylaxis (e.g. with LMWH) can be initiated 6-8 h
after surgery
41
www.escardio.org/EHR
A

 Discontinue NOAC.
 Try to defer surgery at least 12 h and ideally 24 h after last dose.
 Urgent surgery associated with much higher rates of bleeding than
elective procedures, but lower than VKA-treated patients. 1
 Coagulation tests can be considered (classical test or specific tests) but
strategy based on these results has never been evaluated. Therefore
such strategy cannot be recommended and should not be used routinely.
43
1. Healey et al, Circulation 2012:126;343-8

 No data
 Currently contraindicated

 Warfarin has been the benchmark since long
 But, limitations with warfarin have paved way
for NOAC’S
 NOAC’S have their own limitations
 One not superior over other
 Decide case to case basis

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