NOAC( Novel Oral Anticoagulants) uses in the current era

NOAC( Novel Oral Anti-coagulants)
-
uses in the current era

What are anti-coagulants?
 Anticoagulants, commonly known as blood thinners, are chemical
substances that prevent or reduce coagulation of blood, prolonging the clotting
time.
 Some of them occur naturally in blood-eating animals such
as leeches and mosquitoes, where they help keep the bite area unclotted long
enough for the animal to obtain some blood.
 As a class of medications, anticoagulants are used in therapy for thrombotic
disorders.
 Oral anticoagulants (OACs) are taken by many people in pill or tablet form, and
various intravenous anticoagulant dosage forms are used in hospitals.
 Some anticoagulants are used in medical equipment, such as sample
tubes, blood transfusion bags, heart-lung machines, and dialysis equipment.
 One of the first anticoagulants, warfarin, was initially approved as a rodenticide.

What are the difference between antiplatelet,
anticoagulants and thrombolytics

What are the difference between antiplatelet,
anticoagulants and thrombolytics
 Anticoagulants are closely related to antiplatelet
drugs and thrombolytic drugs by manipulating the various
pathways of blood coagulation.
 Specifically, antiplatelet drugs inhibit platelet aggregation
(clumping together), whereas anticoagulants inhibit
specific pathways of the coagulation cascade, which
happens after the initial platelet aggregation and
ultimately leads to formation of fibrin and stable
aggregated platelet products.

Indications of Anticoagulants
 Atrial fibrillation — commonly forms an atrial appendage clot
 Coronary artery disease
 Deep vein thrombosis— can lead to pulmonary embolism
 Ischemic stroke
 Hypercoagulable states (e.g., Factor V Leiden) — can lead to deep vein thrombosis
 Mechanical heart valves
 Myocardial infarction
 Pulmonary embolism
 Restenosis from stents
 Cardiopulmonary bypass (or any other surgeries requiring temporary aortic occlusion)
 Heart failure

Classification of Anticoagulants

Mechanism of action of anticoagulants

June 2011
Disclaimer: Dabigatran etexilate is only approved for clinical use in stroke prevention in atrial fibrillation in certain countries. Please be aware that there may be national differences between countries regarding specific
medical information, including licensed uses, so please check local prescribing information for further details
Atrial Fibrillation
 Atrial fibrillation, known as AF or Afib, is an
irregular, rapid heart rate that may cause
symptoms like heart palpitations, fatigue, and
shortness of breath.
 AF occurs when the upper chambers of the
heart (atria) beat out of rhythm.
 As a result, blood is not pumped efficiently to
the rest of the body, causing an unusually fast
heart rate, quivering, or thumping sensations
in the heart.
Atrial fibrillation From Wikipedia, the free encyclopedia

June 2011
Classification of A-Fib
paroxysmal atrial fibrillation – episodes come and go, and usually stop
within 48 hours without any treatment
persistent atrial fibrillation – each episode lasts for longer than 7 days
(or less when it's treated)
long-standing persistent atrial fibrillation – where you have had
continuous atrial fibrillation for a year or longer
permanent atrial fibrillation – where atrial fibrillation is present all the
time

June 2011
Stroke is the leading complication of AF
• AF is associated with a fivefold
higher stroke risk overall1
• Without prevention,
approximately 1in 20 patients will
have a stroke each year2
• AF is responsible for nearly a third
of all strokes,3 and is the leading
cause of embolic stroke4

June 2011
What are the key priorities for stroke prevention
in AF?
As physicians, we
want reassurance that we
can provide our patients
with protection from harm
Our patients view a
moderate stroke as equal to
death, and a severe stroke as
worse than death1
Best
protection
with OAC
OAC, oral anticoagulant
1. Lahaye et al. Thromb Haemost 2014

June 2011
How to Assess Bleeding risk and Stroke
risk of AF Patients?

June 2011
Stroke Risk Assessment With CHA2DS2-VASc
CHA2DS2-VASc criteria1,2 Score
Congestive heart failure/
left ventricular dysfunction
1
Hypertension 1
Age 75 years 2
Diabetes mellitus 1
Stroke/transient ischaemic attack/TE 2
Vascular disease (prior myocardial infarction,
peripheral artery disease or aortic plaque)
1
Age 65–74 years 1
Sex category (ie, female gender) 1 *Theoretical rates without therapy; assuming that warfarin provides a
64% reduction in stroke risk, based on Hart RG, et al. 2007.
Total score3,4 Patients
(n = 7329)
Adjusted stroke
rate (%/year)*
0 1 0.0
1 422 1.3
2 1230 2.2
3 1730 3.2
4 1718 4.0
5 1159 6.7
6 679 9.8
7 294 9.6
8 82 6.7
9 14 15.2
1. Lip GY, et al. Chest. 2010;137(2):263-272. 2. Lip G, et al. Stroke. 2010;41:2731-2738. 3. Camm J, et al. Eur Heart J. 2010;31:2369-2429.
4. Hart RG, et al. Ann Intern Med. 2007;146:857-867.

June 2011
Bleeding Risk Assessment on Anticoagulation—HAS-BLED
HAS-BLED risk criteria1 Score
Hypertension 1
Abnormal renal or liver function (1
point each)
1 or 2
Stroke 1
Bleeding 1
Labile INRs 1
Elderly
(eg, age >65 years)
1
Drugs or alcohol
(1 point each)
1 or 2
1. Pisters R, et al. Chest. 2010; [Epub ahead of print]. 2. Camm J, et al. Eur Heart J. 2010;31:2369-2429.
INR = international normalised ratio
HAS-BLED
total score2 N
Number
of bleeds
Bleeds per 100
patient-years*
0 798 9 1.13
1 1286 13 1.02
2 744 14 1.88
3 187 7 3.74
4 46 4 8.70
5 8 1 12.5
6 2 0 0.0
7 0 – –
8 0 – –
9 0 – –
*P value for trend = .007

June 2011
Recommendations Class Level
Oral anticoagulation therapy to prevent thromboembolism is recommended for all male AF patients with a CHA2DS2-
VASc score of 2 or more.
I A
Oral anticoagulation therapy to prevent thromboembolism is recommended in all female AF patients with a CHA2DS2-
VASc score of 3 or more.
I A
Recommendations Class Level
When oral anticoagulation is initiated in a patient with AF who is eligible for a NOAC
(apixaban, dabigatran, edoxaban, or rivaroxaban), a NOAC is recommended in
preference to a Vitamin K antagonist.
I A

June 2011
Limitations/ Disadvantages of Vitamin K Antagonist (VKA)
Unpredictable response
Routine coagulation
monitoring
Slow onset/offset
of action
Warfarin resistance
CYP 2C9, VKORC1 genetic
polymorphisms
Numerous drug-drug
interactions
Numerous food-drug
interactions
Frequent dose adjustments
Narrow therapeutic
window
(INR range 2-3)
Intracranial
bleeding
VKA therapy
has several
limitations that
make it
difficult to use
in practice

June 2011
For Warfarin Target Range of INR 2.0–3.0. Why?
Patients Are at either Increased Risk of Stroke or Bleeding
1.3
1.5
1.7 Nearly 2x
Nearly 3x
7-fold increase
…the risk of stroke rises1
As INR falls…
3.0
4.0
2x
…so does the risk of bleeding2
1. Hylek EM, et al. N Engl J Med. 1996;335:540-546. 2. Reynolds MW, et al. Chest. 2004;126:1938-1945.
As INR rises…

June 2011
Search for an alternative to warfarin started in 1990s

June 2011
Different terminology of NOACs
Keitaro Senoo et al. Oral Anticoagulants for Stroke Prevention in Atrial Fibrillation. Curr ProbCardiol. 2014;39:319–344
• NOACs are no longer novel agents
• Non Vit. K Antagonist (NOAC)
• Europe- Direct OAC (DOAC)
• North America- Target specific OAC

June 2011
Mechanism of Action of NOAC?
26
Fibrin
IX
IXa
X
VIIIa
Thrombin
Fibrinogen
Direct Factor Xa inhibitors
• Apixaban
• Rivaroxaban
• Edoxaban
Va
Xa
II
AT
Direct thrombin inhibitors
• Dabigatran Etexilate
Tissue factor/VIIa
Target specific molecules in the coagulation cascade

June 2011
NOACs Pharmacology
Dabigatran Rivaroxaban Apixaban Edoxaban
Mechanism of
action
Direct thrombin
inhibitor
Selective Fxa
inhibitor
Selective Fxa
inhibitor
Selective Fxa
inhibitor
Time to peak
concentration
(Tmax)
1-3 hours 2-4 hours 3-4 hours 1-2 hours
Plasma protein
binding
35% 92-95% Approx. 87% About 55%
Renal
elimination
80%
(unchanged)
33% (unchanged) 27%
50%
(unchanged)
Half life 12-17 hrs
5-9 hrs (young)
11-13 hrs elderly)
Approximately 12
hrs
10 to 14 hrs

June 2011
Properties of different NOACs????

June 2011
FDA approval of oral anti-coagulants??

June 2011
Superiority of dabigatran(NOAC)
Potent and reversible oral Direct Thrombin Inhibitor1
Inhibiting both clot bound and free thrombin1
Predictable and consistent PK profile2,3
Rapid onset/offset of action 2 (Peak plasma levels within 2 hours)
Anticoagulation monitoring—Not required4
Half-life 12–17 hours (twice-daily dosing)1
Low drug–drug interactions (not metabolised by CYP450 enzymes)1,5
No food–drug interactions
~80% renal excretion
1. Pradaxa: SmPC, 2009; Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151 2. Stangier J, et al. Clin Pharmacokinet 2008;28:47–59.
3. Stangier J. Clin Pharmacokinet. 2008;47:285-295. 4. Stangier J, et al. Br J Pharmacol. 2007;64:292–303. 5. Blech S, et al. Drug Metab
Dispos. 2008;36:386-399.

June 2011
Safety and
efficacy of
NOAC????

June 2011
 RE-LY was a PROBE (prospective, randomized, open-label with
blinded endpoint evaluation) study
 SE, systemic embolism. Connolly et al. N Engl J Med 2009;361:1139
Dabigatran 150 mg BID
n=6076
Dabigatran 110 mg BID
n=6015
Warfarin
(INR 2.0–3.0)
n=6022
R
Blind dosing and blinded end point evaluation Open
AF with ≥1 risk factor for stroke
Absence of contraindications
18113 patients from 951 centers in 44 countries
Primary endpoint: stroke/SE
Treatment assignment not based on
patients’ risk profiles

June 2011
Dabigatran showed a favorable safety profile (bleeding) and
efficacy vs warfarin in the RE-LY trial
P value
1.0
0.5
0.0 2.0
1.5
HR (95% CI)
Vascular mortality
ICH
Major GI bleeding
D150 D110
Favors dabigatran Favors warfarin
Life-threatening bleeding
Stroke/SE
Major bleeding
0.27
<0.001
0.003
0.41
0.21
0.04
<0.001
<0.001
0.52
0.001
<0.001
0.04
 D150, dabigatran 150 mg BID; D110, dabigatran 110 mg BID; ICH, intracranial hemorrhage
 Connolly et al. N Engl J Med 2010;363:1875; Connolly et al. N Engl J Med 2014;371:1464

June 2011
Evolution of NOACs in SPAF
6 trials of
Warfarin
1989-
1993
RE-LY
Dabigatran
2009
ROCKET-AF
Rivaroxaban
2010
ARISTOTLE
Apixaban
2011
ENGAGE
AF-TIMI 48
Edoxaban
2013

June 2011
When do I give which one ???

June 2011
Dabigatran 150 mg is the only agent to achieve
superiority over warfarin compared to all NOAC for most common Ischemic
Strokes
*Only ischaemic strokes are counted here. The no. of strokes with unknown type were 7 and 11 in the rivaroxaban and warfarin groups, respectively.
**Unknown type of stroke occurred in 14 patients in the apixaban group and 21 patients in the warfarin group. Among the patients with ischaemic strokes, haemorrhagic
transformation occurred in 12 patients with apixaban and 20 patients with warfarin.
162 (0.97) 175 (1.05)
149 (1.34) 161 (1.42)
0.5 1.0
Favours NOAC Favours warfarin
0.74–1.13
0.92
0.75–1.17
0.94
159 (1.34) 143 (1.21)
Dabi 110
(ITT)
0.88–1.39
1.11
1.5
0.0
Riva*
(safety AT)
Apixaban**
(ITT)
111 (0.92) 143 (1.21)
Dabi 150
(ITT)
0.59–0.97
0.76
2.0
NOAC Warfarin HR 95% CI
No. of events (%/yr)
Edoxaban**
Low dose (ITT)
High dose (ITT) 236 (1.25) 235 (1.25) 1.00 0.83–1.19
236 (1.25) 333 (1.77) 1.41 1.19–1.67

June 2011
Safety & Efficacy End Points of NOAC Trials
Similar
Similar
15%
CV mortality Similar 14%
Similar Similar
Similar
35% 21%
Stroke/SE
41%
69%
74%
Haemorrhagic
stroke
49% 46%
No direct head-to-head comparison
Relative risk reductions vs warfarin; SE, systemic embolism
1. Connolly et al. N Engl J Med 2014; 2. Connolly et al. N Engl J Med 2010; 3. Pradaxa SPC; 4. Granger et al. N Engl J Med 2011; 5. Lopes et al. Lancet 2012; 6. Patel
et al. N Engl J Med 2011; 7. Giugliano et al. N Engl J Med 2013
Dabigatran1–3 Edoxaban7
Apixaban4,5
Rivaroxaban6
110 mg BID
150 mg BID 60/30 mg OD
5/2.5 mg BID 20/15 mg OD
Similar
Similar
24%
Ischaemic
stroke
Similar Similar
(RE-LY) (ENGAGE AF-TIMI 48)
(ARISTOTLE) (ROCKET AF)

June 2011
No direct head-to-head comparison
Relative risk reductions vs warfarin; ICH, intracranial haemorrhage
1. Connolly et al. N Engl J Med 2014; 2. Connolly et al. N Engl J Med 2010; 3. Granger et al. N Engl J Med 2011; 4. Patel et al. N Engl J Med 2011; 5. Giugliano et al. N
Engl J Med 2013
33% 53%
59% 58%
ICH
70%
Dabigatran1,2 Edoxaban5
Apixaban3
Rivaroxaban4
110 mg BID
150 mg BID 60/30 mg OD
Similar Similar
20% 31% 20%
Major
bleeding
5/2.5 mg BID 20/15 mg OD
(RE-LY) (ENGAGE AF-TIMI 48)
(ARISTOTLE) (ROCKET AF)

June 2011
Four pivotal studies including over 71000 patients have compared
NOACs with warfarin for stroke prevention in AF
6076
6015
6022
5637
1474
7116
8692
428
9081
5251
1784
5249
1785
7036
0
2000
4000
6000
8000
10000
Number
of
patients
150 mg 110 mg W
BID BID
Dabigatran
RE-LY®1
20 mg 15 mg W
OD OD
Rivaroxaban
ROCKET-AF2
5 mg 2.5 mg W
BID BID
Apixaban
ARISTOTLE3
60 mg 30 mg 30 mg 15 mg W
OD OD OD OD
Edoxaban
ENGAGE AF4
Availability of two independently studied dabigatran doses provides robust data
for individualized dosing

June 2011
Which assays can be used to assess coagulation status with the NOACs?
Dabigatran Rivaroxaban Apixaban Edoxaban
aPTT
TT, dTT
ECT
Anti-FXa assays (
PT
INR
† †
*
‡
*
¶
 












()








?

June 2011
How to Switch Patients Form Warfarin to NOAC ?
How to switch:*
Start patient
on dabigatran
Wait for INR
to drop to <2
Stop VKA
Patient
on VKA
*Patient must be eligible for dabigatran (see prescribing information for dosing and contraindications); renal function should be
assessed prior to initiation of treatment with dabigatran to exclude patients with severe renal impairment
(i.e. CrCl <30 mL/min).
Pradaxa®: SPC, 2016
M

How to manage
bleeding of
patients taking
NOAC????

Covid-19 and Role of
anticoagulants????

Anticoagulant
Anti-inflammatory
Endothelial protection
Antiviral?
Potential impact of
Heparin
In COVID
HEPARIN & COVID-19

 strongly recommended each individual should be on DVT
Prophylaxis (LMWH 40 mg SC daily or Heparin 5000 units SC BD) until
there is any contraindication.
 COVID-19 can lead to hypercoagulable state due to systemic
hyperinflammation and direct viral endothelial injury.
D-dimers and DIC screening (INR, APTT, Fibrinogen) should be routinely checked.
Should be vigilant for venous thromboembolism (DVT/PE) and
consider for therapeutic anticoagulation if there is evident clinical or
biochemical (High level of D-dimer >1,000-2,000 ng/ml) suspicion.
There is post discharge 4-6 weeks of oral anticoagulation
(Rivaroxaban 10 mg daily) or prophylactic LMWH also suggested in
high risk cohort.
Anticoagulation in covid-19

• The 31% incidence of thrombotic
complications in ICU patients with
COVID-19 infections is remarkably
high
THROMBOTIC
EVENT
Incidence of thrombotic complications in critically ill ICU patients with COVID-19
Author links open overlay panelF.A.KlokaM.J.H.A.KruipbN.J.M.van der MeercM.S.ArbousdD.A.M.P.J.GommerseK.M.KantfF.H.J.KapteinaJ.van PaassendM.A.M.StalsaM.V.Huismana1H.Endemane1

• UFH may be a better choice of
anticoagulant in the COVID-19
population when compared to LMWH.
In outpatient settings, it may be
appropriate to transition qualified
patients on VKA to a DOAC to reduce
frequency of the needed laboratory
monitoring.
PREVENTION OF
THROMBOTIC EVENT
Anticoagulation Options for Coronavirus Disease 2019 (COVID-19)-Induced Coagulopathy
Alla Turshudzhyan 1. Internal Medicine, University of Connecticut Health Center, Farmington, USA

• The use of LMWH, UFH, or fondaparinux at doses indicated for
prophylaxis of venous thromboembolism (VTE) is strongly
advised in all COVID-19 hospitalized patients; patients with
anticoagulant contraindications should be treated with limb
compression.
• Moreover, it should be noted that approximately 50% of those
patients who have died of COVID-19 in Italy had three or more
comorbidities such as atrial fibrillation or ischemic heart disease,
often requiring anticoagulant or antiplatelet treatment; the
management of these is particularly challenging due to the
potential interactions of concomitant therapies, namely direct
oral anticoagulants (DOAC).
PREVENTION OF
THROMBOTIC EVENT
COVID-19 and haemostasis:a position paper from Italian Society on Thrombosis and Haemostasis
(SISET)
Marco Marietta1, Walter Ageno2, Andrea Artoni3, Erica De Candia4,5, Paolo Gresele6,
Marina Marchetti7, Rossella Marcucci8, Armando Tripodi

• LMWHs may be preferred in
patients unlikely to need
procedures. The benefit of oral
anticoagulation with DOACs
includes the lack of need for
monitoring.
THROMBOTIC
EVENT
JOU RNAL OF THE AME R I CAN COL L EG E OF CARD I OLOGY VOL. 7 5 , NO . 2 3 , 2 0 2 0
ª 20 2 0 B Y THE AME R ICAN C O L L E G E OF CARDI O L O G Y FOUNDAT ION
P U B LI S H ED B Y E L S E VI E R

WHAT IS THE IDEAL
ANTICOAGULANT
STRATEGY AND DOSE?
Bikdeli B, Madhavan MV, Jimenez D, et al. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up. J Am Coll Cardiol. 2020;Epub ahead of print.
• Truthfully, nobody knows what the best answer is
right now, but running the issue by our panel the
consensus was that most of these patients,
especially those that are hospitalized in the ICU,
need the preventive dose of blood thinners,” said
Bikdeli.

D-DIMER
• One of the most common laboratory findings for
patients requiring hospitalization has been an
elevated D-dimer . Tang et al. have identified that
markedly elevated D-Dimer is a mortality predictor
and if increased three- to four-fold, the patient
should be considered for hospitalization even if
asymptomatic as elevated D-dimer increases
thrombin generation .
• Dabigatran reduce D-dimer level by 51%.(Siegbahn
et al)
Tang N, Li D, Wang X, Sun Z: Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020, 18:844-847. 10.1111/jth.14768
D-dimer and factor VIIa in atrial fibrillation – prognostic values for cardiovascular events and effects of anticoagulation therapy
A RE-LY substudy
Agneta Siegbahn, Jonas Oldgren, Ulrika Andersson, Michael D. Ezekowitz, Paul A. Reilly, Stuart J. Connolly, Salim Yusuf, Lars Wallentin, John W. Eikelboom

VTE
• Numerous Journal suggest that, VTE rate is high in Covid-
19 patient particularly who are critically ill.
In critically ill patients with COVID-19, we suggest
anticoagulant thromboprophylaxis with LMWH over
anticoagulant thromboprophylaxis with UFH; and we
recommend anticoagulant thromboprophylaxis with LMWH
or UFH over anticoagulant thromboprophylaxis with
fondaparinux or a DOAC.
Dabigatran has similar effects on VTE recurrence and a
lower risk of bleeding compared with warfarin for the
treatment of acute VTE
Volume 129, Issue 7, 18 February 2014, Pages 764-772
https://doi.org/10.1161/CIRCULATIONAHA.113.004450

STROKE & SAFETY
• In a study(Yaghi et al) in has been seen that,63.6% of
the stroke patients with active SARS-CoV-2 infection
died during their hospitalization. Therefore it is
important to prevent stroke and Dabigatran is the best
option for preventing stroke.
StrokeVolume 51, Issue 7, July 2020;, Pages 2002-2011
https://doi.org/10.1161/STROKEAHA.120.030335

Dose
Suggested Dose from our side:
Pradaxa 150 mg OD for 3 months
Or
Pradaxa 110mg OD for 3 months
Each capsule should be taken
with/without food but with a full glass
of water to prevent dyspepsia.
• Contraindication:
1. Prior GI bleed/ or any history of
bleeding
2. Crcl less than 30 ml/min
3. D-Dimer< 2 fold
4. Mechanical/Prosthetic Heart valve

How to switch from Warfarin to
NOAC/ LMWH/Heparin and Vice-
versa??

June 2011
How to switch a patient from NOAC back to warfarin/Heparin?
CrCl in mL/min Recommendation
≥50 Start VKA 3 days before stopping Dabigatran
≥30 to <50 Start VKA 2 days before stopping Dabigatran
15–30 Start VKA 1 day before stopping Dabigatran
VKA = vitamin K antagonist
Huisman M et al. Thromb Haemost
doi:10.1160/TH11-10-0718
Dabigatran to parenteral
Start parenteral anticoagulant 12 hours after last dose of Dabigatran
Start times for VKAs are based on renal function:
Starting a parenteral anticoagulant:

June 2011

June 2011
Switching between anti-coagulants

June 2011
When and how
anticoagulants stopped
before surgery?

June 2011
Recommendation of Dabigatran for Surgical Intervention

June 2011
Discontinuation of anti-coagulants before surgery?

NOAC( Novel Oral Anticoagulants) uses in the current era

In this document