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NOACS IN ATRIAL
FIBRILLATION
DR SANKHA SUBHRA DAS
MD. MRCP(UK) DNB ( CARDIOLOGY)
CONSULTANT INTERVENTIONAL
CARDIOLOGIST
APOLLO GLENEAGLES HOSPITALS, KOLKATA
ASST PROFESSOR; KPC MEDICAL COLLEGE
FEW WORDS
Commonest arrhythmia in day to day practice
Benign looking but with malignant complications
End stage arrhythmia of several cardiovascular disorder
Acute/ chronic AF can be life threatening
Most disturbing arrhythmia to the EP specialist
Commonest arrhythmia in acute care units
Thromboembolic complications could be fatal
Large undetected population in the elderly
AF begets AF; Structural remodelling aggravates / worsens underlying cardiac disorder
AF INCIDENCE IS INCREASING
WITH AGEING POPULATION
AND
RISE IN CV DISEASE
5-FOLD Increase STROKE
risk
3-FOLD Increase HF risk
2-FOLD Increase DEMENTIA
and MORTALITY
Multiple
HOSPITALIZATIONS
AF causes half of all dangerous embolic strokes
Jan 20, 2015 Author: Michael J Schneck, MD,
MBA;Cardioembolic stroke- Medscape
AF STROKES ARE SEVERE STROKES
20% are fatal
60% are disabling
Compared to non AF strokes:-
70% increased hospital mortality
40% decrease in chance of discharge home
20% increase length of hospital stay
Gladstone DJ, et al. Stroke. 2009; Ther Clin Risk Manag. 2016
Jun 29;12:1057-64.
Jorgensen HS, et al.Stroke 1996;27:1765–9
VKA: 60 YEARS OF USE!YET UNDER-PRESCRIBED, BARRIER
TO STROKE PREVENTION
Average TTR =
63%
Stroke &
Mortality risk
decreased if TTR
>70%
WHAT IS THE NEED FOR A NOAC?
Unpredictable
response
Routine
coagulation
monitoring
Slow onset/offset
of action
Risk of Bleeding
Complications
VKA therapy has
several
limitations that
make it difficult
to use in practiceNumerous drug-
drug interactions
Numerous food-
drug interactions
Frequent dose
adjustments
Narrow
therapeutic
window
(INR range 2-3)
J. Med. Toxicol. (2011) 7:281–287
EVERYTHING CHANGES WITH
TIME ......
TARGETS FOR NOVEL ANTITHROMBOTIC
AGENTS IN THE
COAGULATION CASCADE
AT, antithromb in
Fib rin
IX
IXa
X
VIIIa
Thrombin
Fib rinogen
Direct factor Xa
inhibitors:
Apixaban 4,5
Rivaroxaban 6
Edoxaban 7
Betrixaban 8
Va
Xa
II
AT
Direct thrombin
inhibitors:
Dabigatran etexilate 9
Indirect factor Xa
inhibitors:
Id raparinux 2
Tissue fac tor/ VIIa
1. Adapted from Turpie AG. Eur Heart J. 2008;29:155-165. 2. Bousser MG, et al. Lancet. 2008;371:315-321. 3. NCT00580216. www.ClinicalTrials.gov. Accessed September 9, 2010. 4.Lopes RD, et al. Am Heart J. 2010;159:331-339. 5.Eikelboom JW, et al. Am Heart J. 2010;159:348-353. 6.ROCKET-AF Study Investigators. Am Heart J. 2010;159:340-347. 7.NCT00781391. www.ClinicalTrials.gov. Accessed September 9, 2010. 8.NCT00742859. www.ClinicalTrials.gov. Accessed September 9, 2010. 9. Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151. 10. Lip GY, et al. Eur Heart J. 2009;30:2897-2907
NOVEL ORAL ANTI-
COAGULANTS
Easier administra
tion
Predictable dose
Less drug and
dietary interaction
s
Safety and efficacy profile
New anticoagulants target specific factors in the common
coagulation pathway, unlike warfarin, which affects factors in
the extrinsic, intrinsic pathway. They inhibit
Thromb
in
Key step in coagulation pathway,
that mitigates the propagation of
thrombin
Factor
Xa
EVOLUTION OF NOACS
2. EVALUATION OF AF PATIENTS
ASSESSMENT OF RISK OF STROKE IN AF PATIENT
*
* annual
THE INDIAN SCENARIO: IHRS-AF
REGISTRY
1537 AF Patients enrolled from 24 hospitals for 12 cities, 1 year follow up
52.4% patients had NVAF, Mean Age: 57.4 years
All cause mortality: 6.5% at 1 year
In NVAF patients, only 54% were on anticoagulants
20.4%
33%
35.1%
11%
10.5%
20.3%
45.6%
22.6%
Vora A, et al. Indian Heart J 2017; 69:43-
47.
2/3 pts > 2 Score
1/2 pts > 2 Score
SCORING SYSTEMS MAY BE USED TO SELECT
VKA/DOACS
SAMe-TT2R2 score
• Score of 0–2 : High
probability to achieve a high TTR
and thus, a VKA can be
prescribed
• Score >2: Poor TTR expected,
DOAC would be preferred
European Heart Journal – Cardiovascular Pharmacotherapy 2015; 1; 150–152
ELIGIBILITY FOR NON-VITAMIN K
ANTAGONIST ORAL ANTICOAGULANTSEHRA Type 2 valvular
heart disease
• Native valvular stenoses
• Insufficiencies as well as mitral valve repair
• Bioprosthetic valve replacements
• Transaortic valve intervention
European Heart Journal (2018) 39, 1330–1393
FOOD AND DRUG- DRUG INTERACTIONS
Rivaroxaban taken with food : Significant increase of bioavailability; Not with other NOAC
Apixaban; Rivaroxaban; Edoxaban administered in crushed form : No change in bioavailability
Oral solution of apixaban available
Dabigatran capsules must not be opened –significant increase in bioavailability
P-gp transporter in the gut involved in NOAC resecretion; CYP 3A4 involved in NOAC metabolism.
Amiodarone; Dronedarone; verapamil; quinidine are strong P-gp inhibitors
DRUG – DRUG INTERACTIONS
Rivaroxaban and Apixaban involved in CYP 3A4 mediated elimination.
Inhibitors or inducers of CYP 3A4 alter the plasma concentration of NOACS
Strong inducers of CYP3A4 & P-gp are Rifampicin & Carbamazepine : markedly reduce NOAC plasma level.
Immediate release verapamil may increase Dabigatran level > 180%; Dabigatran to be taken > 2 hrs later; Slow release verapamilcause less rise in dabigatran. 110 mg BD preferred
Ticagrelor is a strong P-gp inhibitor; Loading dose of Ticagrelor cause rise in Dabigatran level
Drug
interactions
with
NOACs.
i n d i a n h e a r t j o u r n a l 6 7 ( 2 0 1 5 ) s 1 3
SAFE PRESCRIBING OF NOACS
Counselling the importance of strict adherence to therapy is the most crucial aspect of NOAC Rx
(reinforce at every FU)
Routine monitoring:
Hb and liver function (annually)
Renal function: Annually for CKD stage I–II (CrCl≥60 ml/min)
6 monthly for CKD stage III (CrCl30–60 ml/min)
3 monthly for CKD stage IV (CrCl≤30 ml/min)
Regular (3 monthly) follow up:
Counselling
Side effects
Medication review (interactions)
INITIATION; MONITORING;SAFETY
Always assess risk benefit ratio
Anticoagulant card
Patient education regarding adherence; missing
Education regarding dose asjustment; Food; DDI;
Intercurrent infection; Renal/ liver dysfunction
Regular assessment of bleeding risk
High bleeding risk goes hand in hand with
embolic risk
Frailty & risk of fall : Not a C/I
Real world adherence : 38-99% for NOACS
IMPROVED ADHERENCE/
COMPLIANCE
On line education/ Booklets/ Group discussion
Family members need to be educated
Pre-specified follow up schedule; Educate GPs;
Pharmacist; Anticoagulation clinics; NP
Day marked blister pack; Smart phone
reminders
OD dose better for compliance; More
anticoagulant fluctuation effect when missed
OD than BD dose
Some patients may voluntarily opt for VKA
In case of non compliant pts : VKA may be preferred;
INR monitoring difficult ; uncertain results
WHEN TO MEASURE THE ANTICOAGULANT EFFECT OF
NOACS
Routine monitoring of coagulation not required, but quantitative
assessment of drug exposure may be needed in emergency
situations:
serious bleeding and thrombotic events
urgent surgery
renal or hepatic insufficiency
potential DDI
suspected overdosing
10
www.escardio.org/EHRA
MEASURING THE ANTICOAGULANT EFFECT OF
NOACSDabigatran Apixaban Edoxaban RivaroxabanPlasma peak 2h after ingestion 1-4h post
ingestion
1-2h after ingestion 2-4h after ingestion
Plasma trough 12-24h after
ingestion
12-24h after
ingestion
12-24h after
ingestion
16-24h after
ingestion
PT cannot be used cannot be used prolonged but no
known relation with
bleeding risk
prolonged: may
indicate excess
bleeding risk but
local calibration
required
INR cannot be used cannot be used cannot be used cannot be used
aPTT at trough >2x ULN
suggests excess
bleeding risk
cannot be used prolonged but no
known relation with
bleeding risk
cannot be used
dTT At trough
>200ng/ml ≥ 65s:
excess bleeding
risk
cannot be used cannot be used cannot be used
Anti-FXa assays n/a no data yet quantitative; no data
on threshold values
for bleeding or
thrombosis
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 used
not affected; cannot
be used
12www.escardio.org/EHRA
NOAC – VKA CHANGEOVER
NOAC -- VKA CHANGEOVER
DOSING ERRORS
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.European Heart Journal (2018) 39, 1330–1393
EHRA 2018 PRACTICAL GUIDE FOR
DOAC USE IN ELECTIVE
PROCEDURES
NOACS AND INTERACTIONS
Obesity affects volume of distribution of NOAC
Obesity increases risk of AF
Concern about NOAC efficacy in very obese
pts
Apixaban showed same efficacy in BW <60/> Kg
VKA are preferred in BMI > 40Kg/m2
Low BW demands reduction of NOAC dose
NOAC C/I in pregnancy and breast feeding
NOACS have significant drug interaction
with anti-epileptics
NOACS AND CKD
No RCT on use of NOACS in Cr Cl< 30
No prospective trial of VKA in severe CKD
Europe : Apixaban; Rivaroxaban; Edoxaban
Apixaban; Rivaroxaban preferred
Dabigatran : 75 mg BD; Approved in USA
Conflicting role of VKA/ NOACS in ESRD Cr Cl< 15
Warfarin : Calciphylaxis ; painful calcification of
arteries & arterioles
Apixaban : 5 mg BD approved ( 2.5 mg BD) RVXN :
10 mg OD; Edoxaban : 15 mg OD
No data regarding use of NOACS after
transplantation
SPECIAL SUBGROUP - CRF
38
ACS WITH AF
Incidence of AF in ACS : 10 – 21 %
Severity of MI and age
In hosp mortality 25 %( With AF) vs 16 %
(Without AF)
30 day mortality 29 % (With AF) vs 19 %
(Without AF)
Stroke rates higher in MI with AF
Triple therapy used for 4 – 6 wks ( US guide)
Only DAPT therapy for ACS with low score of 0-1
RIVAROXABAN IN PCI: PIONEER AF-
PCI
R
A
N
D
O
M
I
Z
E
1 mo: 16%
6 mos: 35%
12 mos: 49%
Rivaroxaban ® 15 mg qd*
Clopi 95%, Ticag 4%,
Prasugrel 1%
Rivaroxaban 15mg
QD
Aspirin 75-100 mg
qd
Rivaroxaban 2.5 mg bid
Clopi 95%, Ticag 4%,
Prasugrel 1% Aspirin
75-100 mg qd‡
VKA (target INR 2.0-
3.0)
Aspirin 75-100 mg qd
TTR 65%
VKA (target INR 2.0-3.0)
Clopi 95%, Ticag 4%,
Prasugrel 1%
Aspirin 75-100 mg qd
≤ 72
hours
After
Sheath
removal
WOEST
Like
ATLAS
Like
Triple
Therapy
1 mo: 16%
6 mos: 35%
12 mos: 49%
Gibson et al. AHA 2016
2100
patients
with NVAF
Coronary
stenting
No prior
stroke/TIA,
GI bleeding,
Hb<10,
CrCl<30
Cu
mu
lati
ve I
nci
den
ce o
f C
lin
ica
lly
Sig
nif
ican
t
Ble
ed
ing(%
)
Gibson et al. NEJM; AUG vol 2016
Riva + P2Y12 (Group 1) v. VKA + DAPT (Group 3)
HR=0.59 (95% CI: 0.47-0.76)
RRR = 41%
p <0.000013
ARR=9.9
NNT=11
Riva + DAPT (Group 2) v. VKA + DAPT (Group 3)
HR=0.63 (95% CI: 0.50-0.80)
RRR = 37%
p <0.00018
ARR=8.7
NNT=12
PIONEER AF PCI : Primary
End Points
0
5
10
15
20
25
30
Group 1 Group 2 Group 3
16.818
26.741
%
37
%
PIONEER AF PCI : ALL CAUSE DEATH &
REHOSPITALIZATION REDUCED WITH
RIVAROXABAN
21% reduction of all cause death and rehospitalization with 15 mg
Rivaroxaban* and clopidogrel
*Rivaroxaban dosed at 10 mg once daily in patients with CrCl of 30 to <50 mL/min.
DABIGATRAN WAS USED IN PCI
PATIENTS IN RE-DUAL-PCI TRIAL
Cannon CP et al. N Engl J Med 2017; 377:1513-1524
BLEEDING WERE LOWER WITH DABIGATRAN, BUT A
TREND TOWARDS INCREASED CV EVENTS* WITH
DABIGATRAN IN RE-DUAL-PCI
* time to death or thromboembolic event (death, MI, stroke or Systemic Embolism)
Cannon CP et al. N Engl J Med 2017; 377:1513-1524
0
5
10
15
20
25
30
D110 +
P2Y12
inhibitor
Warfarin +
DAPT
15.4
26.9
0
5
10
15
20
25
30
D150 +
P2Y12
inhibitor
Warfarin +
DAPT
20.2
25.7
DOUBLE THERAPY (CLOPIDOGREL +VKA/
RIVAROXABAN/DABIGATRAN) IS PREFERRED OVER
TRIPLE THERAPY (DAPT + OAC) FOR NVAF
PATIENTS UNDERGOING PCI
AHA 2019 guidelines for PCI in AF
patients
January CT, et al. Circulation 2019
DOI: 10.1161/CIR.0000000000000665.
AF AND PCI
WHAT IS KNOWN :
AF with chronic CAD patients : OAC better than
OAC + AP
Length of DAPT does not depend on type of stent;
instead on clinical scenario.
Short dual AP therapy safe in high bleeding risk
Both PIONEER AF-PCI and RE DUAL-PCI
has shown reduction in bleeding; but
underpowered to show benefit regarding
rare complications – stroke; embolism; Re-
infarction; stent thrombosis
AF AND PCI
WHAT IS UNKNOWN :
Whether dose of rivaroxaban in PIONEER AF-PCI are safe to prevent thrombo-embolism
Whether NOAC + CPD/Asp is safer concerning bleeding compared to VKA + CPD/Asp –AUGUSTUS
Whether NOAC/VKA + ASP can be an alternative for NOAC/VKA + CPD
Insufficient patients on Prasugrel / Ticagrelor in PIONEER AF-PCI / RE DUAL-PCI to show their safety in dual therapy
Whether Rivaroxaban 15 mg/ Dabigatran 150; 110 mg BD are sufficient to prevent stent thrombosis in PIONEER AF PCI/ RE DUAL PCI
Whether Ticagrelor may be a choice in dual/triple therapy in high risk PCI
AF AND PCI
WOEST Trial : Triple therapy ( VKA + Asp +
Cpd) showed more bleeding compared to (VKA +
Cpd) ; No significant increase in ischemia
TRANSLATE – ACS: Triple therapy with
Prasugrel showed higher bleeding risk
ENTRUST –AF PCI: Edoxaban + AP shows less
bleeding vs VKA + AP
ISAR-TRIPLE Trial : AF with post PCI – On
OAC + Asp randomized to 6 wks vs 6 months of
CPD therapy. No difference in primary or
secondary end points
COMPASS DESIGN
R
Aspirin 100 mg od
Rivaroxaban 5 mg bid Expected follow up
3-4 years
Run-in
(aspirin)
52
Stable CAD or PAD
2,200 with a primary outcomeevent
Rivaroxaban 2.5 mg bid
+ aspirin 100 mg od
N Engl J Med 2017;377:1319-30
PRIMARY END POINT: CV DEATH, STROKE,
MI
53
Rivaroxaban + Aspirin reduced CV events
by 24% in patients with CAD/PAD vs
aspirin alone
N Engl J Med 2017;377:1319-30
NOAC AND ACUTE ISCHEMIC
STROKE
rt- PA is approved within 4.5 hrs of stroke onset
Not for pts on VKA with INR >1.7
Not for pts : Received NOAC in last 24 hrs
For Dabigatran; Use of Idarucizumab – followed
by thrombolysis
For Factor Xa inh : Need to wait for Andexanet alpha
Provision for quick drug assay & NOAC specific coag
tests
Endovascular thrombectomy upto 7.3 hrs after stroke
European guide : Strong recommendation for
endovascular thrombectomy over thrombolysis
No specific AHA recommendations
THE INDIAN CONSENSUS GUIDANCE ON SPAF: SUGGESTED BLEEDING MANAGEMENT PROTOCOL IN
INDIA
Journal of The Association of Physicians of India 2018;66
(supple1):6-26
NOAC ANTIDOTES
ANDEXANET ALFA: DOSING FOR FXA
INHIBITORS DRUGS
NOAC BEFORE ELECTIVE
CARDIOVERSION
Post hoc analysis of major trials RE-LY: Dabigatran
ROCKET-AF: Rivoroxaban
ARISTOTLE: Apixaban
ENGAGE-AF TIMI 48: Edoxaban
Randomized trials X-VeRT: Rivaroxaban
ENSURE-AF: Edoxaban
Risk of TE & bleeding comparable to
Warfarin Shorter time (1-5 days) to conversion than
Warfarin
NOAC RECOMMENDATIONS
Better not to interrupt NOACS prior AF ablation
RE-CIRCUIT trial/ VENTURE AF trial :
Dabigatran/ Rivaroxaban vs VKA prior AF
ablation : No difference in embolism risk; Less
haemorrhage with dabigatran
Not withholding NOAC dose prior intervention
65
JUST AN EXPERIENCE
A pt of Femoral vein DVT ( Idiopathic) on long
term oral anticoagulation
Developed neurocysticercosis: Treated for
adequate duration.
Presently on Levepil and oral steroids
Was on VKA before ; Changed to Dabigatran
Present dose : 110 mg BD
Developed acute headeche; blurring of vision;
hemiparesis
WORD OF CAUTION
We know all good and bad of Warfarin
We are upset with its negatives;
Though we are assured of its undisputed efficacy
Our new friend looks all good apparently
But we know very little about them
Even we don’t have an antidote in a real emergency
We need results of more and more long term studies
We need to know experience of its use in different pt subsets; different scenario; different drugs
All is well….but be cautious….keep your eyes open