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