Oral anticoagulation in AF

Oral anticoagulant therapy in AF – which one is best?

Dr. Pavankumar P Rasalkar

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

Introduction

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

Types of AFFirst diagnosed episode of AF

Paroxysmal (<7 days)

Persistent (>7 days to

12m)

Long standing

persistent (>1year)

Permanent (accepted)

Management strategy

Atrial fibrillation

Anticoagulation Assess TE riskNOACOAC

Aspirin or none

Rate and rhythm control AF type symptoms

Rate control+/- Rhythm control

Ablation

ANTICOAGULATION

CHADS2

C congestive cardiac

failure

H Hypertension

AAge more than 75

D

Diabetes

S2 Previous Stroke or

TIA

Thromboembolic risk

Gage BF, Waterman AD et. al. JAMA 2001;285:2864–2870

CHADS2Age 65-74

Vascular diseaseFemale

CHA2DS2-VASc

Risk Profile Class / LevelCHA2DS2-VASc = 0 No antithrombotic therapy

Class IIa

CHA2DS2-VASc = 1

No antithrombotic therapy Or

AsprinOr

Oral anticoagulation Class IIb

CHA2DS2-VASc ≥ 2 Oral anticoagulationClass I

Indication for anticoagulation in non valvular AF patients

Risk of bleedingH- HypertensionA- Abnormal renal or liver function

(1 point each)S- StrokeB- BleedingL- Labile INRE- Elderly, Age >65D- Drugs or alcohol (1 point each)

INR . international normalized ratio

VKA

Warfarin

Warfarin

Kinetics Absorption Oral: Rapid, complete

Distribution 0.14 L/kgMetabolism Hepatic, primarily via CYP2C9;

minor pathways include CYP2C8, 2C18, 2C19, 1A2, and 3A4

Excretion Urine (92%, primarily as metabolites)

Half-life 20-60 hours

Warfarin Onset of action:

◦ 5-7 days ◦ May requiring bridging

Antidote: ◦ Vitamin K, FFP, PRBC

Interactions:◦ Foods with high vitamin K content

Warfarin

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

Warfarin 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;131:492

WarfarinBetter

ControlBetter

AFASAK

SPAFBAATAF

CAFA

SPINAF

EAFT

100% 50% 0 -50% -100%

Aggregate

Warfarin in atrial fibrillation

VKA

Similar to Warfarin

Lesser pharmacogenimic interaction (VKORC1 and CYP2C9)

Lesser food and drug interactions

Higher potency and longer half life

Acitrom

Difficulties with warfarin use 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?

New anticoagulants

Leung, The Hematologist, 2011

New anticoagulants Ideal anticoagulant:

◦ Equally efficacious◦ Equally safe◦ No monitoring◦ Fewer interactions◦ Oral◦ Reversible

New anticoagulants Direct thrombin inhibitors

◦ Dabigatran

Factor Xa inhibitors◦ Rivaroxaban◦ Apixaban◦ Edoxaban

Absorption and metabolism of NOACDabigatran 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

Mechanisms underlying DDIs in NOACs

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

Action to be taken in case of DDIsThree 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

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Possible drug-drug interactions – Effect on NOAC plasma levels

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%

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Red – contraindicated; orange – reduce dose; yellow – consider dose reduction if another yellow factor present; hatching – no data available; recommendation made from pharmacokinetic considerations


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%

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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

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www.escardio.org/EHRARed – contraindicated; orange – reduce dose; yellow – consider dose reduction if another yellow factor present;hatching – no data available; recommendation made from pharmacokinetic considerations

Factors associated with raised plasma levels of NOACs

Dabigatran Apixaban RivaroxabanAged ≥ 80 years Increased plasma level

Aged ≥ 75 years Increased plasma level

Weight ≤ 60 kg Increased plasma level

Renal function Increased plasma level

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Other increased bleeding risk

Pharmacodynamic interactions – antiplatelet drugs, NSAIDs Systemic steroid therapy Other anticoagulantsRecent 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;hatching – no data available; recommendation made from pharmacokinetic considerations

Clinical Evidence

RE-LY ROCKET-AF ARISTOTLE

Dabigatran 150mg

BID vs. warfarin

Rivaroxaban 20mg daily

vs. warfarinApixaban5mg BID

vs. warfarinStudy 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 AFUse of ASA ≥100 mg/dayCrCl <30 ml/min

Valvular AF;Use of ASA >100 mg/dayCrCl <30 ml/min

Valvular AFNeed for ASA >165 mg/daySCr >2.5mg/dL or CrCl <25ml/min

Follow-up (mean) 2 yr 1.9 yr 1.8 yrOutcome 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 bloodMortality All causes

Baseline CharacteristicsAge (years) 71 (mean) 73 (median) 70 (median) Female (%) 36.4% 39.7% 35.2 %CHADS2 (mean) 2.1 3.5 2.1Previous 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

Rivaroxaban 20mg

daily vs.

warfarin

p ValueApixaban 5mg BID

vs. warfarin

p Value

Primary OutcomeStroke 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<0.001NNT 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=0.03NNT 132 1.3 vs. 1.4 p=0.58 0.97 vs.

1.05%p=0.4

2

Hemorrhagic stroke 0.1vs0.4% p<0.001

NNT 1820.26 vs. 0.44%

p=0.02NNT 333

0.24 vs. 0.47%

p<0.001

NNT 238

All cause death 3.6 vs. 4.1% p=0.051 4.5 vs.

4.9% p=0.15 3.5 vs. 3.9p=0.0

47NNT 132

MI/ACS 0.7 vs. 0.5%

p=0.048NNH 239

0.9 vs. 1.1% p=0.12 0.5 vs.

0.6%p=0.3

7

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<0.001NNT 67

Intracranial bleed

0.3 vs. 0.74%

p<0.001

NNT 116

0.5 vs. 0.7%

p=0.02NNT 250

0.3 vs. 0.8%

p<0.001NNT 128

GI bleed 1.5 vs. 1.0%

p<0.001

NNH 100

3.2 vs. 2.2%**

p=0.001NNH 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

Edoxaban

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)

Edoxaban

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

NOAC’S in valvular AF

NOAC’s Vs Warfarin which one is better?

Wafarin

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

NOAC’S

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

NOAC’S considered in

Atrial Fibrillation

Valvular AF?

Non Valvular AF?

Warfarin IB

Undergoing Procedure

CHA2DS2-VASc IB1In 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. IC2. 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 IA

Bridging 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

Non Valvular AF?

Warfarin Direct thrombin ,Factor Xa inhibitors

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 IIaBThe 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

Practical scenerios

Bleeding management

Warfarin 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 $$$$$

Reversal of new anticoagulants No specific monitoring test available

No reversal agents for new anticoagulants

Measuring the anticoagulant effect of NOACs Dabigatran Apixaban Rivaroxaban

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

Circulation, 2011

Reversal using PCC 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

Reversal using PCC 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

Idarucizumab

Possible measures to take in case of bleeding

37

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

Switching between anticoagulant regimens

VKA to NOAC INR <2.0: immediateINR 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 impairmentStart when next dose would have been given

NOAC to VKA Administer concomitantly until INR in appropriate rangeMeasure INR just before next intake of NOACRe-test 24h after last dose of NOACMonitor 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 concentrationsexpected (e.g. renal impairment)

Aspirin or clodiprogel to NOAC Switch immediately, unless combination therapy needed22


How to deal with 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.

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When to stop NOACs before a planned surgical intervention

Dabigatran Apixaban Edoxaban * RivaroxabanNo 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 ≥48hno

data yet

no data yet ≥24h ≥48h

CrCl 50–80 ml/min ≥36h ≥72h ≥24h ≥48h

no data yet


CrCl 30–50 ml/min § ≥48h ≥96h ≥24h ≥48h

no data yet


CrCl 15–30 ml/min §

not indicate

dnot

indicated ≥36h ≥48hno

data yet


CrCl <15 ml/min no official indication for use

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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).

When to restart NOACs after a planned surgical intervention

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

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Patients undergoing an urgent surgical

intervention 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.

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1. Healey et al, Circulation 2012:126;343-8

No data

Currently contraindicated

Pregnancy and lactation

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

Conclusion

thank you…

Health & Medicine

Oral anticoagulation in AF