Gianluca Botto, MD, FESC,UO Elettrofisiologia, Dip Medicina

Fibrillazione Atriale Non

Valvolare Ischemia o Emorragia le

Due Utopie Rivali nella Scelta dei

NAO

Limitations of VKA TherapyLimitations of VKA Therapy

Routine coagulationmonitoring

Slow onset/offset of action

Warfarin resistance

Numerous drug–druginteractions

Numerous food–druginteractions

Narrow therapeuticwindow (INR range 2.0–3.0)

Ansell J. Chest 2008; 133; 160S-198S.

Umer Ushman MH. J Interv Card Electrophysiol 2008; 22: 129-137.

Nutescu EA. Cardiol Clin 2008; 26: 169-187.

VKA therapy has several limitations that make it difficult to use

in practice

Frequent doseadjustments

Unpredictableresponse

Patient With High INR Variability

Hazards of Warfarin

Budnitz DS. M Engl J Med 2011; 365: 2002-2012

Rationale of a Replacement for

Warfarin in NV-AF

■ W is an effective agent for stroke prevention in NV-AF, however:

■ Pts find frequent INR monitoring difficult

■ Phisicians are reluctant to use W due to the increased risk for bleeds

■ The potential for improvement in bleeding and possibly stroke prevention was seen with more targeted NOAC therapy

Selecting the most appropriate

antithrombotic therapy for

a pt is one of the most important

management decisions in AFIB

The net clinical benefit associated

with a given therapeutic choice

should guide this decision.

The net clinical benefit

associated with a given therapeutic choice

should guide this decision.

Anticoagulation UseBalancing Stroke Prevention and Risk of Bleeding

Anticoagulation In Pts With Non-Valvular AFAnnual Rates Of Major Hemorrhage

Fuster V. ACC/AHA/ESC Practice Guidelines 2006

Ann Intern Med. 2009; 151: 297-305.

CHADS2 annual stroke risk (%)

4-6 ≥8,5

3 5,9

2 4,0

1 2,8

0 1,9

AVERROESPrimary Efficacy and Safety Outcome

AVERROESPrimary Efficacy and Safety Outcome

Connolly SJ. N Engl J Med 2011; 364: 806-17

2011; 155: 579-586.

Net Clinical Benefit for

Warfarin and NOAs by CHA2DS2-VASc and

HAS-BLED Score

Net Clinical Benefit for

Warfarin and NOAs

by CHA2DS2-VASc and HAS-BLED Score

Banerjee A.

Thrombosis Haemost

2012; 107: 584-589

Comparison Between Annualized Thromboembolic Risk Stratified by CHADS2 Risk Score and CHA2DS2-VASc Risk Score

Comparison Between Annualized Thromboembolic Risk Stratified by CHADS2 Risk Score and CHA2DS2-VASc Risk Score

Atrial FibrillationHAS-BLED Bleeding Risk Score

Atrial FibrillationHAS-BLED Bleeding Risk Score

A score ≥ 3 indicates “High Risk” and cautions and regular review of the pt is needed

Although Stroke Is Generally

More Feared By Patients, There Is A Strong Bias

Among Physician Not To Cause Harm

Although Stroke Is Generally

More Feared By Patients, There Is A Strong Bias

Among Physician Not To Cause Harm

� Allocation to a NOAs significantly reduced the composite of stroke or systemic embolic events by 19% as compared to WRF

� The overall beneficial effect was mainly driven by a large

reduction in haemorrhagic stroke(RR on combined data: 0.49, 95%CI: 0.38-0.64, P<0.0001)

� All-cause mortality was significantly reduced with NOAs vs. WRF (RR: 0.90, 95%CI: 0.85-0.95, P=0.0003),

while ischemic stroke and myocardial infarction were not

NOAs vs Warfarin in Pts with AFNOAs vs Warfarin in Pts with AF

Miller CS. Am J Cardiol 2012; 110: 453-460

ALL-CAUSE STROKE or SE

ISCHEMIC STROKE

HEMORRHAGIC STROKE

Major Bleeding in the NOACs SPAF Trial

Intracranial Hemorrage

NOACs Are Associated with Significant

Fewer Intracranial Bleeds than Warfarin

ENGAGE-AFFatal Bleeding

Giuliano RP. ESC Annual Meeting, Barcelona (abstract)

Intracerebral/Hemorragic Stroke and

Mortality in SPAF

■ ICH has a mortality rate of 40-50%

■ Much worse than ischemic stroke, MI, GI bleed

Chatterrjee S. JAMA Neurol 2013; 70: 1486-90

NNT to prevent ICH vs Warfarin

Risk of ICH in Pts with Chonic Cerebral

Microbleeds on Gradient Echo MRI

■ 68% of spontaneous ICH

■ Microbleeds increase the risk of Warfarin-associated ICH 12 fold

Van Etten ES. Stroke 2014: 45; 2280-2285

Reducing the Risk for ICH in SPAF

Pts Receiving Anticoagulation Rx

■ Assesses risk factors

■ Aggressive risk factor reduction

■ Do not add AP to anticoagulant unless pts has recently had a coronary stent deployed

■ Switch from an AVK to a NAOC

Major GI Bleeding

in the NOAC SPAF Trials

Flexible Dosing to Prevent Bleeding

■ High vs low-dose regimens- more ischemic events but less bleeding

■ Dose modification/reduction- preventing excess dose exposure in

vulnerable pts

■ Once-daly vs twice-daily dosing- different plasma concentration carries

differen bleeding risk

Rivaroxaban Dosing

Overlap B/ween OD and BID Regimens• Maximun (Cmax) and minimun (Ctrough) blood concentration of rivaroxaban in bid and od

studies, with 25° and 75° percentiles (orizontal lines) and 5° and 95° percentili (dots)

100

200

300

400

05 10 15 20

Rivaroxaban daily dose (mg)

Riv

aro

xab

an

Cm

ax

(µg

/l)

bid

od

5 10 15 20

120

100

80

60

40

20

0

Rivaroxaban daily dose (mg)

Riv

aro

xab

an

Cva

lle

(µg

/l)

bid

odCmax Ctrough

Mueck W. Thromb Haemost 2008; 100: 453–461

Anticoagulation Rx in Pts With NV-AF

Projected Costs, Cost-Efficacy and Cost-Benefit

Anticoagulation Rx in Pts With NV-AF

Projected Costs, Cost-Efficacy and Cost-Benefit

Harrington AR. Stroke 2013 in press

The VKA Habit is Under Pressure

…but Overall Usage is Still on High Level

100

80

60

40

20

Feb

69%

NovSepJulMayMarJanNovSepJulMayMarJan

13%

6%

81%

19%

Others*

Novel OACs

VKAs

Global AC Market

Volume Shares in % (based on SU) Volume in SU (000)

495.217

137.302

800,000

700,000

600,000

500,000

400,000

300,000

200,000

100,000

FebNovSepJulMayMarJanNovSepJulMayMarJan

2012 2013 2014 2012 2013 2014

* Others = mainly B1B1 Unfractionated Heparin and B1B2 LMWH

IMS MIDAS Database Monthly Sales

Italy: The Paradox Effect of NOAs

IMS MIDAS Database Monthly Sales

Summary

■ Appropriate AC is required to prevent TE events in pts with NV-AF while minimizing the risk for bleeding

■ NOACs provide a similar level of protection from ischemic stroke as VKAs but are associated with a significant lower rate of intracranial bleeding

■ NOACs are powerful drugs, can cause serious bleeding and should be used in strict accordance with their specific scientific evidence

New Guidelines for Anticoagulation of Pts With AF

New Guidelines for Anticoagulation of Pts With AF

� Particular emphasis on identification of pts at low risk that don’t need any antithrombotic Rx

� ASA just for few pts for whom anticoagulation cannot be proposed

� NOAs significantly reduce the major bleedingPrimarily driven by a substantial reduction in ICH

� NOAs are poised to replace warfarin for the majority of the pts