Gianluca Botto, MD, FESC, Fibrillazione Atriale Non

Fibrillazione Atriale Non
Valvolare Ischemia o Emorragia le
Due Utopie Rivali nella Scelta dei
NAO
Gianluca Botto, MD, FESC,
UO Elettrofisiologia, Dip Medicina
Limitations
Limitations of
of VKA
VKA Therapy
Therapy
Unpredictable
response
Narrow therapeutic
window (INR range 2.0–3.0)
Numerous food–drug
interactions
VKA therapy has
several limitations that
make it difficult to use
in practice
Slow onset/
offset of action
Routine coagulation
monitoring
Numerous drug–drug
interactions
Warfarin resistance
Frequent dose
adjustments
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.
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 Use
Balancing Stroke Prevention and Risk of Bleeding
Anticoagulation In Pts With Non-Valvular AF
Annual Rates Of Major Hemorrhage
Fuster V. ACC/AHA/ESC Practice Guidelines 2006
CHADS2 annual stroke risk (%)
4-6
≥8,5
3
5,9
2
4,0
1
2,8
0
1,9
Ann Intern Med. 2009; 151: 297-305.
AVERROES
AVERROES
Primary
Primary Efficacy
Efficacy and
and Safety
Safety Outcome
Outcome
Connolly SJ. N Engl J Med 2011; 364: 806-17
2011; 155: 579-586.
Net
Net Clinical
Clinical Benefit
Benefit for
for
Warfarin
Warfarin and
and NOAs
NOAs
by
by CHA
CHA22DS
DS22-VASc
-VASc and
and
HAS-BLED
HAS-BLED Score
Score
Banerjee A.
Thrombosis Haemost
2012; 107: 584-589
Comparison Between Annualized Thromboembolic Risk
Stratified by CHADS22 Risk Score and CHA22DS22-VASc Risk Score
Atrial
Atrial Fibrillation
Fibrillation
HAS-BLED
HAS-BLED Bleeding
Bleeding Risk
Risk Score
Score
A score ≥ 3 indicates “High Risk” and cautions
and regular review of the pt is needed
Although
Although Stroke
Stroke Is
Is Generally
Generally
More
More Feared
Feared By
By Patients,
Patients,
There
There Is
Is A
A Strong
Strong Bias
Bias
Among
Among Physician
Physician Not
Not To
To
Cause
Cause Harm
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
NOAs vs
vs Warfarin
Warfarin in
in Pts
Pts with
with AF
AF
ALL-CAUSE STROKE or SE
ISCHEMIC STROKE
HEMORRHAGIC STROKE
Miller CS. Am J Cardiol 2012; 110: 453-460
Major Bleeding in the NOACs
SPAF Trial
Intracranial Hemorrage
NOACs Are Associated with Significant
Fewer Intracranial Bleeds than Warfarin
ENGAGE-AF
Fatal 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
NNT to prevent ICH vs Warfarin
Chatterrjee S. JAMA Neurol 2013; 70: 1486-90
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)
120
bid
od
Cmax
300
200
100
Rivaroxaban Cvalle (µg/l)
400
Rivaroxaban Cmax (µg/l)
•
100
bid
od
Ctrough
80
60
40
20
0
0
5
10
15
20
Rivaroxaban daily dose (mg)
5
10
15
20
Rivaroxaban daily dose (mg)
Mueck W. Thromb Haemost 2008; 100: 453–461
Anticoagulation
Anticoagulation Rx
Rx in
in Pts
Pts With
With NV-AF
NV-AF
Projected
Projected Costs,
Costs, Cost-Efficacy
Cost-Efficacy and
and Cost-Benefit
Cost-Benefit
Harrington AR. Stroke 2013 in press
The VKA Habit is Under Pressure
…but Overall Usage is Still on High Level
Global AC Market
Volume Shares in % (based on SU)
Volume in SU (000)
100
800,000
700,000
81%
80
600,000
69%
500,000
60
VKAs
400,000
Novel OACs
40
300,000
Others*
20
13%
19%
200,000
137.302
100,000
6%
Jan Mar May Jul Sep Nov Jan Mar May Jul Sep Nov
2012
2013
2014
495.217
Feb
Jan Mar May Jul Sep Nov Jan Mar May Jul Sep Nov
2012
2013
2014
Feb
* 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
New Guidelines
Guidelines for
for
Anticoagulation
Anticoagulation of
of Pts
Pts With
With AF
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 bleeding
Primarily driven by a substantial reduction in ICH
NOAs are poised to replace warfarin for the
majority of the pts