Nouveaux Anticoagulants Et Anti-plaquettaires - EPGL

Nouveaux anticoagulants et anti-plaquettaires:
Evolution ou révolution ?
Henri Bounameaux
Faculté de Médecine
et
Hôpitaux Universitaires de Genève
Service d’angiologie et d’hémostase
Formation continue des pharmaciens Genevois
27 mars 2012

Disclosures for Henri Bounameaux, MD
In compliance with CME policy, the following disclosures to the
session audience are declared:
Research
support/P.I.
Bayer-Schering Pharma, Schering-Plough,
Daiichi-Sankyo
Employee No relevant conflicts of interest to declare
Consultant Bayer-Schering Pharma, Bristol-Myers Squibb,
GlaxoSmithKline, Pfizer, Boehringer Ingelheim, Canon
pharma, Daiichi-Sankyo, sanofi-aventis
Major
stockholder
Speakers
bureau
Honoraria for
lectures
No relevant conflicts of interest to declare
No relevant conflicts of interest to declare
Bayer-Schering Pharma, Pfizer, sanofi-aventis,
GlaxoSmithKline, Servier, Daiichi-Sankyo

Antithrombotics
� Anticoagulants
� Antiplatelet agents
� (Thrombolytic agents)

Almost 100 years of anticoagulant therapy
Discovery of heparin by McLean & Howell
Isolation of dicoumarol by Link
Warfarin as rat poison
Registration of warfarin by FDA
Landmark study of Barritt & Jordan
on heparin in PE
Development of LMWHs
Development of fondaparinux
Development of the new OACs
1918 1930 1948 1954 1960 1985 1995 2000–2011
FDA=US Food and Drug Administration; LMWH=low-molecular weight
heparin; PE=pulmonary embolism; OAC=oral anticoagulant

Background
Mechanism of action of rivaroxaban and dabigatran
Adapted from Weitz et al, 2005; 2008
TF/VIIa
X IX
Fibrinogen
VIIIa
Xa
II
IIa
Va
IXa
Rivaroxaban
Apixaban
Dabigatran
Fibrin

Comparison of the NOACs with VKAs
Vitamin K
antagonists
New oral
anticoagulants
Onset Slow Rapid
Dosing Variable Fixed
Diet interactions Yes No
Drug interactions Many Few
Monitoring Yes No
Half-life Long Short
Antidote Yes No
NOAC=new oral anticoagulant; VKA=vitamin K antagonist

Comparison of four upcoming specific oral
anticoagulants
Drug
Class Company Half-life
Apixaban
anti-Xa
Edoxaban
anti-Xa
Rivaroxaban
anti-Xa
Dabigatran
DTI
BMS/
Pfizer
Daïchisankyo
Bayer/
J&J
Bioavailability
Elimination
8–15 50–85% 25% renal
75% biliary
10 50% 33% renal
66% biliary
5–13 >80% 33% renal
(unchanged
)
33% renal
(inactive
metabolites)
33% biliary
B-I 14–17 5% 80% renal
20% biliary
Dosage
(oral)
bid
od
od
bid

Phase III development of new anticoagulants
� Thromboprophylaxis
• Total hip replacement
• Total knee replacement
• Acutely ill hospitalized non-surgical patients
• Other types of surgical indications
� Treatment of established DVT or PE
� Long-term secondary prevention of VTE
� Prophylaxis of systemic embolization in patients with AF
� Treatment of ACS
ACS=acute coronary syndrome; AF=atrial fibrillation DVT=deep vein thrombosis; VTE=venous thromboembolism

Apixaban
(ELIQUIS®)
Dabigatran
(PRADAXA®)
Rivaroxaban
(XARELTO®)
Prévention MTEV Traitement
MTEV
Orthopédie
ADVANCE‐1
ADVANCE‐2
ADVANCE‐3
Médecine
ADOPT
Prévention sec –longue durée
AMPLIFY‐Ext NCT00633893
Orthopédie
RE‐NOVATE
RE‐MODEL
RE‐MOBILIZE
Prévention sec –longue durée
RE‐MEDY
RE‐SONATE
Orthopédie
RECORD I
RECORD II
RECORD III
RECORD IV
Médecine
MAGELLAN
Prévention sec –longue durée
EINSTEIN‐Ext
AMPLIFY
NCT00643201
RE‐COVER
RE‐COVER II
EINSTEIN‐DVT
EINSTEIN‐PE
Fibrillation
auriculaire
AVERROES
ARISTOTLE
Re‐LY
RELY‐ABLE
(NCT00808067)
SCA
(APPRAISE)
APPRAISE‐2
RE‐DEEM
ROCKET‐AF ATLAS‐TIMI 46
ATLAS‐TIMI 51
Vert : objectif principal atteint
Rouge : objectif principal non atteint

Thromboprophylaxis in MOS
Cross Trial Comparisons
RR of VTE (and 95% CI)
ADVANCE-3 ADVANCE-3
ADVANCE-2 ADVANCE-2
ADVANCE-1* ADVANCE-1*
RE-MOBILIZE RE-MOBILIZE
RE-MODEL RE-MODEL
RE-NOVATE RE-NOVATE
RECORD-4* RECORD-4*
RECORD-3 RECORD-3
RECORD-2 RECORD-2
RECORD-1 RECORD-1
RR Major or CRNM Bleeding (and 95% CI)
Apixaban trials
Dabigatran trials
Rivaroxaban trials
0.2 0.6 1.0 1.4 0.5 1.0 1.5 2.0
> 1 favors enoxaparin*, < 1 favors NOAC
CRNM=clinically relevant non-major; RR=risk ratio
*vs. enoxaparin 30 mg bid (all other 40 mg od)

Venous thromboembolism (VTE)
� Yearly incidence: ~1.5:1000 1
� Incidence increases with age 2
• Between age 40 and 80, it increases 10-fold
� Three-quarters of VTE events are clinically silent 3
� Half of proximal DVT events are accompanied by clinically overt
or silent PE 4
� PE is often diagnosed late. Untreated PE is associated with a
18–38% mortality 5
� Late complications include the post-thrombotic syndrome and
chronic arterial pulmonary hypertension 6
1 Silverstein MD, et al. Arch Intern Med. 1998;158:585–559; 2 Anderson FA, et al. Arch Intern Med. 1991;151:933–938;
3 Bounameaux H. Thromb Haemost. 1999;82:931–937; 4 Kearon C. Circulation. 2003;107:I22–30;
5 Ghaye B. JBR-BTR. 2007;60:100–108; 6 Geerts WH, et al. Chest. 2008;133:381–453.

VTE recurrence is preventable
Phases of the disease
Acute Intermediate Chronic
« Bridging »
Standard treatment 1
Initial Early maintenance Long-term secondary prevention
UFH, LMWH, VKA INR 2.0–3.0 VKA INR 2.0–3.0
fondaparinux
At least 5 days At least 3 months >3 months/years/indefinite
with periodic re-evaluation
1 Kearon C, et al. Chest. 2008;133(Suppl.):454S–545S.
INR=international normalized ratio; UFH=unfractionated heparin

Study protocols
Symptomatic
VTE
RE-COVER
Confirmed
symptomatic
DVT without
symptomatic PE:
EINSTEIN DVT
N=2,564
R
N=3,449
R
Rivaroxaban
15 mg bid
Predefined treatment period of 6 months
Parenteral
anticoagulant
Dabigatran etexilate 150 mg bid
Parenteral
VKA target INR 2.5
anticoagulant (INR range 2.0–3.0)
Day 1 Day 6
Predefined treatment period: 3, 6 or 12 months
Enoxaparin 1.0 mg/kg bid ≥5 days, followed by VKA
INR range 2.0–3.0
Rivaroxaban
20 mg od
Day 1 Day 21
Schulman S, et al. N Engl J Med. 2009;361:2342–2352; EINSTEIN Investigators. N Engl J Med. 2010;363:2499–2510.
30-day observation
period

INR control in the comparator groups of
EINSTEIN DVT and RE-COVER
Type of VKA Warfarin or
acenocoumarol
Time in therapeutic
range (TTR)
EINSTEIN DVT RECOVER
Warfarin
57.7% 60%
Time below INR 2.0 24.4% 21%
TTR in first month 54% 53%
TTR after first month 60% (57%–66%)* 66%**
*Weekly variations
**Last month

Design of the studies with the new oral anticoagulants
in established acute VTE (all vs VKA)
Dabigatran Rivaroxaban
Target Thrombin Factor Xa
Study acronym RE-COVER EINSTEIN DVT
Study design Double-blind, R, NI Open-label, R, NI
Dosage 150 mg bid 15 mg bid (21days)
then 20 mg od
Initial UFH/LMWH Mandatory
(≥5d)
Optional
(max. 48 hours)
Schulman S, et al. N Engl J Med. 2009;361:2342–2352; EINSTEIN Investigators. N Engl J Med. 2010;363:2499–2510.

Main efficacy and safety results of RE-COVER
Dabigatran 150 mg bid vs INR-monitored warfarin in acute VTE
Cumulative risk of recurrent venous thromboembolism or related death
during 6 months of treatment among patients randomly assigned to
dabigatran or warfarin
4.0
3.5
3.0
Dabigatran
2.5
2.0
Warfarin
1.5
1.0
0.5
Estimated cumulative
risk (%)
Number at risk
0.0
0 1 2 3 4 5 6
Months since randomization
Dabigatran 1274 1238 1221 1203 1192 1181 1024
Warfarin 1265 1215 1204 1194 1187 1174 998
Schulman S, et al. N Engl J Med. 2009;361:2342–2352.
Major bleeding (%)
W 1.9
D 1.6
HR 0.82 (0.45–1.48)
Major or NMCR
bleeding (%)
W 8.8
D 5.6
HR 0.63 (0.47–0.83)

EINSTEIN DVT: Efficacy results
0
Rivaroxaban
(n=1731)
Enoxaparin/VKA
(n=1718)
n (%) n (%)
First symptomatic recurrent VTE 36 (2.1) 51 (3.0)
Recurrent DVT 14 (0.8) 28 (1.6)
Recurrent DVT + PE 1 (

EINSTEIN DVT: Safety results
First major or non-major
clinically relevant bleeding
Rivaroxaban
(n=1718)
Enox/VKA
(n=1711) HR (95% CI)
n (%) n (%) p-value
139 (8.1) 138 (8.1) 0.97 (0.76–1.22)
p=0.77
Major bleeding 14 (0.8) 20 (1.2)
Contributing to death 1 (

Pre-randomization use of
heparins/fondaparinux in EINSTEIN DVT
Rivaroxaban
(n)
Pre-randomization heparins/fondaparinux
Enoxaparin/VKA
(n) Total
No 465 500 965 (28.1%)
1 day 1184 1135 2319 (67.6%)
2 days 66 68 134 (3.9%)
>2 days 3 8 11 (0.3%)
EINSTEIN Investigators. N Engl J Med. 2010;363:2499–2510.

Primary efficacy and safety by
pre-treatment with heparins/fondaparinux
Efficacy*
Rivaroxaban
(N=1731)
p-value for interaction efficacy = 0.41; Safety = 0.66
*ITT population; § Safety population
VKA
(N=1718)
HR
(95% CI)
Pre-treatment 2.1% 3.4% 0.61
(27/1264) (41/1213) (0.38–0.99)
No pre-treatment 1.9% 2.0% 0.98
Safety §
(9/467) (10/505) (0.40–2.41)
Pre-treatment 7.3% 7.5% 0.94
(92/1253) (91/1211) (0.70–1.26)
No pre-treatment 10.1% 9.4% 1.02
(47/465) (47/500) (0.68–1.54)
EINSTEIN Investigators. N Engl J Med. 2010;363:2499–2510. CI=confidence interval; HR=hazard ratio

EINSTEIN-EXT study design
Confirmed
symptomatic DVT
or PE completing
6 or 12 months of
rivaroxaban or VKA
in EINSTEIN VTE
programme
Confirmed
symptomatic DVT
or PE completing
6 or 12 months
of VKA
Randomized, double-blind, placebo-controlled,
event-driven (n=30), superiority study
~53%
~47%
N=1,197
R
Day 1
EINSTEIN Investigators. N Engl J Med. 2010;363:2499–2510.
Treatment period of 6 or 12 months
Rivaroxaban 20 mg od
Placebo
30-day observational period

EINSTEIN-Extension: Efficacy results
Main efficacy criterion (duration until first outcome)
Cumulative event rate (%)
10
9
8
7
6
5
4
3
2
1
0
NNT: 15 Placebo
(n=594*)
HR=0,184; p

EINSTEIN-EXT: Safety results
Rivaroxaban 20 mg od vs placebo for secondary VTE prevention
Mean treatment
period: 190 days
Rivaroxaban
(n=602)
Major bleeding 4 (0.7%)
p=0.106
Major or NMCR
bleeding
36 (6.0%)
HR 5.2 (2.3–11.7)
p

The ideal anticoagulant drug
� Rapidly inhibits thrombus progression
� Can be administered orally
� Exhibits a large therapeutic margin
� Has predictable pharmacokinetics and dose–response relationship
� Exhibits a low non-specific binding to plasma proteins
� Does not require laboratory monitoring
� Does not need frequent dose adjustments
� Produces few bleeding complications
� Produces few adverse events
� Exhibits few interactions with other drugs and with food

Phases of the disease and treatment
Acute Intermediate Chronic
« Bridging »
Standard treatment
Initial Early maintenance Long-term secondary prevention
UFH, LMWH, VKA INR 2.0–3.0 VKA INR 2.0–3.0
Fondaparinux
At least 5 days At least 3 months >3 months/years/indefinite
with periodic re-evaluation
A
B
New potential treatment schemes with the novel oral anticoagulants
« Switching » »
« Single « Single dose drug approach » »

Atrial fibrillation (AF)
� AF is the most common heart rhythm disturbance 1
� It is estimated that 1 in 4 individuals aged 40 years will develop AF 1
� In 2007, 6.3 million people in the US, Japan, Germany, Italy, Spain,
France and UK were living with diagnosed AF 2
� Due to the ageing population, this number is expected to double
within 30 years 3
1 Lloyd-Jones DM et al. Circulation. 2004;110:1042–1046; 2 Decision Resources. Atrial Fibrillation Report. Dec 2008;
3 Go AS, et al. JAMA. 2001;285:2370–2375.

AF increases the risk of stroke
� AF is associated with a prothrombotic state
• ~Fivefold increase in stroke risk 1
� Risk of stroke is the same in patients with AF regardless of
whether they have paroxysmal or sustained AF 2,3
� Cardioembolic stroke has a 30-day mortality of 25% 4
� AF-related stroke has a 1-year mortality of ~50% 5
1 Wolf PA, et al. Stroke. 1991;22:983–988; 2 Rosamond W, et al. Circulation. 2008;117:e25–146; 3 Hart RG, et al. J Am
Coll Cardiol. 2000;35:183–187; 4 Lin H-J, et al. Stroke. 1996;27:1760–1764; 5 Marini C, et al. Stroke. 2005;36:1115–1119.

AF-related stroke is preventable
� Two-thirds of strokes due to AF
are preventable with appropriate
anticoagulant therapy with a
vitamin K antagonist (VKA)
(INR 2.0–3.0) 1
� Anticoagulation with a VKA is
recommended for patients with
more than one moderate
risk factor 2
� A meta-analysis of 29 trials in
28,044 patients showed that
adjusted-dose warfarin results in
a reduction in ischaemic stroke
and in all-cause mortality 1
Effect of VKA compared to placebo
Stroke
Death
67% 26%
1 Hart RG, et al. Ann Intern Med. 2007;146:857–867; 2 Camm AJ, et al. Eur Heart J. 2010;19:2369–2429.

Effect of warfarin on the risk of stroke in AF
AFASAK
SPAF
BAATAF
CAFA
SPINAF
EAFT
All trials
Warfarin better Placebo better
RRR 64%*
(95% CI: 49−74%)
100 50 0 –50
–100
RRR (%)†
Random effects model; Error bars = 95% CI; *P>0.2 for homogeneity; †Relative risk reduction (RRR) for all strokes
(ischaemic and haemorrhagic)
Hart RG, et al. Ann Intern Med. 2007;146:857–867.

VKAs: Not used in accordance
with stroke risk, Euro Heart survey
Oral anticoagulant therapy (%)
90
80
70
60
50
40
30
20
10
0
58
59
1 2 3 4 5 6
CHADS2 score
*5,333 patients with AF in 35 countries 2003–2004, Euro Heart Survey
Presented data estimated from Figure 2 in Nieuwlaat et al. 2006
Nieuwlaat R, et al. Eur Heart J. 2006;27:3018–3026.
64
61
62
85

INR control in routine practice is suboptimal
% INRs
Retrospective, multicentre cohort study (ISAM)
100
80
60
40
20
0
Time in therapeutic range
INR 3
US Canada France Italy Spain
Ansell J, et al. J Thromb Thrombolysis. 2007;23:83–91.

INR control: RCTs vs Clinical Practice
% of eligible patients receiving
warfarin
INR control in clinical trial versus clinical practice (TTR)
25%
38%
66%
44%
** TTR = Time in Therapeutic Range (INR2.0‐3.0)
1 Kalra L, et al. BMJ. 2000;320:1236-1239 * Pooled data: up to 83% to 71% in individualized trials;
2 Samsa GP, et al. Arch Intern Med. 2000;160:967-973; 3 Matchar DB, et al. Am J Med. 2002;113:42-51.
9%
Clinical trial 1
Clinical practice 2,3
18%
3.0 INR

N Engl J Med. 2009;361:1139-1151.

RE-LY – study design
Warfarin
1 mg, 3 mg, 5 mg
(INR 2.0-3.0)
N=6000
Open
Connolly, S, et al. N Engl J Med. 2009;361:1139-1151.
Atrial fibrillation with ≥ 1 risk factor
Absence of contraindications
R
Dabigatran etexilate
110 mg bid
N=6000
Double-blinded
Dabigatran etexilate
150 mg bid
N=6000

Main efficacy and safety results of RE-LY
Dabigatran 110 or 150 mg bid vs INR monitored warfarin in AF
Connolly, S, et al. N Engl J Med. 2009;361:1139-1151.
Major
bleeding
(%/year)
W 3.36
D110 2.71*
D150 3.11**
*p=0.003
** NS

Adverse events and discontinuations
Connolly, S, et al. N Engl J Med. 2009;361:1139-1151.

Acute coronary events: meta-analysis

Study design of RE-LY and ROCKET AF
RE-LY
Dabigatran
� Phase III
� Prospective
� Randomized
� Multicenter
� Open-label (vs. Warfarin)
� Independent DSMB
� event adjudication committee
blinded
� Doses 110 or 150 mg bid
� Average CHADS 2.1
ROCKET AF
Rivaroxaban
� Phase III
� Prospective
� Randomized
� Multicenter, event-driven study
� Double-blind, double-dummy
� Independent DSMB
� event adjudication committee
blinded
� Single dose approach (20 mg qd)
� Average CHADS 3.5

Primary Efficacy Outcome in ROCKET-AF
Stroke and non-CNS Embolism – Per protocol analysis
Cumulative event rate (%)
Event
Rate
Days from Randomization
No. at risk:
Rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 634
Warfarin 7004 6327 5911 5542 4461 3478 2539 1538 655
Event Rates are per 100 patient-years
Based on Protocol Compliant on Treatment Population
Rivaroxaban Warfarin
1.71 2.16
Warfarin
Rivaroxaban
HR (95% CI): 0.79 (0.66, 0.96)
P-value Non-Inferiority:

Cumulative Rates of the Primary End Point
(Stroke or Systemic Embolism) in the Per-Protocol Population and in the
Intention-to-Treat Population
HR (95% CI): 0.79 (0.66, 0.96)
P‐value Non‐Inferiority:

Primary Efficacy Outcome in ROCKET-AF
Stroke and non-CNS Embolism
Rivaroxaban
better
On
Treatment
N= 14,143
ITT
N= 14,171
Warfarin
better
Rivaroxaban Warfarin
Event
Rate
Event
Rate
1.70 2.15
2.12 2.42
HR
(95% CI)
0.79
(0.65,0.95)
0.88
(0.74,1.03)
Kenneth W. Mahaffey, MD and Keith AA Fox, MB ChB on behalf of the ROCKET AF Investigators, AHA (Nov. 2010)
Event Rates are per 100 patient-years
Based on Safety on Treatment or Intention-to-Treat thru Site Notification populations
P-value
0.015
0.117

Primary Safety Outcomes in ROCKET-AF
Major and non-major
Clinically Relevant
Rivaroxaban Warfarin
Event Rate Event Rate
HR
(95% CI)
Pvalue
14.91 14.52 1.03 (0.96, 1.11) 0.442
Major 3.60 3.45 1.04 (0.90, 1.20) 0.576
Non-major Clinically
Relevant
Event Rates are per 100 patient-years
Based on Safety on Treatment Population
11.80 11.37 1.04 (0.96, 1.13) 0.345
Kenneth W. Mahaffey, MD and Keith AA Fox, MB ChB on behalf of the ROCKET AF Investigators, AHA (Nov. 2010)

INR control in the comparator groups of
RE-LY and ROCKET AF
RE-LY ROCKET AF
Type of VKA Warfarin (open) Warfarin (DB)
Time in therapeutic
range (TTR)
64% 58%
Time below INR 2.0 19.7%

Effects of the different compounds on
intracranial bleeding in AF studies
Study Study arm Intracranial bleed
(% per year)
RE-LY Warfarin 0.74
Dabigatran 150 mg bid 0.30*
Dabigatran 110 mg bid 0.23*
ROCKET AF Warfarin 0.44
Rivaroxaban 20 mg od 0.26**
Compared to warfarin arm of the corresponding study *p

Hemorrhagic stroke
Haemorrhagic stroke (no. of events)
50
40
30
20
10
0
RR 0.31 (95% CI: 0.17–0.56)
14
0.12%
Dabigatran
110 mg BID
P

All cause mortality
All cause mortality (%/yr)
4.0
3.0
2.0
1.0
0.0
RR 0.91 (95% CI: 0.80–1.03)
3.75 3.64
Dabigatran
110 mg BID
P=0.13 (Sup)
RR 0.88 (95% CI: 0.77–1.00)
Dabigatran
150 mg BID
P=0.051 (Sup)
4.13
Warfarin
Events / N: 446 / 6015 438 / 6076 487 / 6022
Connolly SJ, et al. N Engl J Med. 2009;361:1139–1151.

Connolly SJ, et al. Ν Εngl J Med. 363;19, November 4, 2010

Connolly SJ, et al. N Engl J Med. 2011 (10 Feb)
AVERROES Study

ARISTOTLE
Primary efficacy and safety outcomes
Granger CB, et al. N Engl J Med. 2011;365:981-992.

NOACS and AF studies
RELY (150mg)
(n=3X6000)
ROCKET-AF
(n=2X7000)
ARISTOTLE
(n=2X9000)
Drug Dabigatran Rivaroxaban Apixaban
Design Open label lower
risk pts
Stroke and non-
CNS Embolism
Hemorrhagic
stroke
Myocardial
infarction
Double blind high
risk pts
Double blind
lower risk pts
0.65 (P

Problems with the NOACS
• Exhibit interactions with other drugs (and VKA ?)
• Can be associated with hepatotoxicity (ximelagatran only)
• May be associated with decreased compliance (?)
• Cannot be monitored (« do not need be monitored » and
can be quantitated)
• Cannot be antagonized (need ? Ongoing studies,
candidate antagonists being developed)

Rivaroxaban and interactions
CYP3A4 and
P-gp inhibitors
Antithrombotics
NSAIDs / platelets
inhibitors
CYP3A4 – inductors
Erythromycin (+34% AUC and Cmax) and clarithromycin (+54%
AUC, +40% Cmax) did not alter the pharmacokinetic of rivaroxaban in
a clinically relevant manner.
�
Ketoconazol (Nizoral® Azole-Antimycotics) and HIV protease
�
inhibitors (Ritonavir) are contraindicated.
LMWH such as Enoxaparin did not influence the
pharmacokinetic of Rivaroxaban.
Naproxen, Acetylsalicylic acid nor Clopidogrel did
prolong bleeding time in a clinically relevant way.
Rifampicin or Phenobarbital or other inductors may cause a
reduction of the AUC mean value of Rivaroxaban, yet this reduction is
not considered to be clinically relevant (-50% AUC, -20%Cmax).
�
�
�

Dabigatran etexilate and interactions
• No interactions with CYP inhibitors/inductors expected
• Interaction with efflux transporter P-gp:
P-gp inhibitors: amiodarone, quinidine, clarithromycine,
cyclosopirine, ritonavir, verapamil
P-gp inductors: rifampicin
have possible effects on absorption
- Amiodarone (potent P-gp inhibitor) increases Cmax
and AUC of dabigatran by 50% and 60%)
- Quinidine (strong P-gp inhibitor) is contra-indicated
with dabigatran etexilate

Why monitoring drugs?
• To optimize dosage in order to increase efficacy and/or
safety (especially with drugs exhibiting a narrow
therapeutic window and/or a variable individual response):
UFH, LMWH (in special cases), digoxine, lithium, ciclosporine
• To improve compliance ?

Monitoring anticoagulant drugs
Reason for
monitoring
UFH LMWH Fondaparinux VKA
Narrow window + + + +
Food
interactions
Drug
interactions
Renal
clearance
Existing
antidote
Relation with
clinical outcome
- - - +
- - - ++
- (+) (+) -
+ (+) - +
+ (+) - ++
Overall
assessment + (+) - ++

Monitoring anticoagulant drugs
Reason for
monitoring
Narrow
window
Food
interactions
Drug
interactions
Renal
clearance
Existing
antidote
Relation with
clinical
outcome
UFH LMWH Fondaparinux VKA New drugs
+ + + + -
- - - + -
- - - ++ (+)
- (+) (+) - (+)
+ (+) - + -
+ (+) - ++ -
Overall
assessment + (+) - ++ -

Monitoring versus measuring
• Monitoring implies dose adaptation according to test result
• Measuring (or quantifying) the drug or drug effect may be useful in
- overdosage
- urgent surgery
- extreme body weights
- (children)
- (pregnancy)
- (renal insufficiency)
• but, in the absence of an antidote, measuring the drug merely
allows to approximate after which time the drug effect will
vanish (which can be calculated however knowing time of
administration and dose administered)
Bounameaux H and Reber G. J Thromb Haemost. 2010;8:627-630.

Nouveaux antiplaquettaires
Thanks P. to Fontana, Pierre Fontana, PD MD, PhD
Service d’angiologie-hémostase
Colloque CHARADE, Hôpital de La Tour, le 9 février 2012

Les nouveaux antiplaquettaires
2011…
sont parmi nous
2012…

Papyrus d’Ebers, 1550 av J.-C.
Aspirine (1899)
Clopidogrel (‘90)
Prasugrel (2011)
Ticagrelor (2012)
Cangrelor
Elinogrel
Terutroban
SCH53048
EV-077
….

Plan de la présentation
� Mode d’action des antiplaquettaires
� Pourquoi avons-nous besoin de nouveaux antiplaquettaires ?
� Pharmacocinétique et pharmacodynamique
� Les nouveaux antiplaquettaires : études cliniques
� Prasugrel : étude TRITON-TIMI 38
� Ticagrelor : étude PLATO
� Comment choisir ?
� Les directives 2011 de la Société Européenne de Cardiologie

Mécanisme d’action des
principaux antiplaquettaires
TxA 2
Aspirine
TP
GPIIbIIIa
Platelet activation
(thrombine par exemple)
PAR
TxA 2
Anti-GPIIbIIIa
P2Y 12
Thiénopyridines
Ticagrelor
ADP

Pourquoi de nouveaux
antiplaquettaires ?
� Efficacité
� Délai d’action
� Variabilité de réponse biologique
� Effets secondaires
� Antidote

Variabilité de réponse au clopidogrel
et événements cliniques
Combescure C et al, J Thromb Haemost 2010;8:923

Evaluation biologique de l’effet
du clopidogrel
• Agrégation plaquettaire induite par l’ADP dans un PRP
• Quantification de certaines GP plaquettaires (GPIIbIIIa, P‐
sélectine) au repos et après activation par des agonistes
• Platelet function analyzer (PFA)‐100 (cartouche ADP)
• Analyse de la phosphorylation du VASP (vasodilator
stimulated phosphoprotein): niveau de phosphorylation
(activité) inversément corrélée à l’état de stimulation du
récepteur P2Y12 (cytométrie en flux)
• Aggregation‐based POCT (VerifyNow®)

Notion de résistance au clopidogrel
• Défaut d’observance
• Variabilité d’absorption intestinale
• Métabolisation hépatique et interactions
médicamenteuses
• Caractéristiques cliniques (diabète, obésité)*
• Polymorphismes génétiques du récepteur à l’ADP (P2Y12),
cytochrome P450 2C19, …**
*22% de la variabilité; **12% (volontaires sains)

Les nouveaux antiplaquettaires
� Plus puissants (tous)
� Réponse biologique moins variable (presque tous)
� Réversibles (ticagrelor, cangrelor, elinogrel)
� Administration IV (cangrelor, elinogrel)

Simon T et al, NEJM 2009
Thiénopyridines
1 ère génération: ticlopidine
2 ème génération: clopidogrel
3 ème génération: prasugrel
Absorption
CYPs
Récepteur P2Y12

Métabolisme des thiénopyridines

Prasugrel : pharmacodynamique
Clopidogrel
Prasugrel
Wallentin L et al, EHJ 2008;29:21

Fonction plaquettaire
Seuil critique
Arrêt du prasugrel
clopidogrel
J
J + …
prasugrel
Risque
hémorragique
Temps (jours
après l’arrêt du ttt)

� Action plus rapide
� 10 mg de prasugrel
Prasugrel
� 10 fois plus puissant que 75 mg de clopidogrel
� Recouvrement d’une fonction plaquettaire plus lente
liaison irréversible au récepteur (comme le clopidogrel)

Interactions médicamenteuses
� Clopidogrel : CYP1A2, 2C9, 2C19
� IPP (omeprazole); statine (atorvastatine)
� Impact biologique
� Impact clinique ?
� Prasugrel : CYP 3A (2B6, 2C9, 2C19)
� Ketoconazole, rifampicine, antirétroviraux
� peu ou pas d’impact biologique

TICAGRELOR, BRILIQUE®
Cyclo-pentyltriazolo–
pyrimidine
Réversible
Schömig A et al, NEJM 2009;361:1108-11

Ticagrelor
Gurbel PA et al, Circulation 2009;120:2577

Gestion péri-opératoire
Recommandations
Si le risque de la poursuite de l’inhibiteur du P2Y12 > que celui de son arrêt :
Clopidogrel : 5j
Ticagrelor : 5j
Prasugrel : 7j
Accord HAS, SFAR, SFC, GACI, GEHT, GIHP

Interactions médicamenteuses
inactif
CYP3A4
actif actif
CYP3A4/5
Kétoconazole, clarythromicine, antirétroviraux :
augmentation du métabolite actif � contre-indication
Rifampicine : diminution de l’efficacité biologique, impact clinique ?
Zhou D et al, Drug Metab Disp 2011;39:703

Prasugrel et ticagrelor
Par rapport au clopidogrel :
� Inhibition plaquettaire plus intense
� Action plus rapide
� Variabilité biologique moindre…

clopidogrel prasugrel
Aleil B et al, J Thromb Haemost 2005;3:85‐92
Bonello L et al, JACC 2011:58:467

Bonello L et al, JACC 2011:58:467

Plan de la présentation
� Mode d’action des antiplaquettaires
� Pourquoi avons-nous besoin de nouveaux antiplaquettaires ?
� Pharmacocinétique et pharmacodynamique
� Les nouveaux antiplaquettaires : études cliniques
� Prasugrel : étude TRITON-TIMI 38
� Ticagrelor : étude PLATO
� Comment choisir ?
� Les directives 2011 de la Société Européenne de Cardiologie

UA/NSTEMI
(TIMI Risk Score ≥ 3)
ASA
Clopidogrel
300 mg LD/ 75 mg MD
n = 13,608
Duration of therapy: 6–15 months
1 o endpoint: CV death, MI, stroke
2 o endpoint: Stent thrombosis
Safety endpoints: TIMI major bleeds, life-threatening bleeds
Mean FU 14.5 months
TRITON-TIMI 38
Study design
ACS (STEMI or UA/NSTEMI) and planned PCI
Double-blind
Prasugrel
60 mg LD/ 10 mg MD
STEMI
(Primary PCI ≤ 12
hours of symptoms
or post-STEMI within
14 days)
Wiviott SD et al. Am Heart J 2006;152:627–35.

TRITON‐TIMI 38
BASELINE CHARACTERISTICS
Clopidogrel
(N=6’795)
%
Prasugrel
(N=6’813)
%
UA/NSTEMI 74 74
STEMI 26 26
Age, median
> 75 y
Wgt, median (IQR)
< 60 kg
CrCl (ml/min)
>60

PRASUGREL VS CLOPIDOGREL : TRITON‐TIMI38
60/10 MG 300/75 MG 13 608 PATIENTS SCA‐PCI
Wiviott SD, et al, N Engl J Med 2007;357:2001

Prasugrel vs. clopidogrel : TRITON-TIMI38
La majorité des patients ont reçu
leur dose de charge APRES la coro…
Serebruany V et al, Thromb Haemost 2009 ;101 :14

TRITON‐TIMI 38:
MAJOR EFFICACY END POINTS
% Risk
Reduction
0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5
HR
Prasugrel Better Clopidogrel Better
P-value
Primary Endpoint 19

End Point (%)
TRITON‐TIMI 38: DIABETIC SUBGROUP
ANALYSIS (N=3,146)
18
16
14
12
10
8
6
4
2
0
Clopidogrel
Prasugrel
HR 0.70
P

TRITON‐TIMI 38
NET CLINICAL BENEFIT BLEEDING RISK SUBGROUPS
Prior
Stroke / TIA
Age
Wgt
Yes
No
>=75
< 75
< 60 kg
>=60 kg
OVERALL
Post-hoc analysis
0.5 1 2
Prasugrel Better Clopidogrel Better
HR
P int = 0.006
P int = 0.18
P int = 0.36
Risk (%)
+ 54
-16
-1
-16
+3
-14
-13

SWISSMEDIC

Clopidogrel
If pre-treated, no additional loading dose;
if naive, standard 300 mg loading dose,
then 75 mg qd maintenance;
(additional 300 mg allowed pre PCI)

All Pts
(n=18624)
Pts with planned
Invasive strategy
(n= 13408)
Conservatively
treated pts
(n=5216)
Significance*
Age >75 yrs (%) 2878 (15.5) 1770 (13.2) 1108 (21.2) P

TICAGRELOR VERSUS CLOPIDOGREL IN ACS
CV DEATH, MI OR STROKE
p=0.0003
HR 0.84 (95% CI 0.77–0.92)
MI HR 0.84 (0.75-0.95), P=0.005
RRR = 16%, ARR = 1.87%, NNT = 54
Prob/def stent thrombosis HR 0.75 (0.59-0.95), P=0.02
Death HR 0.78 (0.69-0.89), P

Essai clinique PLATO
18624 patients avec SCA (STEMI et NSTEMI)
Critère de jugement principal : mort d’origine vasculaire + IM + AVC
↓ RR : 16% (23% - 8%); 11,7% � 9,8%
Hémorragies majeures : 11,6% 11,2%
P=0.43
Hg non liées à un pontage : 4,5% 3,8% P=0.03
Dyspnée : 13,8% 7,8%
Pauses ventriculaires :
Ticagrelor Clopidogrel
5,8% 3,6%
Non adhésion au traitement : 7,4% 6,0%
P

Comment choisir ?
� Type de traitement choisi (PCI vs médical)
� Etudes de sous-groupes
� médical: ticagrelor (bid)
STEMI � prasugrel > ticagrelor
Diabétiques � prasugrel > ticagrelor
Poids < 60Kg � ticagrelor > prasugrel
âge > 75 ans � ticagrelor > prasugrel
Insuffisance rénale � ticagrelor > prasugrel

Montalescot G et al. Circulation 2010;122:1049

Oral Antiplatelet Agents

� Avancée thérapeutique claire
Conclusions
Prasugrel et ticagrelor
� Importance de l’évaluation du risque hémorragique
� Sélection des patients (mode de présentation, caractéristiques
cliniques)
� Attention à la compliance

Morrow et al. ACC 2012, Chicago, March 24, 2012

Morrow et al. ACC 2012, Chicago, March 24, 2012

Morrow et al. ACC 2012, Chicago, March 24, 2012

Morrow et al. ACC 2012, Chicago, March 24, 2012

Morrow et al. ACC 2012,
Chicago, March 24, 2012

Morrow et al. ACC 2012, Chicago, March 24, 2012

EVOLUTION OU REVOLUTION ?
A vous de décider
‐ De nouveaux agents anticoagulants oraux après 50 ans
d’héparine et d’AVK
‐ De nouveaux antiplaquettaires après deux décennies de
clopidogrel et plus d’un siècle d’aspirine (et le voraxapar)
Merci de votre attention