Transcript Comment aires sur les principaux essais cliniques

Commentaires sur les principaux
essais cliniques présentés à l’ESC
2009
Damien Coisne
Différentes voies d’inhibition= différentes voies de recherche
ADP
clopidogrel
Prasugrel
Cangrelor
ADP P2Y12
SCH 530348
E 5555
ADP
cAMP
Activation
GP IIb/IIIa
(fibrinogen
receptor)
COX-1
TXA2
aspirin
adapted from Schafer AI. Am J Med. 1996;101:199-209.
Thrombin
Key Phase I result
Rapid reversal of dose-dependent effect
% Inhibition of Aggregation
100
8
7
+ placebo
80
Aggregation
6
5
60
4
40
3
2
20
Bleeding time
1
0
0
50
AR-C69931
(ng.kg-1.min-1)
100
500
Stepped infusion period
1000
2000
7
15 20 45 60 min
Recovery period
PLATO
Lars Vallentin
Perspective
Clopidogrel
Prasugrel
Ticagrelor
Rapidité d’action
Variabilité interindividuelle
Reversibilité
Risque hémorragique
Efficacité clinique
Albert Schoming Editorial NEJM 2009, 361,11, 1108
Perspective Cure/Triton/Plato
Study Design
ACS (STEMI or UA/NSTEMI) & Planned PCI
N= 13,600
ASA
Double-blind
CLOPIDOGREL
300 mg LD/ 75 mg MD
PRASUGREL
60 mg LD/ 10 mg MD
Median duration of therapy - 12 months
1o endpoint:
2o endpoints:
CV death, MI, Stroke
CV death, MI, Stroke, Rehosp-Rec Isch
CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
Le progression de CURE vers TRITON s’est accompagné d’un augmentation du risque
hémorragique Pas dans le cas de PLATO
CURE et Triton: pas de réduction de la mortalité globale, Ici réduction (mais
étude non dimensionnée pour) mais effet très probable.
Les “nouveaux” effets secondaires découverts par PLATO:
dyspnée,bradyarythmie,élévation créat, ac urique!!!!!
Is CURE a Cure for Acute Coronary
Syndromes? Statistical Versus Clinical
Significance Editorial U Khot JACC 2002
These are not trivial risks. If clopidogrel is administered
to 1,000 patients with ACS to prevent 15 nonfatal MIs, 10
additional patients develop major bleeding, 69 additional
patients have minor bleeding, and 200 patients have
surgical decisions complicated by its administration. In
addition, 978 patients taking clopidogrel derive no
significant benefit from this drug, and all of this occurs
without saving one life.
Commentaires
Essai relativement court: 1 an
Dose de charge du Clopidogrel: 600 mg pout tous
Reduction de l’interaction potentielle avec l’omeprazole
Apects Pratiques potentiels
Ticagrelor a utiliser en cas de chirugie très probable.
Le s SCA en attente de chirurgie
Prudence en cas d’ins respiratoire chronique, ins rénale??
Quid des patients à faible compliance potentielle ( essai thérapeutique vs vraie vie)
Albert Schoming Editorial NEJM 2009, 361,11, 1108
Coagulation Cascade
TF (Tissue Factor)
XIa
XI
IX
IXa
Intrinsic Pathway
VIIa + TF
VII
Extrinsic Pathway
VIIIa
X
Xa
Va
Rivaroxaban
II
Dabigatran
IIa (Thrombin)
ATLAS
Fibrinogen
Fibrin
Gibson CM, AHA 2008
sommaire
sommaire
sommaire
Rely
J Connolly NEJM Sept 2, 361
Editorial
Can we rely on RELY
B Gage NEJM Sept 2, 361
• In patients with atrial fibrillation, warfarin prevents 64% of strokes.
• Despite clear and consistent recommendations, warfarin is
prescribed to only two thirds of appropriate candidates
• After conversion to its active form,dabigatran competitively inhibits
thrombin.
• The quality of warfarin management in RELY was assessed by
measuring the percentage of time (excluding the first week of
therapy) during which the INR was within the therapeutic range,
which averaged 64%. (Similar to ACTIVE trial).
• RE-LY participants who were randomly assigned to receive warfarin
would have needed to have an INR within the therapeutic range
approximately 79% of the time to have a stroke rate as low as that
in the group receiving 150 mg of dabigatran
Connolly SJ, Pogue J, Eikelboom J, et al. Benefit of oral anticoagulant
over antiplatelet therapy in atrial fibrillation depends
on the quality of international normalized ratio control achieved
by centers and countries as measured by time in therapeutic
range. Circulation 2008;118:2029-37.
Dabigatran 150
Effets secondaires interactions
• In RE-LY, rates of dyspepsia (including abdominal
pain) were elevated with dabigatran (11.8% in the
110-mg group and 11.3% in the 150-mg group).
• Dabigatran is not without important drug
interactions P-glycoprotein inhibitors — including
verapamil, amiodarone, and especially quinidine
• Which dose for elderly patients, renal
impairement (patients with CR cl less than
30ml/mn were excluded)
• To prevent one nonhemorrhagic stroke, the
number of patients who would need to be
treated with dabigatran at a dose of 150 mg
twice daily, rather than warfarin, is
approximately 357.
• The rates of hemorrhagic stroke with the
110mg and 150-mg dabigatran doses (0.12%
and 0.10%) were significantly lower than that
with warfarin (0.38%).
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