commentaires sur les principaux essais cliniques présentés à lesc 2009 damien coisne
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Commentaires sur les principaux essais cliniques présentés à l’ESC
2009Damien Coisne
Différentes voies d’inhibition= différentes voies de recherche
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50 100 500 1000 2000
Aggregation
Bleeding time
+ placebo
AR-C69931 (ng.kg -1.min-1) Stepped infusion period Recovery period
7 15 20 45 60 min
Key Phase I resultRapid reversal of dose-dependent effect
PLATO Lars Vallentin
Perspective ClopidogrelPrasugrelTicagrelor
Albert Schoming Editorial NEJM 2009, 361,11, 1108
Rapidité d’actionVariabilité interindividuelleReversibilitéRisque hémorragiqueEfficacité clinique
Perspective Cure/Triton/Plato
Study Design
Double-blind
ACS (STEMI or UA/NSTEMI) & Planned PCI
ASA
PRASUGREL60 mg LD/ 10 mg MD
CLOPIDOGREL300 mg LD/ 75 mg MD
1o endpoint: CV death, MI, Stroke2o endpoints: CV death, MI, Stroke, Rehosp-Rec Isch
CV death, MI, UTVRStent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleedsKey Substudies: Pharmacokinetic, Genomic
Median duration of therapy - 12 months
N= 13,600
Le progression de CURE vers TRITON s’est accompagné d’un augmentation du risque hémorragique Pas dans le cas de PLATO
Les “nouveaux” effets secondaires découverts par PLATO: dyspnée,bradyarythmie,élévation créat, ac urique!!!!!
CURE et Triton: pas de réduction de la mortalité globale, Ici réduction (mais étude non dimensionnée pour) mais effet très probable.
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 administeredto 1,000 patients with ACS to prevent 15 nonfatal MIs, 10additional patients develop major bleeding, 69 additionalpatients 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 anDose de charge du Clopidogrel: 600 mg pout tousReduction 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 chirurgiePrudence 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
XI XIa
IX IXa
Xa
II IIa (Thrombin)
Fibrinogen Fibrin
VIIIa
Va
VIIa + TF VII
TF (Tissue Factor)
X
Rivaroxaban
Extrinsic PathwayIntrinsic Pathway
Gibson CM, AHA 2008
Dabigatran
ATLAS
sommairesommaire
sommairesommaire
sommairesommaire
Rely
J Connolly NEJM Sept 2, 361
EditorialCan 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 anticoagulantover antiplatelet therapy in atrial fibrillation dependson the quality of international normalized ratio control achievedby centers and countries as measured by time in therapeuticrange. 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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