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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