Coronarien à haut risque Risque hémorragique: Le patient sous anticoagulant

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1 Coronarien à haut risque Risque hémorragique: Le patient sous anticoagulant Grigoris T Gerotziafas Groupe de Thrombose Equipe de recherche ER2UPMC Interactions cellulaires tumorales et leur environnement et réponses aux agents anticancéreux. Service d Hématologie Biologique Hôpital Tenon, APHP, Paris, France

2 Disclosures

3 Agenda Acute Coronary Sryndromes and Bleeding Basic pathophysiology for the use of anticoagulants in ACS Anticoagulant options in ACS Timing of bleeding during the acute phase of ACS The New AntiThrombotic Agents in ACS Conclusions

4 Atherothrombosis Represents a Risk Continuum? Subclinical disease Acute ischemia PCI Surgery Post-event CHARISMA and REACH population 1. Drouet L. Cerebrovasc Dis 2002; 13(Suppl 1): Qureshi A et al. Stroke 2004; 35: Haffner SM et al. N Engl J Med 1998; 339:

5 Platelet activation Inflammation Thrombin generation In patients with atherothrombosis Platelet activation Hypercoagulable state Increase of inflammation markers

6 Thrombin genera-on thrombin ύ thrombin FXa FVIIa thrombin thrombin FXa

7 Thrombogenicity of thrombus Thrombin FXa Thrombin FXa

8 Thrombogenicity of thrombus In accelerated lysis Ac#va#on of platelets Thrombin genera-on Re- occlusion thrombin FXa thrombin FXa Rivaroxaban, dabigatran, bivalirudin : Inhibition of clot bound FXa and thrombin

9 Acute Coronary Syndromes and antithrombotic treatment Acute phase Antiplatelet treatment ASA mg Clopidogrel ASA + 60 mg Prasugrel ASA mg Ticagrelor Anticoagulant treatment UFH i.v. at doses to target aptt ratio 2-3 Enoxaparin 1 mg/kg b.i.d s.c. Fondaparinux 2.5 mg/kg o.d. s.c. Secondary Prevention ASA + 75 mg Clopidogrel o.d. ASA + 10 mg Prasugrlel o.d. ASA + 90 mg Ticagrelor b.i.d not recommended

10 Profile of thrombin genera-on thrombine (nm) normal Hypercoagulable state Antithrombotic treatment 50 0 hypocoagulability time (min)

11 Adverse Impact of Bleeding on Prognosis in Patients with ACS Study of patients # # #- OASIS registry # # #- OASIS 2 and CURE # Increasing risk of death with increasing # #severity of bleeding # Similar association of major bleeding and #ischemic events (acute MI and stroke) # Major bleeding (2.3%) in the first 3 days Eikelboom JW et al, Circulation 2006;114:

12 Adverse Impact of Bleeding on Prognosis in Pa-ents with ACS Major bleeding is associated with a 5 fold increase in risk of death Compared with those who did not develop major bleeding pa-ents who did develop major bleeding had been more ogen treated during hospitaliza-on with a GP IIb/IIIa inhibitor, UFH or LMWH or fibrinolysis and more ogen underwent coronary angiography, CABG. Eikelboom JW et al, Circula3on 2006;114:

13 Dose- Ranging Trial of Enoxaparin for Unstable Angina : TIMI 11A Characteris3cs of Pa3ents with Major Hemorrhage Higher Dose ( 1.25 mg/kg every 12 h) Lower Dose ( 1.0 mg/kg every 12 h) Major Hemorrhage (n=21) No Major Hemorrhage (n=299) Major Hemorrhage (n=6) No Major Hemorrhage (n=303) An-- Xa (IU/liter) 3rd WA dose - Peak 1.8 (1.6, 2.1) [n=14] 1.4 (1.2, 1.7) [n=213] 1.2 and 1.9 [n=2] 1.0 (0.9, 1.2) [n=161] - Trough 0.5 (0.3, 1.0) [n=14] 0.6 (0.3, 1.0) [n=202] 0.7 and 1.0 [n=2] 0.5 (0.3, 0.7) [n=162] TIMI inves3gators (J Am Coll Cardiol 1997;29: )

14 Distribu-on of effec-ve an-coagula-on dura-on (>0.5 IU ml - 1 of an-- Xa ac-vity) ager 0.5 mg kg - 1 dose of i.v. enoxaparin Frequency Dura-on (hrs) Sanchez- Pena P. et al, Br J Clin Pharmacol 2005 [60:4]

15 Protocol : Pharmacokine-cs of IV/SC enoxaparin in pa-ents undergoing PCI Ini-al dose 0.75 mg/kg (iv), subsequent doses 1 mg/kg (sc) begining 8 hr following the iv dose Pa-ents undergoing PCI within 4 hr of the iv dose or 8 hr of the sc dose did not receive addi-onal enoxaparin. All others have received mg/kg addi-onal iv enoxaparin at the -me of PCI All pa-ents undergoing PCI received an-- IIb/IIIa and clopidogrel Aslam MS et al, Catheter Cardiovasc Interv (2)

16 Mean Plasma An-- Xa ac-vity (u/ml) ± ± ± ± ± ± ± ± ± ± ± min 2 hrs 4 hrs 6 hrs 8 hrs 2 hrs 4 hrs 6 hrs 8 hrs 10 hrs 12 hrs IV Enoxaparin SC Enoxaparin Therapeu-c an-- Xa ac-vity (0.5 u/ml) Aslam MS et al, Catheter Cardiovasc Interv oct;57(2):187-90

17 Mean Plasma Ac-vity An-- Xa U/mL IV dose 0.75 mg/kg SC dose 1 mg/kg 10 min 3.2 ± min min 1 ± min 1.01 ± hrs 0.64 ± hrs 1.13 ± hrs 0.36 ± hrs 1.10 ± hrs 0.24 ± hrs 0.84 ± hrs 0 10 hrs 0.62 ± hrs 0 12 hrs 0.46 ± 0.21 Mean plasma an#- Xa ac#vity at the start and at the end of PCI was [1.27 ± 0.41] and [1.07 ± 0.42] respec#vely. Aslam MS et al, Catheter Cardiovasc Interv oct;57(2):187-90

18 Acute Coronary Syndromes 14 pts with UA given enoxaparin 1 mg/kg s.c. q 12h 3,5 3 2,5 2 1,5 1 0,5 0 enoxaparin prothrombin F 1+2 (nm) enoxaparin anti-xa activity (IU/ml) time from start (hours) 1 0,9 0,8 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0 Upper normal limit of F 1+2 Gerotziafas GT, Samama MM et al, Br J Haemat 2003;120:611-7

19 Enoxaparin in PCI Adequate an-coagula-on with enoxaparin may be achieved within 10 minutes ager an iv dose of 0.75 mg/kg High risk ACS pa-ents may benefit from this approach PCI may be performed without addi-onal an-coagula-on within 4 hr of iv or 8 hr of sc enoxaparin. PCI 4 more than hr ager iv dose or 8 more than hr ager sc dose will require addi-onal iv enoxaparin mg/kg to ensure therapeu-c an-- Xa/ac-vity. Aslam MS et al, Catheter Cardiovasc Interv (2)

20 OASIS- 5 : A randomized, double- blind, double- dummy trial 20,078 pa-ents with UA/NSTEMI Randomiza-on Aspirin. Clopidogrel. an#- GPIIb/IIIa. planned Cath/PCI as per local prac#ce Fondaparinux 2.5 mg sc od up to 8 days Enoxaparin 1 mg/kg sc bid for 2 8 days 1 mg/kg sc od if ClCr <30 ml/min 1. Michelangelo OASIS- 5 Steering CommiWee. Am Heart J 2005;150:1107.e1 e10 2. OASIS- 5 Inves#gators. N Engl J Med 2006;354:

21 Major bleeds: Fondaparinux vs enoxaparin up to day Enoxaparin Cumula-ve hazard HR: % CI: p<0.001 Fondaparinux 0.0 Fondaparinux: 2.2% (n=217) Enoxaparin: 4.1% (n=412) OASIS- 5 Inves#gators. N Engl J Med 2006;354: Days

22 OASIS- 6 study design: Randomised, double- blind, double- dummy 12,000 pa-ents with STEMI <12 h of symptom onset Inclusion: ST 2 mm prec leads or 1 mm limb leads Exclusion: Contra- ind. for an-coagulant, INR>1.8, pregnancy, ICH<12 months Ly-cs (SK, TPA, TNK, RPA), primary PCI or no reperfusion (eg, late) Stra-fica-on UFH not indicated UFH indicated Randomisa*on Randomisa*on Fondaparinux 2.5 mg Placebo Fondaparinux 2.5 mg UFH The OASIS- 6 Trial Group. JAMA 2006;295:

23 OASIS- 5 and OASIS 6 combined: 30- day main efficacy and bleeding outcomes for UFH/ enoxaparin vs fondaparinux End point UFH/enox Fondaparinux HR (95% CI) p-value n=13,242 (%) n=13,270 (%) Death/MI/st ( ) Death ( ) MI ( ) Stroke ( ) Major bleeding ( ) < Mehta S. World Congress of Cardiology 2006; September 6, 2006; Barcelona, Spain

24 ATLAS ACS 2- TiMi 51 : efficacy of rivaroxaban in ACS Mega et al N Engl J Med. 2012;366(1):9 19.

25 ATLAS ACS 2- TiMi 51 : safety of rivaroxaban in ACS Mega et al N Engl J Med. 2012;366(1):9 19.

26 hypercoagulability > 1 month acer PCI MRI (nm/min) treatment aspirin hypogoagulability clopidogrel aspirin+clopidogrel ADP AUC (U) Gerotziafas GTI. Clin Appl Thromb Haem 2011

27 Conclusion How to minimize bleeding without reducing antithrombotic efficacy? Finding of the appropriate dose according #to the results of large clinical trials Biomarkers could help to determine that the therapeutic hypocoagulability #has been reached, especially in patients #with an increased risk of bleeding.

28 Conclusion The intensity of antithrombotic treatment should be tailored to individual risk The correct dose and probably the most appropriate drug and timing must bedetermined to maximize efficacy and safety Recent data regarding the role of newer factor Xa inhibitors especially rivaroxaban are encouraging although less clear-cut in the context of PCI.