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The Cardiovascular Institute Mount Sinai School of Medicine, New York Vulnerable Plaque + Vulnerable Blood = High-Risk Patient Juan Jose Badimon, Ph.D.

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Presentation on theme: "The Cardiovascular Institute Mount Sinai School of Medicine, New York Vulnerable Plaque + Vulnerable Blood = High-Risk Patient Juan Jose Badimon, Ph.D."— Presentation transcript:

1 The Cardiovascular Institute Mount Sinai School of Medicine, New York Vulnerable Plaque + Vulnerable Blood = High-Risk Patient Juan Jose Badimon, Ph.D Juan Jose Badimon, Ph.D Professor of Medicine Director, Cardiovascular Biology Research Laboratory Facultad de Medicina Tucumán, Argentina Abril 26th, 2006

2 Plaque - Blood - High Risk Patient Vulnerable (High-Risk) Plaque + Vulnerable (High-Risk) Blood = High-Risk (Vulnerable) Patient

3 Vulnerable (High-risk) Plaque Plaque - Blood - High Risk Patient

4 Atherosclerosis Progression

5 TF + VIIa TF:VIIa Xa ProthrombinThrombin FibrinFibrinogen Fibrinolysis PlasminogenPlasmin Fibrin FDP Endothelium Media Plateletsaggregation NO NO SMC relaxation NO Macrophagesadhesion/migration PGI 2 PAI-1 tPA TxA 2 Lumen SMC migration & proliferation MCP-1 SMC contraction ET-1 VEGFTF ET-1 TFMMPsCRP Normal Endothelium Dysfunctional Endothelium ATHEROSCLEROSIS Coagulation M-CSF CAMs Corti R and Badimon JJ Curr Opin Lipidol. 2001;12:629-37 Blood

6 TFMMPs ET-1 SMC Contraction ET-1ET-1 ET-1 Endothelium Media Smooth Muscle Cells (SMC) Lumen TF + VIIa TF:VIIa Xa ProthrombinThrombin FibrinFibrinogen Coagulation  Blood Flow Platelets Aggregation  TxA 2 TxA 2 TF TxA 2 Dysfunctional Endothelium PAI-1 tPA Fibrinolysis  Corti R and Badimon JJ Curr Opin Lipidol. 2001;12:629-37 ATHEROTHROMBOSIS

7 Atherosclerosis vsAtherothrombosis Atherosclerosis vs Atherothrombosis Atherosclerosis Progression Atherothrombosis

8 Ethiopathogenesis of Acute Coronary Syndromes

9 Ischemic strokeIschemic stroke Transient ischemic attackTransient ischemic attack Myocardial infarctionMyocardial infarction Angina pectorisAngina pectoris (stable, unstable) (stable, unstable) Intermittent claudicationIntermittent claudication Critical limb ischemia, rest pain, gangrene, necrosisCritical limb ischemia, rest pain, gangrene, necrosis Major Clinical Manifestations of Atherothrombotic Diseases

10 Cost of Coronary Heart Disease Hospital /Nursing Home $41.8 billion Physicians/Other Professionals $8.6 billion Home Health Care $1.6 billion United States: 2002 Total Cost = $111.8 billion American Heart Association. 2002 Heart and Stroke Statistical Update. 2001 American Heart Association. 2002 Heart and Stroke Statistical Update. 2001. Indirect Costs $53.6 billion Direct Costs $58.2 billion Drugs/Other Medical Durables $6.2 billion

11 Not all Atherosclerotic lesions are equal Falk E. 2006 JACC ;47:C7-C13

12 Stenotic Severity and CVD Falk E et al; Circulation 1995

13 Vulnerable Atherosclerotic Lesion Falk E. 2006 JACC ;47:C7-C13

14 Definition of Vulnerable Plaque Pathologist: mildly stenosed (50%) > 40% of their volume lipid-rich material thin fibrotic cap Cell Biologist: Proportion of SMC and Inflammatory cells Macrophage-rich lesions being more vulnerable Clinician: Those lesions triggering an ACS, independently of biochemical, cellular independently of biochemical, cellular composition or location. High-risk lesions?

15 Is this a Vulnerable Lesion ???

16 Imaging MRI MDCT IVUS Is this a Vulnerable Lesion ???

17 Glagov S et al. NEJM 1987;316:1371 Normal Vessel Minimal CAD Moderate CAD Severe CAD Compensatory Expansion outluminal plaque growth Expansion Overcome: Lumen Narrows Coronary Plaque Remodeling

18 IVUS at multiple sites in an angiographically normal artery Nissen S et al 2002 Angiography vs IVUS

19 LumenWallArteryInvasiveRadiationTimeCost Angiography +++-All+++++ +++ IVUS +++++ Co, Ca, Per ++++++++ B-mode doppler ++++ Ca, Per --++ TEE ++++ Ao, Co Prox -, ?-++ Ultrafast CT EBCT ++++, ?Mostly Cor -++- Nuclear Scintigraphy ++, ? Co, Ca, Per -+++ ++ MRI +++ All - (claust) -+++? IMAGING MODALITIES Ao.- Aorta Co.- Coronaries Ca.- Carotids Per.- Peripherals

20

21 THROMBOSIS 70-80 % PLAQUE RUPTURE 30-20 % PLAQUE EROSION Clinical Event

22 ++++++Peripherals +++++Carotids ++++++Coronaries Blood Thrombogenicity Rheology Plaque Disruption Thrombotic Factors and Arterial Beds Virchow’s triad

23 Vulnerable (High-risk) Plaque + Vulnerable (High-Risk) Blood = High-Risk (Vulnerable) Patient Plaque - Blood - High Risk Patient Vulnerable (High-Risk) Blood

24 “ Vulnerable /Hyper-reactive” Blood Several risk factors correlate with hyperreactive blood. These factors may contribute to the clinical presentation after plaque disruption “Classic” DiabetesSmoking Hyperlipidemia Inflammation/ Apoptosis/ Infection? Cathecholamines Fibrinogen Lp(a)Homocysteinemia Factor V Leiden Platelet polymorph Shear rate Genetic Protein deficiencies (AT III, Prot C or S) Hypercoagulable state (  FVII,  F1.2,  FPA) Hypofibrinolytic state (  PAI-1,  t-PA,  u-PA) “Not so-classic” DepressionCirculating TF activity Stress

25 X Xa IX IXa X Xa IX IXa + + + + Va VIIIa Va VIIIa Xa:Va VIIIa:IXa Xa:Va VIIIa:IXa + Va + Va Prothrombin Thrombin TF + VIIa TF:VIIa TF:VIIa TF Pathway and its potential inhibition TFPI

26 Human plaques thrombogenicity is modulated by their content in Tissue Factor Fernandez-Ortiz et al. JACC 1994 Toschi V et al. Circulation 1997

27 Blood Borne - Tissue Factor Giesen P et al. PNAS 1999; 96:2311 Thrombus formation is inhibited by the systemic administration of an anti-TF antibody

28 Risk factors and circulating TF activity ControlSmokersHyperlipidemicDiabetics 0 100 200 300 400 500 Tissue Factor activity (pmol FXa/L) Sambola A. Circulation 2003; 107: 973-979

29 Blood Thrombogenicity Circulating TF activity Glycemic Improvement No Glycemic Improvement Glycemic Control & Blood Thrombogenicity Sambola Circ. 2003

30 Tissue Factor: a key player for thrombosis and inflammation Two versions of a similar story: 1.- The classical 2.- The newer Juno, the two-faced God

31

32 Inflammation Thrombosis Atherosclerosis Apoptosis Tissue factor micro-particles Aggregated Platelets PDGF Thrombin IL-6 TF MMP ICAM-1 IL-1 CV Risk Factors ACS The Inflammation-Thrombosis Link Clinical evidence: Septic shock Inflammation subsequent to bacterial endotoxin induces endothelial TF and PAI-1 expression leading to thrombotic complications (DIC) CD40L/CRP

33 Inhibitors of the intrinsic pathway HEPARINWARFARIN LOW MOLECULAR WEIGHT HEPARINS DIRECT THROMBIN INHIBITORS Antiplatelet agents ASPIRIN TICLOPIDIN, CLOPIDOGREL (±ASA) GP IIb/IIIa RECEPTOR ANTAGONISTS DIRECT THROMBIN INHIBITORS Other Approaches : THROMBOLYTICS, ANTI IX, P2T and TX-ANTAGONISTS Antithrombotic Therapy Antithrombotic agents have reduced approx. 20% of ACS in CAD patients BMJ 2002;324:71-86). of ACS in CAD patients ( BMJ 2002;324:71-86).

34 Inhibitors of the intrinsic pathway HEPARINWARFARIN LOW MOLECULAR WEIGHT HEPARINS DIRECT THROMBIN INHIBITORS Antiplatelet agents ASPIRIN TICLOPIDIN, CLOPIDOGREL (±ASA) GP IIb/IIIa RECEPTOR ANTAGONISTS DIRECT THROMBIN INHIBITORS Other Approaches : THROMBOLYTICS, ANTI IX, P2T ANTAGONISTS, TX-ANTAGONISTS Antithrombotic Therapy Inhibitors of Tissue Factor Pathway TFPITAPDirect Thrombin Inhibitors Inhibitors Of Clotting Factors VIIa and/or Xa

35 Virmani R. ATVB 2000;20:1262 Smooth Muscle Cells Macrophages Extracellular lipid Cholesterol Clefts Calcified Plaque Thrombus Healed thrombus Collagen Thrombosis and Atherosclerotic Lesions

36 ATHERO - THROMBOTIC DISEASE MAN LIVES WITH ATHEROSCLEROSIS BUT DIES FROM THROMBOSIS

37 Clopidogrel - Clopidogrel is superior to ASA - Several large trials have clearly established that Clop+ASA combination is safe and more effective than either agent alone. -Requires hepatic metabolization that results in delayed onset of action (unless using Loading doses). -Irreversible platelet inhibition causes persistent antithrombotic effects (Ying-Yang). -Commonly used “maintenance” dose (75 mg/day) only inhibits 40-50% of ADP induced platelet aggregation. - Clopidogrel-treated patient should wait several days prior undergoing surgical procedures. Clopidogrel + ASA combination is considered the treatment of choice for ACS patients

38 What’s new in the antithrombotic horizon ?

39 P2Y12 Inhibitors Clopidogrel; Sanofi/BMS Orally active fast acting (loading) long-lastingirreversible Prasugrel CS-747: Sankyo Orally active fast acting irreversible AZD6140 (AZ, ARC-66941) orally active fast acting reversible (24hrs)

40 Storey R et al. Thromb Haemost 2001;85:401 Study on the safety and tolerability of AR-C69931 N=39 CAD patients 4  g/Kg/min x 69 hour

41 Additive Effect of AZD6140 to Clopidogrel Clopidogrel 75mg/day AZD 1mM; 523ng/mL WB impedance 10  M ADP

42 Clinical Trials with new PY12 Inhibitors JUMBO - TIMI 26 (Circulation 2005;111:3366-73) Prasugrel vs Clopidogrel in PCI. The study showed similar safety and tolerability. Effectiveness being tested in the TRITON. AZD 6140 vs Clopidogrel in stable CAD DISPERSE-1: Greater and more consistent platelet inhibition than Clopidogrel (ESC-2005). DISPERSE-2 Similar safety and tolerability than Clopidogrel (AHA 2005)

43 AZD 6140 AR-C6993 Cangrelor Is an oral, potent, selective and competitive ADP receptor antagonist via P2Y 12 receptor. Fully and reversibly blocks ADP-platelet aggregation. Maximal effect achieved within 2 hours with a half-life of approx 8 hours. At 200 mg dose abolishes ADP-platelet aggregation up to 12 hours. Will be “the lower the better” like in lipid lowering? or or the more powerful the more bleeding?

44 CHARISMA Trial Following the CURE (UA patients) and COMMIT (MI patients) the event-driven CHARISMA trial, was designed to test whether the benefits of Clop+ASA vs ASA would also apply to a broad atherosclerotic population 15,603 patients with a F/U of 28 months. The results showed no difference in primary end-points but a significant increase in bleeding complications. IMPORTANT: Do not stop Clop+ASA treatment in stented patients. stented patients.

45 Lessons Learned from CHARISMA Primary Prevention: ASA seems to be enough. Secondary Prevention: Clop+ASA in high-risk patients offers more robust benefits. After Stenting: Clop+ASA should be given for one year. It should be maintained in patients with recurrent ACS or strokes w/o history of bleeding. Otherwise ASA alone should be enough. Always use “clinical common sense” based on individual risks

46 F X F Ixa F VIIIa Prothrombin F Xa Tenase complex Prothrombinase complex F Xa F Va F VIIa Tissue factor Potential therapeutic targets TF: FVIIa FXa Thrombin

47 FDA’s did not approve Exanta Despite all the clinical data and excitement generated by EXANTA; it was not approved by the FDA (September 10th, 2004) The major concern was the high incidence of “high risk” adverse events associated with long-term use. 1 in each 2300 patients will develop severe liver toxicity resulting in death. The committee requested further assessment of the liver toxicity,cardiovascular events and incidence of bleeding observed in the studies. Inability to identify patient at risk for liver toxicity

48 Ximelagatran was thought to be a significant break-through in antithrombotic therapy but it as not approved by the FDA. How will the FDA’s decision affect the development of new thrombin inhibitors? Would it result in a “delay” or the “death” of antithrombins in general ? Certainly, it has triggered and accelerated the development of other P2Y12 and FXa inhibitors Future Of Direct Thrombin Inhibitors

49 Factor Xa Inhibitors Parenteral agents: Fondaparinux Idraparinux 1 DX 9065a Otamixaban Orally Active agents: Raxazaban/Apixaban Bay 59-7939 Lilly 517717 PD-5348292 (Pfizer) PD-5348292 (Pfizer) DU-697 (Sankyo-Daiichi) Factor II Inhibitors Parenteral agents: LepidurinBivalirudinArgatroban Orally Active agents: XimelagatranDabigatran 1 VG trial DVT positive VG trial PE negative AF trial stopped bleeding What’s new in the TF pathway inhibition

50 Idraparinux is a synthetic analogue of Fondaparinux (Arixtra) which binds with high affinity to AT (Kd = 1.2nM) resulting in the formation of a highly potent and selective inhibitor of coagulation factor Xa. It is targeted to chronic treatment of venous thrombosisIdraparinux is a synthetic analogue of Fondaparinux (Arixtra) which binds with high affinity to AT (Kd = 1.2nM) resulting in the formation of a highly potent and selective inhibitor of coagulation factor Xa. It is targeted to chronic treatment of venous thrombosis Idraparinux was well tolerated after a single iv (up to 14 mg) or sc (2 and 10 mg) administration in healthy young male volunteers. Extended half life up to one-weekIdraparinux was well tolerated after a single iv (up to 14 mg) or sc (2 and 10 mg) administration in healthy young male volunteers. Extended half life up to one-week Idraparinux (SanOrg34006)

51 Fondaparinux Mechanism of Action

52 Fondaparinux - VTE Clinical Trials Bauer K et al. Curr Opin Pulm Med. 2002;8:398-404 Koopman M, Buller H. J Intern Medicine 2003;254:335 Orthopedic Surgery Venous Thromboembolism:effective (55%) and equally safe (2.7vs1.7% bleeds) than LMWH ACS: (Pentalyse Thrombolysis vs UFH) and Pentua (Enox) comparable effectiveness and safety

53 20,078 ACS patients randomized to Fondaparinux (2.5 mg/d) or Enoxaparin (1mg/Kg twice/day) for 6 days. No significant difference on primary end-points at short time (9 days), but Fondaparinux had lowerbleeding leading to reduced mortality at 90 and 180 days (p<0.02). NEJM 2006;354:1464-1476 No significant difference on primary end-points at short time (9 days), but Fondaparinux had lower bleeding leading to reduced mortality at 90 and 180 days (p<0.02). NEJM 2006;354:1464-1476 OASIS 5:Fondaparinux vs Enoxaparin in ACS

54 Antithrombotic Effects of Razaxaban an orally active FXa Inhibitor an orally active FXa Inhibitor

55 3 hours 12 hours 25 mgs 80±725±7 100 mgs 325±4291±11 Antithrombotic Effects of Razaxaban, a FXa Inhibitor Plasma levels (ng/ml) There is dose-response pattern In their antithrombotic and anticoagulation activities

56 Dose (concentration) of Anticoagulant Thrombosis Bleeding SAFE RANGE Thrombus Bleeding The Ideal Antithrombotic

57 No le canto a la Luna En algo nos parecemos porque alumbre mas que el Sol, Luna de la soledad le canto porque ella sabe Yo voy andando y cantando de mi largo caminarque es mi modo de alumbrar Ay, Luna tucumana, Mas cuando salga la Luna tamborcito calchaki, cantaré, cantaré compañera de los gauchos a mi Tucuman querido por la senda del tapir cantaré, cantaré. Luna Tucumana

58 Muchas Gracias por su atención


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