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:
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
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
Not all Atherosclerotic lesions are equal Falk E. 2006 JACC ;47:C7-C13
Stenotic Severity and CVD Falk E et al; Circulation 1995
Vulnerable Atherosclerotic Lesion Falk E. 2006 JACC ;47:C7-C13
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?
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
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).
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
ATHERO - THROMBOTIC DISEASE MAN LIVES WITH ATHEROSCLEROSIS BUT DIES FROM THROMBOSIS
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
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)
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
Additive Effect of AZD6140 to Clopidogrel Clopidogrel 75mg/day AZD 1mM; 523ng/mL WB impedance 10 M ADP
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)
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?
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.
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
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
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
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
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
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)
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
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
Antithrombotic Effects of Razaxaban an orally active FXa Inhibitor an orally active FXa Inhibitor
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
Dose (concentration) of Anticoagulant Thrombosis Bleeding SAFE RANGE Thrombus Bleeding The Ideal Antithrombotic
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