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Continuous Cardiovascular Risk and Management of Atherosclerosis in Prior MI Patients - Dr. M. Elisaf, University of Ioa

This study explores the ongoing cardiovascular risk in patients who have experienced a prior myocardial infarction (MI) and discusses the management strategies. It provides valuable insights into mortality rates and outcomes in patients with a first MI, as well as the recurrence of MI post-discharge. The role of platelets in atherothrombosis and thrombosis is also examined, along with potential long-term secondary prevention therapies with oral antiplatelet agents.

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Continuous Cardiovascular Risk and Management of Atherosclerosis in Prior MI Patients - Dr. M. Elisaf, University of Ioa

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  1. Η ΣΤΕΦΑΝΙΑΙΑ ΑΘΗΡΟΘΡΟΜΒΩΣΗ: Ο ΣΥΝΕΧΙΖΟΜΕΝΟΣ ΚΑΡΔΙΑΓΓΕΙΑΚΟΣ ΚΙΝΔΥΝΟΣ ΚΑΙ Η ΑΝΤΙΜΕΤΩΠΙΣΗ ΤΟΥ ΜΩΥΣΗΣ ΕΛΙΣΑΦ ΚΑΘΗΓΗΤΗΣ ΠΑΘΟΛΟΓΙΑΣ ΙΑΤΡΙΚΗΣ ΣΧΟΛΗΣ ΠΑΝΕΠΙΣΤΗΜΙΟΥ ΙΩΑΝΝΙΝΩΝ

  2. Continuous cardiovascular risk in patients who have experienced a prior MI

  3. Patients with prior MI have a higher risk of CV mortality compared with controls Epidemiology study of mortality in patients aged ≥30 years with a first MI over a 10-year period in Denmark (n=3,092,580)[Norgaard2010] 100 Females with incident MI Reference females Males with incident MI Reference males 80 60 CV mortality (%) 40 20 0 0 1 2 3 4 5 Time from event (years) CV, cardiovascular; MI, myocardial infarction.1. Norgaard ML et al. Diabetologia 2010;53:1612–1619.

  4. Despite improvements in survival rates, ~1 in 8 patients will die within 3 years of a STEMI Prospective study of 3-year outcomes in a consecutive series of STEMI patients (n=6820)[Nauta2011] 40 1985–1990 1990–2000 2000–2008 30 27% 25% 20 Cumulative mortality in STEMI patients (%) 13% 10 Overall log-rank p<0.001 0 1 2 0 3 Time from event (years) STEMI, ST-segment elevation myocardial infarction. Adapted from: Nauta ST et al. PLoS One 2011;6:e26917.

  5. Survival rates post-NSTEMI have not markedly improved – ~1 in 8 patients will die within 3 years of a NSTEMI Prospective study of 3-year outcomes in a consecutive series of NSTEMI patients (n=7614)[Nauta2011] 40 1985–1990 1990–2000 2000–2008 30 20 Cumulative mortality in NSTEMI patients (%) 15% 14% 12% 10 Overall log-rank p<0.001 0 0 1 2 3 Time from event (years) NSTEMI, non-ST-segment elevation myocardial infarction. Adapted from: Nauta ST et al. PLoS One 2011;6:e26917.

  6. The highest risk of recurrent MI occurs in the initial year post-discharge, but the risk is continuous and linear up to year 5 OACIS registry: Observational study of recurrent MI in Japanese patients with acute MI with up to 5 years of follow-up (n=7870)[Nakatani2013] 10 8 6 Cumulative rate of recurrent MI (%) 4 2 0 0 400 800 1200 1600 Time from discharge (days) A patient is at the same risk at 1, 2, 3, 4 and 5 years post-discharge MI, myocardial infarction; OACIS, Osaka Acute Coronary Insufficiency Study.Nakatani D et al. Circ J 2013;77:439–446.

  7. ~1 in 5 patients, event-free for 1 year post-MI suffered an MI, stroke or CV death within 3 years APOLLO HELICON Sweden analysis 1-year event-free MI survivors (n=76,687)[Jernberg2014] Cumulative 3 year incidence of CV death, MI or stroke (%) CV, cardiovascular; MI, myocardial infarction. Jernberg, T. et al. Eur Heart J 2015: doi:10.1093/eurheartj/ehu505

  8. Revisiting the pathophysiology of coronary atherothrombosis

  9. Stages in the development of atherogenesis Monocyte T cell Endothelial cell Foam cell Intima Dendritic cell SMCs Media Adventitia Mast cell Fibroblast Thrombus formation Platelet Apoptotic bodies Fibrous cap rupture Dividing SMC Lipid core Collagen Foam cell Apoptotic macrophage Vasa vasorum Cholesterol crystal Migrating SMC Libby P et al. Nature 2011;473(7347):317–325.

  10. The role of the platelet in coronary atherothrombosis

  11. Platelets may be involved in all stages of atherothrombosis Initiation and progression Plaque rupture Acute thrombus formation • Platelet adhesion & activation • Release of inflammatory mediators, cell recruitment • Platelet activation • Release of inflammatory mediators, plaque instability Platelet aggregation Fuentes QE et al. Platelets 2013;24(4):255–262; Gawaz M. Eur Heart J Suppl 2008:10(Suppl 1);14–17.

  12. The role of the platelet in thrombosis • Platelet-activated thrombosis involves three principal steps:[Franchi2014] • Platelet adhesion • Activation and recruitment of additional platelets • Platelet aggregation 1. Franchi F, Angiolillo DJ. Nat Rev Cardiol 2014; Epub ahead of print Oct 7.

  13. Potential role of the platelet in inflammation • Laboratory studies show that activated platelets produce inflammatory molecules that can contribute to all stages of atherosclerosis. CCR1, chemokine (CC motif) receptor 1; CD40L, soluble CD40L; IL-1, interleukin-1; GPIb, glycoprotein Ib; JAM-3, junctional adhesion molecule 3; Mac-1, macrophage 1 antigen; PSGL-1, P-selectin glycoprotein ligand 1; RANTES, regulated on activation, normal t cell expressed and secreted;SDF-1, stroma cell-derived factor-1; TLR, toll-like receptor; TP, thromboxane A2 receptor; TXA2, thromboxane A2. Fuentes QE et al. Platelets 2013;24(4):255–262.

  14. Studies supporting long-term secondary prevention therapy with oral antiplatelet agents

  15. ΜΕΛΕΤΗ CAPRIE-ΣΥΜΠΕΡΑΣΜΑΤΑ • Clopidogrel vs aspirin σε ασθενείς με Ηχ ΟΕΜ, ΑΕΕ, περιφερικής αγγειοπάθειας • Clopidogrel >aspirin κυρίως σε ασθενείς με περιφερική αγγειοπάθεια • Σε μετεμφραγματικούς ασθενείς: clopidogrel >aspirin • Παρόμοια επίπτωση αιμορραγιών-λιγότερες ΓΕΣ αιμορραγίες με κλοπιδογρέλη

  16. CHARISMA: Study design Clopidogrel 75 mg QD (n=7802) Low-dose ASA 75162 mg/day Patients aged ≥45 years at high risk of atherothrombotic events R Double-blind treatment until a total of 1040 CV death, MI or stroke events recorded (n=15,603) Low-dose ASA 75162 mg/day Placebo 1 tablet QD (n=7801) 1-month visit 6-month visit Ongoing visitsevery 6 months Final visit (fixed study end date) 3-month visit ASA, acetylsalicylic acid; CV, cardiovascular;MI, myocardial infarction; QD, once daily; R, randomisation. Bhatt DL, Topol EJ. Am Heart J 2004;148:263–268;Bhatt DL, et al. N Engl J Med 2006;354:1706–1717.

  17. CHARISMA: Cumulative incidenceof CV death, MI or stroke (primary endpoint) 7.3% Placebo + ASA 6.8% Clopidogrel + ASA RR=0.93 (95% CI: 0.83–1.05); p=0.22 No. at risk Clopidogrel 7802 7653 7510 7363 5299 2770 Placebo 7801 7644 7482 7316 5212 2753 ASA, acetylsalicylic acid; CI, confidence interval; CV, cardiovascular; MI, myocardial infarction; RR, relative risk. Bhatt DL, et al. N Engl J Med 2006;354:1706–1717.

  18. ΜΕΛΕΤΗ CHARISMA-ΣΥΜΠΕΡΑΣΜΑΤΑ • Διπλή αντιαιμοπεταλιακή αγωγή vs μονοθεραπεία: όχι διαφορά σε θανάτους/ΟΕΜ/ΑΕΕ • Όμως σε άτομα με εγκατεστημένη αγγειακή νόσο: • συμβαμάτων κατά 17%, p=0.001 • αιμορραγιών, όχι όμως των σοβαρών αιμορραγικών επιπλοκών

  19. Clopidogrel ή Prasugrel

  20. Cumulative Incidence of Stent Thrombosis 12–30 mo: Thienopyridine vs. placebo, 0.4% vs. 1.4%; hazard ratio, 0.29; P <0.001 12–33 mo: Thienopyridine vs. placebo, 0.7% vs. 1.4%; hazard ratio, 0.45; P <0.001 8 100 Thienopyridine Placebo 6 80 4 60 2 Cumulative Incidence (%) 40 0 0 12 15 18 21 24 27 30 33 20 0 0 12 15 18 21 24 27 30 33 Months Since Enrollment No. at Risk 5020 4934 4870 4828 4765 4686 4642 3110 Thienopyridine 4941 4845 4775 4721 4651 4603 4556 3105 Placebo Mauri L, et al. N Engl J Med. Nov 16, 2014. DOI: 10.1056/NEJMe1413297. .

  21. Cumulative Incidence of MACCE 12–30 mo: Thienopyridine vs. placebo, 4.3% vs. 5.9%; hazard ratio, 0.71; P <0.001 12–33 mo: Thienopyridine vs. placebo, 5.6% vs. 6.5%; hazard ratio, 0.82; P <0.02 8 100 Thienopyridine Placebo 6 80 4 60 2 Cumulative Incidence (%) 40 0 0 12 15 18 21 24 27 30 33 20 0 0 12 15 18 21 24 27 30 33 Months Since Enrollment No. at Risk 5020 4917 4840 4778 4702 4611 4554 3029 Thienopyridine 4941 4799 4715 4635 4542 4476 4412 2997 Placebo Mauri L, et al. N Engl J Med. Nov 16, 2014. DOI: 10.1056/NEJMe1413297. .

  22. All-Cause Mortality The rate of death from noncardiovascular causes (1.1% vs. 0.6%; hazard ratio, 1.80; P = 0.01) accounting for the difference in rates between the two analysis period HR 1.36; P = 0.04 HR 1.36; P = 0.05 Mauri L, et al. N Engl J Med. Nov 16, 2014. DOI: 10.1056/NEJMe1413297. .

  23. DUAL ANTIPLATELET THERAPY (DAT) vs PLACEBO (>12months) PLACEBO R.R. DAT Stent thrombosis1.4% 0.29 0.4% Μείζονα συμβάματα 5.9% 0.71 4.3% ΟΕΜ 4.1% 0.47 2.1% Θάνατοι 1.5% 1.36 2% Αιμορραγίες 1.6% 1.56 2.5% N Engl J Med 2014;371: 2155-2166

  24. κινδύνου εμφάνισης αιμορραγιών κατά 61% • Ενδοκράνιες αιμορραγίες 0.6% vs 0.4% -20%

  25. Ορισμένα άτομαμε στεφανιαία νόσο πολύ υψηλού κινδύνου με Ηχ ρήξης αθηρωματικών πλακών και θρόμβωση πιθανά ωφελούνται από παρατεταμένη διπλή αντιαιμοπεταλιακή αγωγή

  26. PEGASUS-TIMI 54 A randomised, double-blind, placebo-controlled, parallel-group, multinational trial, to assess the prevention of thrombotic events with ticagrelor compared with placebo on a background of acetylsalicylic acid therapy in patients with a history of myocardial infarction

  27. ΧΑΡΑΚΤΗΡΙΣΤΙΚΑ ΤΗΣ TICAGRELOR (1) Αναστολέας του υποδοχέα P2Υ12 Προκαλεί αντιστρεπτή και εκλεκτική αναστολή Διακοπή (offset) της δράσης σε 3-5 ημέρες Δεν είναι προφάρμακο-χορηγείται ανεξάρτητα απότην τροφή Έχει γρηγορότερη έναρξη δράσης (vsclopidogrel) –έναρξη δράσης 30’-4h Δοσολογία: φόρτιση 180mg/d / δόση συντήρησης 90mg X 2/d Χρόνος ημίσειας ζωής 8-12h Μεταβολίζεται σε ενεργό μεταβολίτη με τα CYP3A4, CYP3A5 Απεκκρίνεται κυρίως διαμέσου ηπατικού μεταβολισμού

  28. ΧΑΡΑΚΤΗΡΙΣΤΙΚΑ ΤΗΣ TICAGRELOR (2) • Μειώνει τα καρδιαγγειακά συμβάματα και την ολική θνητότητα σε σύγκριση με clopidogrel • Δεν αυξάνει τις μείζονες αιμορραγίες-αύξηση αιμορραγικών επιπλοκών • Έχει και επιπρόσθετες δράσεις ( ΑΔΕΝΟΣΙΝΗΣ) • στεφανιαία αγγειοδιαστολή • μείωση ισχαιμικών βλαβών και βλαβών επαναγγείωσης • αντιφλεγμονώδης δράση • αρνητική ινότροπη και χρονότρoπη δράση •  GFR-διέγερση των πνευμονικών ινών C του πνευμονογαστρικού δύσπνοια

  29. PLATO: TICAGRELOR vs CLOPIDOGREL • (acute coronary syndromes) •  OEM, AEE, θανάτων κατά 16%, p=0.003 •  καρδιαγγειακής θνητότητας κατά 21%, p=0.001 •  θρομβώσεων των stent κατά 33% • Όχι  μειζόνων ή θανατηφόρων αιμορραγιών •  όλων των αιμορραγικών επιπλοκών κατά 11%, p=0.008-ενδοκράνιες αιμορραγίες 0.3% vs 0.2% • Δύσπνοια (διακοπή στο 1%)

  30. 60mg/d: θεραπεία 10.000 ασθενών για ένα έτος  42 λιγότερα συμβάματα και 31 περισσότερες αιμορραγίες

  31. BALANCING THE RISKS AND BENEFITS OF DUAL PLATELET INHIBITORS συμβαμάτων-  αιμορραγικών επιπλοκών Ανάγκη εξατομίκευσης της αγωγής Ερωτήματα: Ποιο φάρμακο? Διάρκεια αγωγής?

  32. ΑΛΛΗΛΕΠΙΔΡΑΣΕΙΣΤΗΣ TICAGRELOR ΜΕ ΑΛΛΑ ΦΑΡΜΑΚΑ • Όχι με ισχυρούς αναστολείς του CYP3A4/CYP3A5 • [ketoconazole, clarithromycin, nefazodone, zitonavir, atazanavir]* • Επαγωγείς της CYP3A4 (ριφαμπικίνη) δράσης TICAGRELOR • Αναστέλλει το P4503A4 SIMVA,LOVA SIMVA<40mg/d • Grapefruit* επιπέδων ticagrelor • Υπόστρωμα και ασθενής αναστολέας της Pgpπροσοχή με δακτυλίτιδα *ΠΡΟΣΟΧΗ ΜΕ ΜΕΤΡΙΟΥΣ ΑΝΑΣΤΟΛΕΙΣ ΤΟΥ P4503A4 [diltiazem, verapamil, fluconazole, erythromycin]

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