ΤΑ ΝΕΑ ΑΝΤΙΘΡΟΜΒΩΤΙΚΑ ΦΑΡΜΑΚΑ ΣΕ ΕΙΔΙΚΕΣ ΟΜΑΔΕΣ ΑΣΘΕΝΩΝ ΚΑΛΛΙΡΡΟΗ ΚΑΛΑΝΤΖΗ

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1 ΤΑ ΝΕΑ ΑΝΤΙΘΡΟΜΒΩΤΙΚΑ ΦΑΡΜΑΚΑ ΣΕ ΕΙΔΙΚΕΣ ΟΜΑΔΕΣ ΑΣΘΕΝΩΝ ΚΑΛΛΙΡΡΟΗ ΚΑΛΑΝΤΖΗ

2 Subgroup analysis Do we need them? Usually small groups or excluded as Diabetes, CKD, Elderly, Women, PVD, Stroke, CABG

3 Angiolillo et al. Circ 2011; 123:

4 Oral, Direct thrombin and Factor Xa Inhibitors in Development for the Prevention and Treatment of Thromboembolic Diseases Rivaroxaban Apixaban Edoxaban Ximelagatran Dabigatran Alexander G.G. Turpie. Arterioscler Thromb Vasc Biol. 2007;27:

5 Novel Antiplatelets and Anticoagulants drugs Prasugrel Ticagrelor Dabigadran Rivaroxaban Apixaban Diabetes CKD Elderly

6 DM DM is a predictor of worse outcomes in ACS Abnormalities in DM platelets (dysfunctional): increased platelet reactivity reduced responsiveness to antiplatelet agents Increased platelet reactivity and reduced responsiveness to standard DAPT (aspirin plus clopidogrel) are associated with atherothrombotic risk Specific ( tailored ) drug regimens in DM patients are warranted Novel and more potent antiplatelet agents may improve blockade of the diabetic platelet

7 IMPACT OF PRASUGREL IN PLATELET FUNCTION IN DM PATIENTS Prasugrel (standard dose) vs Clopidogrel (high dose) in DM patients VN-P2Y 12 % PRU Inhibition B Verify Now LD -P2Y MD 12 % Inhibition Washout A LD MD Washout *** *** *** *** *** *** *** Mean±SE *** ***p< days No study drug 0 4 Hours post LD 24 7 days No (7 study days) drug Hours post LD (7 days) prasugrel 60 mg LD/10 mg MD clopidogrel 600 mg LD/150 mg MD Similar findings obtained with MPA to 5 and 20 µm ADP, VASP PRI, and Verify Now PRU Angiolillo DJ et al. Eur Heart J. 2011; 32:

8 PRASUGREL AND POOR RESPONSIVENESS /34 22/35 1/32 24/34 0/32 12/34 0/ /35 PRU > 235 MPA>50% IPA 20% PRI>50% 0/34 22/35 1/32 24/34 0/32 12/34 0/34 29/35 C PRU > 235 MPA>50% IPA 20% PRI>50% Poor R at 4 Ho Poor responder analyses at: A) 4 h post LD ; B) 24 h post LD; and 100 C) 7 days post MD Poor Re at 4 Hou PRU > 235 MPA>50% IPA 20% PRI>50 Poor Responder Rate at 4 Hours post LD (%) Poor Responder Rate at 24 Hours Post LD (%) A p< p< p< p< p= /34 19/35 0/30 26/33 0/30 17/33 0/33 25/ /34 22/35 1/32 24/34 0/32 12/34 0/34 PRU 29/35 > 235 MPA>50% IPA 20% PRI>50% 0/34 19/35 0/30 26/33 0/30 17/33 0/33 25/35 20 PRU > 235 MPA>50% IPA 20% PRI>50% PRU > 235 MPA>50% IPA 20% PRI>50% C Poor Responder Rate at 24 Hours Post LD (%) B p< p< Poor Responder Rate at 24 Hours Post LD (%) Poor Responder Rate at 7 Days (%) p< Poor Responder Rate at 7 Days (%) B 100 p< p< p< p< p< C B 100 C p< p< p=0.01 p< p< p< p= p< p= p= p= p= /35 10/34 7/33 18/34 1/33 8/34 3/34 16/ /34 19/35 0/30 26/33 0/30 17/33 0/33 25/35 0 PRU > 235 MPA>50% IPA 20% PRI>50% 1/35 10/34 7/33 18/34 1/33 8/34 3/34 16/34 PRU > 235 MPA>50% IPA 20% PRI>50% PRU > 235 MPA>50% IPA 20% PRI>50% prasugrel 60 mg LD/10 mg MD clopidogrel 600 mg LD/150 mg MD prasugrel 60 mg LD/10 mg MD Angiolillo DJ et al. Eur Heart J. 2011; 32: clopidogrel 600 mg LD/150 mg MD Poor Responder Rate at 7 Days (%) p= p= PRU > 235 MPA>50% IPA 20% prasugrel 60 mg LD/10 mg MD clopidogrel 600 mg LD/150 mg MD p< /35 10/34 7/33 18/34 1/33 8/34 3/34 16/ PRI>50

9 NEW DRUGS/APPROACHES IN DM TRITON-TIMI ( ) n:3146 PLATO ( ) n:4662 Study % of Events Hazard Ratio (95% confidence interval) Standard New Drug/Approach CURRENT OASIS ( ) (PCI Cohort) n: New Drug/Approach Better Standard Clopidogrel Better Ferreiro JL et al. Circulation :

10 Endpoint (%) DM AND PRASUGREL (TRITON-TIMI substudy) CV Death/MI/Stroke (n=3146) Clopidogrel TIMI Major Non-CABG Bleeds HR 1.06 P<0.81 Prasugrel Days Wiviott SD et al. Circulation 2008;118: Prasugrel 12.2 HR 0.70 P<0.001 NNT=21 Clopidogrel

11 DM AND TICAGRELOR CV death, MI, stroke CV death, MI, and stroke Major Bleeding Major Bleeding James S et al. Eur Heart J. 2010;31:

12 Chronic Kidney Disease 35% to 40% of patients presenting with ACS have some degree of renal insufficiency. Patients with CKD: have a higher risk of ACS have a significantly higher mortality are predisposed to increased bleeding complications.

13 Chronic kidney disease National Kidney Foundation practice guidelines Levey AS et al. Ann Intern Med 2003; 139: TIGC

14 Reduced Antiplatelet Response in CKD N = 306 patients with type 2 diabetes mellitus Reprinted from Angiolillo DJ, et al. J Am Coll Cardiol. 2010;55: , with permission from Elsevier.

15 From Montalescot G, et al. Circulation. 2010;122: Republished with permission. Prasugrel and Ticagrelor Benefit *Significant RRR or significant interaction between subgroups

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17 Ticagrelor (PLATO) and PLATO defined major bleeding according to creatinine clearance James S et al. Circulation 2010; 122: TIGC

18 PLATO: Non-CABG TIMI Major Bleeding by CKD Status

19 Clopidogrel: No information Ticagrelor: No dose reduction in GFR <60 ml/min/1.73 m2 Prasugrel: No dose adjustment No information for haemodialysis patients Wijns W et al. EHJ 2010; 31:

20 Prevalence (%) Prevalence of AF increases with age 20 Women (n=4053) Men (n=2590) >85 Age (yrs) Prevalence at baseline assessed in 6808 participants in a European population-based study Data from Heeringa J et al. Eur Heart J 2006;27:

21 Established and new anticoagulants Oral, direct TF/VIIa Parenteral, indirect X IX VIIIa IXa Rivaroxaban Apixaban Edoxaban Va Xa II AT AT AT Fondaparinux LMWH UFH Dabigatran IIa Fibrinogen Fibrin

22 Comparison of the characteristics of new oral anticoagulants (Active 36%) Active 36% Inactive 30% Protein binding >90% >87% 55% 35% (dialysable) Hepatic metabolism CYP3A4 CYP3A4 CYP3A4 Conjugation Weitz JI, et al. Thromb Res. 127 Suppl. 2 (2011) S5 S12

23 New OAC in SPAF: Summary and Overview Outcome Dabigatran 150 mg bid Rivaroxaban 20 mg od Apixaban 5 mg bid Stroke / periph. embolism Superior (RRR 34%) Non-inferior (ITT) Superior (RRR, 21%) Ischaemic strokes Superior (RRR, 24%) Non-inferior Non-inferior Haemorrhagic strokes Superior (RRR, 74%) Superior (RRR, 41%) Superior (RRR, 49%) All deaths Non-inferior Non-inferior Superior (RRR, 11%) All major bleeds Non-inferior* Non-inferior Superior (RRR, 31%) Intracranial bleeds Superior (RRR, 60%) Superior (RRR, 33%) Superior (RRR, 68%) GI bleeds RR, % vs. 2.16% Non-inferior Myocardial infarctions RR, 1.27 (n.s.) Non-inferior Non-inferior RENAL DYSFUNCTION Contraindicated if Ccr <30 ml/min Dose 15 mg od if Ccr ml/min Dose 2.5 mg bid if Cr>1.5 mg/dl

24 Renal Profiles of Anticoagulants Dabigatran Rivaroxaban. Apixaban excretion is also partly dependent on renal function, although the impact of renal insufficiency has not been determined Harder S. J Clin Pharmacol, 2012, in press

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26 ROCKET- AF trial- Rivaroxaban in AF Pts with Moderate Renal Impairment αζζελείο κε ΚΜ κε CHADS 2 score 2 θαη κέηξηα λεθξηθή δπζιεηηνπξγία: rivaroxaban 20 mg/day or 15 mg/day if CrCl ml/min or dose-adjusted warfarin (INR: ) - Μεγαιύηεξε ζπρλόηεηα AEE θαη κεηδόλωλ θαη θιηληθά ζεκαληηθώλ αηκνξξαγηώλ ζε αζζελείο κε ΝΑ, αλεμάξηεηα από ην είδνο ηεο ζεξαπείαο - Παξόκνηα ζπρλόηεηα αηκνξξαγηώλ κε κεηωκέλε δνζνινγία rivaroxaban θαη ζεξαπείαο κε warfarin - Ληγόηεξεο ζαλαηεθόξεο αηκνξξαγίεο κε rivaroxaban (0.28 vs. 0.74% per 100 p-y; P = 0.047) Fox K, et al: Eur Heart J 2011; 32:

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28 Switching: Pradaxa βαξθαξίλε (Cr Cl > 50 ml/min) (Cr Cl ml/min) 1. Έναπξη βαπθαπίνηρ 1. Έναπξη βαπθαπίνηρ 2. 3 ημέπερ απγόηεπα, διακοπή Pradaxa 2. 2 ημέπερ απγόηεπα, διακοπή Pradaxa 3. Αποδπομή δπάζηρ Pradaxa ενηόρ 24 ωπών 3. Αποδπομή δπάζηρ Pradaxa ενηόρ 3 ημεπών

29 Stopping dabigatran for elective surgery Renal function Τ1/2 Stop dabigatran (CrCl in ml/min) (hrs) High bleeding Usual risk or major surgery risk >80 ~ 13 2 days 24 hrs ~ days 1-2 days ~~18 4 days 2-3 days (>48 hrs)

30 STROKE-ELDERLY

31 Elderly

32 Major bleeding by age and renal function

33 Dose of dabigatran Generally recommended dose: 150mg x2. 110mg x2 : In pts 80 year old In pts with moderate renal impairment In pts year old with low embolic and high bleeding risk (CHA 2 DS 2 VASC <2, HAS-BLED >3) In pts taking verapamil and in pts with gastritis, oesophagitis or reflux 75 mg x2: Only FDA suggests this dose for pts with severe renal dysfunction (CrCl ml/min) Contraindicated if CrCl < 30 ml/min

34 CABG and P2Y12 Inhibitors cessation

35 Comparison of AntiPLTs Agents Clopidogrel Prasugrel Ticagrelor Potency Rapidity of onset(50% IPA) 2-4 h 30 min 30 min Variable response YES YES No Reversibility No No Yes Hold before CABG(D) Clinical Experience Bleeding risk Side Effects Rare Rare Common Prior Stroke Preferred Contraindicated Age >75 y Preferred Contraindicated Diabetes Preferred Complex stenting Preferred STEMI Preferred CKD preferred

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38 Προηεινόμενες ζσζηάζεις ζτεηικά με ηην ανάλσζη σπο-ομάδων Περιοριζμός αναλύζεων ζε προκαθοριζμένες σπο-ομάδες με γνώμονα κάποια λογική παθοθσζιολογική βάζη προηγούμενης έρεσνας Ανάλσζη μόνο εθόζον σπάρτει ζηαηιζηική ζημανηικόηηηα ζηο ζσνολικό αποηέλεζμα Διόρθωζη ηιμής p για πολλαπλές ζσγκρίζεις (0.05/n, πτ εάν γίνοσν 20 ζσγκρίζεις να απαιηείηαι p<0.05/20=0.0025) Να θεωρείηαι όηι ηα εσρήμαηα απαιηούν περαιηέρω έρεσνα και όηι δεν είναι αποδεικηικά Να μην σπερεκηιμώνηαι