ΤΑ ΝΕΑ ΑΝΤΙΘΡΟΜΒΩΤΙΚΑ ΦΑΡΜΑΚΑ ΣΕ ΕΙΔΙΚΕΣ ΟΜΑΔΕΣ ΑΣΘΕΝΩΝ ΚΑΛΛΙΡΡΟΗ ΚΑΛΑΝΤΖΗ

ΤΑ ΝΕΑ ΑΝΤΙΘΡΟΜΒΩΤΙΚΑ ΦΑΡΜΑΚΑ ΣΕ ΕΙΔΙΚΕΣ ΟΜΑΔΕΣ ΑΣΘΕΝΩΝ ΚΑΛΛΙΡΡΟΗ ΚΑΛΑΝΤΖΗ

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

Angiolillo et al. Circ 2011; 123: 798-813

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;27:1238-1247

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

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

IMPACT OF PRASUGREL IN PLATELET FUNCTION IN DM PATIENTS Prasugrel (standard dose) vs Clopidogrel (high dose) in DM patients VN-P2Y 12 % PRU Inhibition 350 300 100 250 80 200 60 150 40 100 50 20 0 B Verify Now LD -P2Y MD 12 % Inhibition Washout A LD MD Washout *** *** *** *** *** *** *** Mean±SE *** ***p<0.0001 0 4 24 7 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: 838-46.

35.3 40 35.3 20 PRASUGREL AND POOR RESPONSIVENESS 20 0 3.1 0 0 0 0 3.1 0 0 0/34 22/35 1/32 24/34 0/32 12/34 0/34 0 29/35 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 (%) 100 80 60 40 20 0 100 80 60 40 20 0 A p<0.0001 62.9 p<0.0001 70.6 p<0.0001 40 35.3 p<0.0001 80 82.9 20 20 p=0.03 0 0 0 0 29.4 0 3.1 0 0 00/34 19/35 0/30 26/33 0/30 17/33 0/33 25/35 0 0 0 0 0 21.2 0/34 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 (%) 100 60 B p<0.0001 54.3 p<0.0001 78.8 Poor Responder Rate at 24 Hours Post LD (%) Poor Responder Rate at 7 Days (%) p<0.0001 Poor Responder Rate at 7 Days (%) B 100 p<0.0001 80 60 40 p<0.0001 54.3 p<0.0001 78.8 p<0.0001 p<0.0001 C B 100 C 0 100 p<0.0001 80 78.8 p<0.0001 71.4 80 p=0.01 p<0.0001 p<0.000160 p<0.0001 52.9 p=0.01 54.3 51.5 60 47.1 p<0.0001 52.9 40 p=0.006 47.1 p=0.03 29.4 40 p=0.006 21.2 23.5 p=0.03 29.4 20 21.2 23.5 20 8.8 2.9 3.0 8.8 0 0 0 0 01/35 10/34 7/33 18/34 1/33 8/34 3/34 16/34 2.9 3.0 0/34 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: 838-46. clopidogrel 600 mg LD/150 mg MD Poor Responder Rate at 7 Days (%) 51.5 80 71.4 60 40 p=0.006 2.9 p=0.01 52.9 51.5 3.0 71.4 23.5 PRU > 235 MPA>50% IPA 20% prasugrel 60 mg LD/10 mg MD clopidogrel 600 mg LD/150 mg MD p<0.000 8.8 47 1/35 10/34 7/33 18/34 1/33 8/34 3/34 16/ PRI>50

NEW DRUGS/APPROACHES IN DM TRITON-TIMI 38 17.0 12.2 0.70 (0.58 0.85) n:3146 PLATO 16.2 14.1 0.88 (0.76 1.03) n:4662 Study % of Events Hazard Ratio (95% confidence interval) Standard New Drug/Approach CURRENT OASIS 7 5.6 4.9 0.87 (0.66 1.15) (PCI Cohort) n: 7647 0 0.5 1 1.5 New Drug/Approach Better Standard Clopidogrel Better Ferreiro JL et al. Circulation 2011. 123:798-813.

Endpoint (%) DM AND PRASUGREL (TRITON-TIMI substudy) 18 16 14 CV Death/MI/Stroke (n=3146) Clopidogrel 17.0 12 10 8 6 4 2 0 TIMI Major Non-CABG Bleeds HR 1.06 P<0.81 Prasugrel 0 30 60 90 180 270 360 450 Days Wiviott SD et al. Circulation 2008;118:1626 36. Prasugrel 12.2 HR 0.70 P<0.001 NNT=21 Clopidogrel 2.6 2.5

DM AND TICAGRELOR CV death, MI, stroke CV death, MI, and stroke Major Bleeding Major Bleeding James S et al. Eur Heart J. 2010;31:3006-16.

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.

Chronic kidney disease National Kidney Foundation practice guidelines Levey AS et al. Ann Intern Med 2003; 139: 137-47 2011 - TIGC

Reduced Antiplatelet Response in CKD N = 306 patients with type 2 diabetes mellitus Reprinted from Angiolillo DJ, et al. J Am Coll Cardiol. 2010;55:1139-1146, with permission from Elsevier.

From Montalescot G, et al. Circulation. 2010;122:1049-1052. Republished with permission. Prasugrel and Ticagrelor Benefit *Significant RRR or significant interaction between subgroups

Ticagrelor (PLATO) and PLATO defined major bleeding according to creatinine clearance James S et al. Circulation 2010; 122: 1056-67 2011 - TIGC

PLATO: Non-CABG TIMI Major Bleeding by CKD Status

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: 2501-55

Prevalence (%) Prevalence of AF increases with age 20 Women (n=4053) Men (n=2590) 15 10 5 0 55 59 60 64 65 69 70 74 75 79 80 84 >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;27:949 53 20

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

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

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, 1.5 3.15% 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 30-49 ml/min Dose 2.5 mg bid if Cr>1.5 mg/dl

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

ROCKET- AF trial- Rivaroxaban in AF Pts with Moderate Renal Impairment 14264 αζζελείο κε ΚΜ κε CHADS 2 score 2 θαη κέηξηα λεθξηθή δπζιεηηνπξγία: rivaroxaban 20 mg/day or 15 mg/day if CrCl 30 49 ml/min or dose-adjusted warfarin (INR: 2.0 3.0) - 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: 2387 2394

Switching: Pradaxa βαξθαξίλε (Cr Cl > 50 ml/min) (Cr Cl 30-50 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

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 50-80 ~15 2-3 days 1-2 days 30-50 ~~18 4 days 2-3 days (>48 hrs)

STROKE-ELDERLY

Elderly

Major bleeding by age and renal function

Dose of dabigatran Generally recommended dose: 150mg x2. 110mg x2 : In pts 80 year old In pts with moderate renal impairment In pts 75 80 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 15-30 ml/min) Contraindicated if CrCl < 30 ml/min

CABG and P2Y12 Inhibitors cessation

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) 5-7 7-10 2-3 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

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