Patras University Hospital

ACS 2011 Class-I Anticoagulation is recommended for all pts in addition to antiplatelet therapy (I-A) The anticoagulation should be selected according to both ischaemic and bleeding risks, and according to the efficacy safety profile of the chosen agent (I-C) In a purely conservative strategy, anticoagulation should be maintained up to hospital discharge (I-A) Patras University Hospital

Eikelboom JW. Circulation 2006

ACS 2011 Class-I If fondaparinux or enoxaparin are not available, UFH with a target aptt of 50 70 s or other LMWHs at the specific recommended doses are indicated (I-C) Patras University Hospital

STEMI 2012 An injectable anticoagulant must be used in ppci (I-C) Class-I UFH with or without routine GP IIb/IIIa blocker must be used in pts not receiving bivalirudin or enoxaparin (I-C) Anticoagulation is recommended in STEMI pts treated with lytics until revascularization (if performed) or for the duration of hospital stay up to 8 days (I-A) The anticoagulant can be: UFH given as a weight-adjusted i.v. bolus and infusion (I-C) Patras University Hospital

Greater anti-iia activity with increasing molecular weight... Patras University Hospital

However, those trials were not really interventional Patras University Hospital Patras University Hospital

9,978 patients within 24 h high-risk UA/NSTEMI Enoxaparin vs UFH early inv strategy Other meds: aspirin, clopidogrel, GP IIb/IIIa @ physician discretion Enox noninferior for death/mi @ 30 d, 6 mo 1 y Patras University Hospital Ferguson JJ, et al. JAMA 2004;292:45 54.

SYNERGY Primary Outcomes 16 14 12 10 8 6 14,5 14 UFH Enoxaparin Freedom from Death/MI 1.0 0.95 0.9 0.85 Enoxaparin 4 0.8 UFH 2 0 5 10 15 20 25 30 0 Death or MI at 30 d Days from Randomization Kaplan Meier Curve Absolute Risk Reduction 0.5 Hazard Ratio 0.96 95% CI 0.86 1.06 p 0.40 Patras University Hospital Ferguson JJ, et al. JAMA 2004;292:45 54.

9,978 patients within 24 h high-risk UA/NSTEMI Enoxaparin vs UFH early inv strategy Other meds: aspirin, clopidogrel, GP IIb/IIIa @ physician discretion Enox noninferior for death/mi @ 30 d, 6 mo 1 y Major bleeding with enox? due to crossover to UFH @ time of PCI Patras University Hospital Ferguson JJ, et al. JAMA 2004;292:45 54.

EXTRACT TIMI 25 Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment STEMI < 6 h Lytic eligible ASA Lytic choice by MD (TNK, tpa, rpa, SK) Double-blind, double-dummy ENOX < 75 y: 30 mg IV bolus SC 1.0 mg / kg q 12 h (Hosp DC) 75 y: No bolus SC 0.75 mg / kg q 12 h (Hosp DC) CrCl < 30: 1.0 mg / kg q 24 h UFH 60 U / kg bolus (4000 U) Inf 12 U / kg / h (1000 U / h) Duration: at least 48 h Cont d at MD discretion Day 30 1 Efficacy Endpoint: Death or Nonfatal MI 1 Safety Endpoint: TIMI Major Hemorrhage Patras University Hospital Antman EM, Am Heart J 2005;149:217-26

SEX Male Female AGE (years) < 75 > 75 EXTRACT TIMI 25 Death or Nonfatal MI at 30 Days RRR (%) ARD 18 All Interaction 16 Tests P = NS 20 6 1.9 2.9 2.0 1.5 INFARCT LOCATION Anterior Other 11 23 1.5 2.3 DIABETES No DM DM 17 21 1.9 3.5 PRIOR MI No Prior MI Prior MI 17 20 1.9 3.5 FIBRINOLYTIC Streptokinase Fibrin-Specific 13 18 1.6 2.2 TIME TO RX < Median > Median 23 12 2.6 1.5 OVERALL 20,479 P < 0.0001 17 2.1 Patras University Hospital 0.5 1 2 ENOX Better Relative Risk UFH Better Antman EM, Am Heart J 2005;149:217-26

EXTRACT TIMI 25 5 UFH ENOX Bleeding Endpoints at 30 Days % Events 4 3 2 1 ARD 0.7% RR 1.53 P<0.0001 1,4 2,1 ARD 0.4% RR 1.84 P = 0.001 0,4 0,8 ARD 0.4% RR 1.39 P = 0.014 0,9 1,3 ARD 0.1% RR 1.27 P = 0.14 0,7 0,8 0 Major Bleed (Total) Fatal Major Bleed Nonfatal Major Bleed ICH Patras University Hospital Antman EM, N Engl J Med 2006;354:1477-88

EXTRACT TIMI 25 PCI Cohort Event ENOX UFH RR P-Value n=2,236 n=2,375 TIMI Major Bleed 1.4% 1.6% 0.87 (0.55-1.39) 0.56 TIMI Minor Bleed 3.3% 2.4% 1.34 (0.95-1.88) 0.09 TIMI Major or 4.6% 4.0% 1.15 (0.88-1.51) 0.31 Minor Bleed ICH 0.2% 0.4% 0.42 (0.13-1.35) 0.18 Stroke 0.3% 0.9% 0.30 (0.12-0.75) 0.006 Patras University Hospital Gibson CM, ESC Hotline Presentation 2006

ACS 2011 Class-I Enoxaparin (1 mg/kg twice daily) is recommended when fondaparinux is not available (I-B) Crossover of heparins (UFH and LMWH) is not recommended (III) Patras University Hospital

Primary Endpoint Death, Complication of MI, Procedure Failure or Major Bleeding Main Safety Endpoint Non-CABG Major Bleeding (STEEPLE definition) Patras University Hospital

Montalescot, G. et al. J Am Coll Cardiol Intv 2010

STEMI 2012 An injectable anticoagulant must be used in ppci (I-C) Class-I Enoxaparin (with or without routine GP IIb/IIIa blocker) may be preferred over unfractionated heparin (IIb) Anticoagulation is recommended in STEMI pts treated with lytics until revascularization (if performed) or for the duration of hospital stay up to 8 days (I-A) The anticoagulant can be: Enoxaparin i.v followed by s.c. (preferred over UFH) (I-A) Patras University Hospital

No additional enoxaparin is recommended during PCI if the last SC enoxaparin injection was administered < 8 h before PCI An additional 0.3 mg/kg i.v. bolus is recommended if the last SC enoxaparin injection was administered > 8 h before PCI Crossing over to another anticoagulant during PCI is strongly discouraged Patras University Hospital

In ACS, a 2.5 mg fixed daily dose of fondaparinux is recommended.

NSTE/ACS: Fondaparinux & Adjunctive UFH during PCI

3,788 pts with STEMI undergoing ppci randomized to UFH for 4-48 hrs vs. fonda 2.5 mg SQ QD for up to 8 ds in a placebo-controlled double-blind trial Patras University Hospital

Overall Pre-Specified Subgroup Analyses N 12092 Death or MI at 30 days UFH/Placebo 11.2% Fonda 9.7% Interaction P value Initial Reperfusion Rx 0.04 None 2867 15.1 12.2 Thrombolytic 5436 13.6 10.9 Primary PCI 3789 4.9 6.0 GRACE Risk Score 0.03 < 112 5958 4.3 4.6 >=112 6134 18.0 14.5 0.5 0.7 0.8 1.0 1.2 1.4 1.6 2.0 Patras University Hospital Fonda better UFH/Plac better Hazard Ratio

Fondaparinux 2.5 mg/d => 50% lower anticoagulant effect vs. enoxaparin as assessed by anti-xa activity. Inhibition of thrombin generation is also twice as low with fondaparinux, as assessed by thrombin generation potential. A low level of anticoagulation is sufficient to prevent further ischaemic events during NSTE-ACS in pts on full antiplatelet therapy including ASA and clopidogrel, plus GP IIb/IIIa receptor inhibitors in many This low level of anticoagulation explains the significant reduction in the risk of bleeding Patras University Hospital

However, such a low level of anticoagulation is not sufficient to prevent catheter thrombosis during PCI in a highly thrombogenic environment This also confirms that an additional bolus of UFH is needed at the time of PCI in patients initially treated with fondaparinux. In ppci fondaparinux may be harmful Patras University Hospital

ACS 2011 Class-I Fondaparinux (2.5 mg SC daily) is recommended as having the most favourable efficacy safety profile with respect to anticoagulation (I-A) If the initial anticoagulant is fondaparinux, a single bolus of UFH (85 IU/kg adapted to ACT, or 60 IU in the case of concomitant use of GP IIb/IIIa receptor inhibitors) should be added at the time of PCI (I-B) Patras University Hospital

STEMI 2012 Class An injectable anticoagulant must be used in ppci (I-C) Fondaparinux is not recommended for primary PCI (III) Anticoagulation is recommended in STEMI pts treated with lytics until revascularization (if performed) or for the duration of hospital stay up to 8 days (I-A) The anticoagulant can be: In pts treated with streptokinase, fondaparinux i.v. bolus followed by s.c. dose 24 h later (IIa) Patras University Hospital

ACUITY Patras University Hospital

HORIZONS AMI: Acute Stent Thrombosis; Impact of Antithrombin (Primary Randomization) More deaths at 30 ds occurred after major bleeding (n=26) than after reinfarction (n=10) or definite stent thrombosis (n=5) Def/Prob Stent Thrombosis (%) Number at risk Bivalirudin UFH+GPIIb/IIIa 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 Patras University Hospital Bivalirudin monotherapy Heparin + GPIIb/IIIa inhibitor HR (95%CI) = 5.93 [2.06,17.04] P = 0.0002 0 6 12 18 24 Time in Hours 1611 1583 1580 1578 1577 1591 1587 1584 1583 1583 1.5% 0.3%

HORIZONS AMI:Acute Stent Thrombosis; Impact of Pre Randomization Heparin Def/Prob Stent Thrombosis (%) Number at risk P-R R Heparin 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 No P-R P R Heparin P-R R Heparin No P-R P R Heparin Patras University Hospital No Pre-Randomization Heparin Pre-Randomization Heparin P int antithrombin x pre-rand rand hep = 0.39 HR [95%CI] = 3.07 [1.33,7.09] P = 0.006 HR [95%CI] = 9.64 [1.00,92.70] P = 0.02 0 6 12 18 24 Time in Hours 1066 1052 1051 1050 1049 545 531 529 528 528 1211 1208 1207 1207 1207 378 377 375 374 374 Bivalirudin Bivalirudin UFH+GPI UFH+GPI 2.6% 0.9% 0.8% 0.1%

NACE (%) 20 Number at risk Bivalirudin alone Heparin+GPIIb/IIIa 18 16 14 12 10 8 6 4 2 0 Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 0 1 2 3 4 5 6 7 8 9 10 11 12 Time in Months Diff [95%CI] = -2.6% [-5.1,[ -0.1] HR [95%CI] = 0.84 [0.71, 0.98] P=0.03 1800 1559 1514 1483 1343 1802 1499 1459 1427 1281 18.3% 15.7% *MACE or major bleeding (non CABG) Patras University Hospital Mehran R, TCT 2008

Landmark analysis All-cause mortality or reinfarction (%) 5 4 3 2 1 0 Heparin + GPIIb/IIIa (n=1802) Bivalirudin (n=1800) 3-year HR (95% CI) 30-day HR (95% CI) 0.72 (0.58 0.91) 0.84 (0.61 1.16) p=0.005 10.6% p=0.30 4.5% 3.8% 0 3 6 9 12 15 18 21 24 27 30 33 36 Months 7.8% Patras University Hospital Stone, GW Lancet 2011 Published online June 13.

ACS 2011 Class-I Bivalirudin plus provisional GP IIb/IIIa receptor inhibitors are recommended as an alternative to UFH plus GP IIb/IIIa receptor inhibitors in pts with an intended urgent or early invasive strategy, particularly in pts with a high risk of bleeding (I-B) Patras University Hospital

STEMI 2012 Class An injectable anticoagulant must be used in ppci (I-C) Bivalirudin (with use of GP IIb/IIIa blocker restricted to bailout) is recommended over UFH and a GP IIb/IIIa blocker (I-B) Anticoagulation is recommended in STEMI pts treated with lytics until revascularization (if performed) or for the duration of hospital stay up to 8 days (I-A) The anticoagulant can be: No data for bivalirudin Patras University Hospital

Coagulation Cascade Intrinsic Pathway FXII, FXI, FIX, FVIII, PL, Ca 2+ Extrinsic Pathway Tissue factor, FVII Common Pathway Factor X Factor Xa OTAMIXABAN Specific, Direct, IV, Factor Xa Inhib Proximal inhib of coag cascade Small molecule Inhibits clot-bound factor Xa, which is inaccessible to large molecule & indirect inhibitors Factor V Prothrombin (F II) Thrombin (F IIa) Favorable PK/PD profile Short-acting (half-life 30 min) Wt-based bolus & infusion No need for monitoring No significant renal elimination Patras University Hospital Fibrin Formation Platelet Aggregation 80

Definition of the optimal dose range of otamixaban for future study OTAM 0.035 OTAM 0.070 OTAM 0.105 OTAM 0.140 OTAM 0.175 Inadequate anticoagulation Decreased risk of death or ischemic events, with comparable risk of maj/min bleeding c/w UFH + eptifi Excessive bleeding Otamixaban 0.105-0.140 mg/kg/h appears to be best range for further study as a replacement for UFH + GP IIb/IIIa Patras University Hospital 81

These results suggest an unfavorable efficacy/safety balance for acute Xa inhibition in the modern era of DAPT and routine early intervention for ACS. Patras University Hospital

Reversal agent: factor IXa with an aptamer technology Reverse 25%, 50%, or 75%. At least 50% of reversal is needed in ACS pts, especially those undergoing PCI

Aptamers: small oligonucleotides to inhibit specific protein targets with high affinity. Made of oligonucleotide sequences, provide the code for their own complement (reversal agent) used to inhibit their function. REG1 anticoagulation system: aptamer-based, factor IXa inhibitor that is being developed for use in patients undergoing percutaneous coronary intervention and the treatment of acute coronary syndrome.

Ποιό από τα παρακάτω είναι σωστό Α. Το fondaparinux όπως και η οταμιξαμπάνη είναι άμεσοι αναστολείς του παράγοντα Χα Β. Οι LMWH πλεονεκτούν της UFH διότι έχουν μικρό χρόνο ημίσειας ζωής κ η δράση τους αναστέλλεται ταχέως Γ. Η μπιβαλιρουδίνη συνδέεται με τον PF4 και γι αυτό έχει μικρά ποσοστά HIT Δ. Κανένα από τα παραπάνω Patras University Hospital

Ασθενής με NSTEMI υπό 2,5 mg fondaparinux υποβάλλεται σε PCI. Χορηγείτε πλήρη δόση UFH καιμειωμένηδόσηεάν Α. Έχει νεφρική ανεπάρκεια Β. Πρόκειται να χρησιμοποιήσετε GPA-I Γ. Δε χρήζει καθόλου ηπαρίνη Δ. Το Α & το Γ είναι σωστά Patras University Hospital

Σε ασθενή με NSTEMI που νοσηλεύεται Σαββατοκύριακο στη CCU, το προτιμώμενο φάρμακο είναι Α. Fondaparinux Β. Ενοξαπαρίνη αν δεν υπάρχει fondaparinux Γ. Κλασσική ηπαρίνη Δ. Μπιβαλιρουδίνη E. Το Α & Β είναι σωστά Patras University Hospital

Σε ασθενείς με NSTEMI που αντιμετωπίζονται συντηρητικά, ή μετά από αγγειοπλαστική, τα αντιπηκτικά μπορούν να διακοπούν και να μείνει σε διπλή αντιαιμοπεταλιακή αγωγή Α. ΣΩΣΤΟ Β. ΛΑΘΟΣ Patras University Hospital

Σε ασθενή με NSTEMI που λαμβάνει ενοξαπαρίνη και πρόκειται να κάνουμε αγγειοπλαστική, επιπρόσθετη UFH ενδείκνυται Α. Δεν ενδείκνυται Β. Αν η τελευταία δόση ενοξαπαρίνης χορηγήθηκε > 8 ώρες πριν Γ. Αν το ACT < 200 Δ. Το Β & Γ είναι σωστά Patras University Hospital

Σε ασθενή με STEMI και θρμομβόλυση με TNK που θα διακομιστεί για καθετηριασμό χορηγούμε άμεσα: Α. Ενοξαπαρίνη ή UFH με προτιμώμενη την πρώτη Β. Fondaparinux Γ. Μπιβαλιρουδίνη Δ. Δε χορηγούμε αντιπηκτικά πριν περάσουν 24 ώρες Patras University Hospital

Aσθενής με STEMI διακομίζεται για ppci. Μπορείτε να χορηγήσετε Α. Ενοξαπαρίνη ή UFH με προτιμώμενη την πρώτη Β. Fondaparinux Γ. Μπιβαλιρουδίνη Δ. Δε χορηγούμε αντιπηκτικά Ε. Το Α ή το Γ (προτιμώμενοτογ) Patras University Hospital

Aσθενής με STEMI διακομίζεται για ppci και έχει χορηγηθεί 5000 ΙU UFH. Κατά την αγγειοπλαστική χορηγείτε: Α. Ενοξαπαρίνη IV B. UFH IV κατευθυνόμενη από το ACT Β. Fondaparinux IV Γ. Μπιβαλιρουδίνη IV Δ. To B ή το Γ με προτιμώμενη την μπιβαλιρουδίνη Patras University Hospital

Aσθενής με ΝSTEMI διακομίζεται για ppci και έχει χορηγηθεί Ενοξαπαρίνη πριν 1.5 ώρα. Κατά την αγγειοπλαστική χορηγείτε: Α. Ενοξαπαρίνη IV στημισήδόση B. UFH IV κατευθυνόμενη από το ACT Β. Fondaparinux IV Γ. Μπιβαλιρουδίνη IV Δ. Τίποτα Patras University Hospital

Γυναίκα με ΣΔ, 82 ετών, με σοβαρή ΧΝΑ (CrCl <30mL/min) και ΝSTEMI με ΗΚΓ αλλαγές και ctn-i 20, θα άντιμετωπιστεί πρώιμα επεμβατικά. Καταλληλότερη αγωγή: Α. UFH IV (bolus & inf) κατευθυνόμενη από PTT B. Ενοξαπαρίνη 1 mg/kg ΜΙΑ φορά τη μέρα Γ. Fondaparinux SC Δ. Μπιβαλιρουδίνη IV (bolus & inf) Patras University Hospital

In the case of severe renal failure, when fondaparinux or enoxaparin are contraindicated, UFH should be used The advantages of UFH over other anticoagulants in CKD are that it is easily monitored with aptt, and it can be quickly neutralized in the event of bleeding. Fondaparinux has a much safer profile than enoxaparin in moderate CKD, as shown by the much lower risk of bleeding complications observed in OASIS-5 Patras University Hospital

Άνδρας 62 ετών με STEMI υποβάλλεται σε ppci. Έχει λάβει 60 mg πρασουγρέλης και 5000 IU UFH, στα επείγοντα. Καταλληλότερη αγωγή κατά την ppci : Α. UFH IV (bolus) κατευθυνόμενη από ACT @ provisional GPI B. Ενοξαπαρίνη IV @ provisional GPI Γ. Μπιβαλιρουδίνη IV (bolus & inf) @ provisional GPI Patras University Hospital

Little bivalirudin was used in the landmark trials comparing prasugrel and ticagrelor to clopidogrel -- only 3% and 2% in TRITON TIMI 38 and PLATO, respectively There is scarce evidence of efficacy/safety of prasugrel @ bivalirudin compared to clopidogrel @ bivalirudin during PCI for ACS No data for ticagrelor Patras University Hospital