NSTEMI ΑΣΤΑΘΗΣ ΣΤΗΘΑΓΧΗ Αντιπηκτική αγωγή (ποια, πότε και για πόσο) Σωτήρης Πατσιλινάκος Κωνσταντοπουλείο Γ.Ν. Ν. Ιωνίας

ΑΝΤΙΠΗΚΤΙΚΑ ΣΤΑ ΟΣΣ ΟΞΕΙΑ ΦΑΣΗ Ηπαρίνη Ηπαρίνη ΧΜΒ Βιβαλιρουδίνη ΜΑΚΡΟΧΡΟΝΙΑ ΧΟΡΗΓΗΣΗ Κουμαρινικά

Sites of Antithrombotic Drug Action Fondaparinux Heparin LMWHs AT AT AT Bivalirudin Hirudin Argatroban Tissue factor Thrombin Fibrinogen Aspirin Platelet activation Platelet aggregation Fibrin Collagen Plasma clotting ADP cascade Thromboxane A 2 Prothrombin Factor Xa Clopidogrel Prasugrel Cangrelor Eptifibatide Abciximab Tirofiban (GPI) Fibrinolytics Thrombus

Anti-Thrombin Rx Heparin Milestones in ACS Management LMWH Bivalirudin [ Fondaparinux ] Anti-Platelet Rx Aspirin Treatment Strategy Conservative GP IIb/IIIa blockers Clopidogrel Early invasive PRISM-PLUS PLUS REPLACE 2 ICTUS PURSUIT CURE OASIS-5 ISAR-REACT 2 ESSENCE TACTICS TIMI-18 SYNERGY ACUITY 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 PCI ~ 5% stents ~85% stents PCI Drug-eluting stents Ischemic risk Bleeding risk Adapted from and with the courtesy of Steven Manoukian,, MD.

Association Between Bleeding and Outcome in ACS and PCI

Impact of Major Bleed and MI after Elective and Urgent PCI 1-Year Mortality (N=6,012) Cumulative % Mortality With major bleed 8.8% With MI 5.7% Without major bleed 2.0% Without MI 1.9% Time from Randomization in Days Stone GW. J Inv Cardiol 2004;16(suppl G):12 17. 17.

30-Day Death According to Bleeding OASIS Registry, OASIS-2, CURE Cumulative Events, % 0 2 4 6 8 10 12 14 Bleeding No Bleeding No. at Risk No Bleeding Bleeding 0 5 10 15 20 25 30 33676 33419 33157 32990 32879 32769 32710 470 (1.4%) Days 459 440 430 420 410 408 J Eikelboom et al Circulation 2006

The landmark message from these and other studies, which was incorporated into the 2007 NSTEACS Guidelines, is that prevention of bleeding MUST be regarded at least as important as the prevention of major ischemic events, such as myocardial infarction.

Blood Transfusion is Associated with an Increased 30-Day Mortality in NSTEMI N=24,112 ACS patients from GUSTO IIb,, PURSUIT and PARAGON 0.10 0.08 0.06 HR=3.94*; 95%CI: 3.26 to 4.75 Log-rank p<0.001 Transfusion 30-day death rate 8.00% Cumulative mortality 0.04 0.02 0 No Transfusion 5 10 15 20 25 30 3.08% Day *Adjusted for baseline characteristics, bleeding and transfusion propensity and nadir hematocrit Rao et al. JAMA 2004;292:1555-62

Potential Relationship Between Bleeding and Mortality Major Bleeding Hypotension Cessation of ASA/Clop Transfusion Ischemia Stent Thrombosis Inflammation Mortality Bhatt DL et al. In Braunwald: : Harrison s s Online 2005.

Major bleeding (with or without blood product transfusions) has emerged as a powerful independent predictor of early and late mortality in pts with NSTEMI, STEMI and is at least as important as MI and myocardial reinfarction

Dramatic Improvement of Outcome over the Last 30 years Antiplatelet agents Anticoagulants Revascularization / Reperfusion / Thrombolysis Long term treatment / secondary prevention Implementation of guidelines

Recommendation for Invasive evaluations and revascularization ESC Guidelines European Heart Journal doi:10.1093/eurheart/ehr236

Algorithm for Patients with UA/NSTEMI Managed by an Initial Invasive Strategy Diagnosis of UA/NSTEMI is Likely or Definite ASA (Class I, LOE: A) Clopidogrel if ASA intolerant (Class I, LOE: A) Select Management Strategy Invasive Strategy Init ACT (Class I, LOE: A) Acceptable options: enoxaparin or UFH (Class I, LOE: A) bivalirudin or fondaparinux (Class I, LOE: B) B A B1 Proceed with an Initial Conservative Strategy Prior to Angiography Init at least one (Class I, LOE: A) or both (Class IIa, LOE: B) of the following: Clopidogrel IV GP IIb/IIIa inhibitor B2 Factors favoring admin of both clopidogrel and GP IIb/IIIa inhibitor include: Delay to Angiography High Risk Features Early recurrent ischemic discomfort Proceed to Diagnostic Angiography Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1-e157, Figure 7. ACT = anticoagulation therapy; LOE = level of evidence.

Algorithm for Patients with UA/NSTEMI Managed by an Initial Conservative Strategy Diagnosis of UA/NSTEMI is Likely or Definite ASA (Class I, LOE: A) Clopidogrel if ASA intolerant (Class I, LOE: A) A Select Management Strategy Proceed with Invasive Strategy Conservative Strategy Init ACT (Class I, LOE: A): Acceptable options: enoxaparin or UFH (Class I, LOE: A) or fondaparinux (Class I, LOE: B), but enoxaparin or fondaparinux are preferable (Class IIa, LOE: B) C1 Init clopidogrel (Class I, LOE: A) Consider adding IV eptifibatide or tirofiban (Class IIb, LOE: B) C2 (Continued) Anderson JL, et al. J Am Coll Cardiol. 2007;50:e1-e157, Figure 8. ACT = anticoagulation therapy; LOE = level of evidence.

OASIS 5: 5 : An International, Multicenter, Randomized, Double-Blind, Double-Dummy Dummy Trial in 41 Countries 20,078 patients with UA/NSTEMI Aspirin, Clopidogrel, anti-gpiib/iiia, planned Cath/PCI as per local practice Randomization Fondaparinux 2.5 mg s.c. od up to 8 days Enoxaparin 1 mg/kg s.c. bid for 2-8 days 1 mg/kg s.c. od if ClCr<30mL/min Vital status ascertained in 20,066 (99.9%) Lost to follow-up at day 9: fondaparinux: n=7 and enoxaparin: n=5 1. Michelangelo OASIS 5 Steering Committee. Am Heart J 2005;150:1107.e1-.e10 2. OASIS 5 Investigators. N Engl J Med 1464-76

Study Objectives and Outcomes Objectives Primary efficacy objective: To demonstrate non-inferiority of fondaparinux compared with enoxaparin Primary safety objective: To determine whether fondaparinux was superior to enoxaparin in preventing major bleeding Outcomes (centrally adjudicated) Primary efficacy: 1st occurrence of the composite of death, MI, or refractory ischemia (RI) up to day 9 Primary safety: Major bleeding up to day 9 Risk benefit: Death, MI, refractory ischemia, major bleeds up to day 9 Secondary: Above & each component separately at days 30 and 180 1. Michelangelo OASIS 5 Steering Committee. Am Heart J 2005;150:1107.e1-.e10 2. OASIS 5 Investigators. N Engl J Med 2006;354:1464-76

Death/MI/RI: Day 9 HR 1.01 95% CI 0.90-1.13 Enoxaparin Fondaparinux 0 1 2 3 4 5 6 7 8 9 Days Cumulative Hazard 0.0 0.01 0.02 0.03 0.04 0.05 0.06

Major Bleeding: 9 Days Cumulative Hazard 0.0 0.01 0.02 0.03 0.04 HR 0.53 95% CI 0.45-0.62 P<<0.00001 Enoxaparin Fondaparinux 0 1 2 3 4 5 6 7 8 9 Days

Mortality: Day 30 Enoxaparin Cumulative Hazard 0.0 0.01 0.02 0.03 Fondaparinux HR 0.83 95% CI 0.71-0.97 0.97 P=0.022 0 3 6 9 12 15 18 21 24 27 30 Days

Mortality at 6 Months Cumulative Hazard 0.0 0.02 0.04 0.06 Enoxaparin Fondaparinux HR 0.89 95% CI 0.79-0.99 0.99 P=0.037 0 20 40 60 80 100 120 140 160 180 Days

Increased Mortality at Days 30/180 in Patients with Major Bleeds by Day 9 in OASIS 5 0,2 Maj Bleed 9 days Cumulative Hazard 0,15 0,1 0,05 No Maj Bleed 9 days 0 Budaj et al. JACC 2006;abstract 972-224 Adjusted HR (95% CI) at day 30: 5.06 (4.59-5.62); at day 180: 3.16 (2.92-3.44) 0 30 60 90 120 150 180 Days

Categories of Major Bleeds at 9 Days Enox (No. Pts) Fonda (No. Pts) No. Rand. 10021 10057 Total Bleeding 412 (4.1%) 217 (2.2%) <<0.0001 Intracranial 7 7 Surgery req d to stop bleed 77 41 0.0001 Retroperitoneal 37 9 0.0001 Hb 3 g/dl 312 150 0.0001 Transfusion 2 units 287 164 0.0001 P

Does the Lower Bleeding Rate at 9 Days Translate into Lower Long Term Mortality? Patients with No Bleeds Minor Bleeds Major bleeds Total: No. Bleeds Minor Bleeds Major Bleeds Total: No. Deaths at 30 Days Enox Fonda 278 260 19 10 55 25 352 295 No. Deaths at 180 Days 528 518 31 13 76 35 635 566 Difference -18-9 -39 (68.4%) -30-57 -10-18 -59 (85.5%) -41-69

Relative Impact of MI, Refractory Ischemia or Bleeding on Mortality OASIS-5 Nonfatal MI Refractory Ischemia Major Bleeds 30 Days 9.6 (7.7-12.0) 4.0 (2.9-5.6) 6.5 (5.1-8.2) Crude Odds Ratio for Death (95% CI) 30 to 180 Days 2.2 (1.5-3.3) 1.4 (0.8-2.3) 2.1 (1.4-3.0) 180 Days 5.6 (4.6-6.7) 2.6 (2.0-3.5) 4.1 (3.3-5.0) Minor Bleeds 3.0 (2.1-4.3) 1.5 (0.9-2.4) 2.2 (1.6-2.9)

OASIS-5 Less Bleeding = Less Deaths Bleeding Reduced by 50% Deaths Reduced by 17% Cumulative Hazard 0.0 0.01 0.02 0.03 0.04 HR: 0.52 95% CI: 0.44-0.61 p<0.001 Enoxaparin Fondaparinux Cumulative Hazard 0.0 0.01 0.02 0.03 Enoxaparin Fondaparinux HR: 0.83 95% CI: 0.71-0.97 p=0.02 0 1 2 3 4 5 6 7 8 9 Days 0 3 6 9 12 15 18 21 24 27 30 Days Yusuf S, Mehta S, et al. OASIS-5 Investigators NEJM 2006

A Shift in the Paradigm Fondaparinux makes it possible to reduce both ischemic risk (death, death/mi, death/mi/stroke) and bleeding risk First ever observed with an anticoagulant in ACS

Guidelines Recommendations for Anticoagulation Anticoagulation is recommended for all patients in addition to antiplatelet therapy (I-A) Anticoagulation should be selected according to the risk of both ischaemic and bleeding events (I-B) Several anticoagulants are available, namely UFH, LMWH, Fondaparinux, bivalirudin. The choice depends on the initial strategy (urgent invasive, early invasive, or conservative strategies (I-B) In an urgent invasive strategy UFH (I-C), or enoxaparin (IIa-B) or bivalirudin (I-B) should be immediately started 2007 ESC Guidelines

Guidelines Recommendations for Anticoagulation In a non-urgent situation, as long as decision between early invasive or conservative strategy is pending: Fondaparinux is recommended on the basis of the most favourable efficacy/safety profile (I-A) Enoxaparin with a less favourable efficacy/safety profile than fondaparinux should be used only if the bleeding risk is low (IIa-B) 2007 ESC Guidelines

Fondaparinux in PCI

OASIS 5 Conclusions Patients Undergoing PCI 1. A lower incidence of vascular access site complications was observed with fondaparinux 2. Fewer bleeding complications with fondaparinux irrespective of the timing of last study drug administration 3. Fewer bleeding complications with fondaparinux irrespective of the use of UFH prior to PCI 4. A higher rate of guiding catheter thrombosis was observed with fondaparinux when PCI was performed without UFH, but this was largely avoided if UFH was used just before/during the procedure OASIS 5 Investigators. N Engl J Med 2006;354:1464-76

PCI Procedural Complications Events (30 Days) Enoxapari n n=3089 Fondaparin ux n=3118 P value Any UFH during PCI 53.8% 18.8% Any procedural complication 8.6% 9.6% 0.18 Abrupt closure 1.1% 1.5% 0.20 Catheter thrombus 0.5% 1.3% 0.001 Vascular access 8.1% 3.3% <0.0001 Pseudo-aneurysm 1.6% 1.0% 0.39 Large hematoma 4.4% 1.6% <0.0001 Yusuf S, et al. N Engl J Med. 2006;354(14):1464-76

Clinical Events after PCI: Day 30 P=0.004 Event Rate (%) 14 12 10 8 6 4 2 0 P=0.68 2,1 2 P=0.60 5,4 5,7 5,4 P<0.0001 2,8 11,7 Death MI Major Bleeds Death, MI,Stroke or Major Bleed 9,5 Enox (n=3089) Fonda (n=3118)

Vascular Access Site Complications, Large Hematomas and Pseudo-aneurysms 9 8 7 6 5 4 3 2 1 0 8,1 HR 0.41 P<<0.0001 3,3 HR 0.63 P=0.033 1,6 1 HR 0.36 P<<0.0001 4,4 1,6 Enox Fonda Vasc Access Site Complication Pseudo-aneurysm Large Hematoma

Adding UFH to Fondaparinux for PCI is Safe and Preserves the Lower Bleeding with Fondaparinux Enox Fonda HR CI No UFH post- Randomization 1.2 (n=1,277) UFH or equivalent placebo 1.1 mandated by protocol (n=1,229) during PCI Open Label UFH 2.7 (n=598) Overall 1.5 (n=3,104) 0.5 (n=1,313 0.4 ) (n=1,279 ) 1.3 (n=543) 0.6 (n=3,135 ) Mean dose of UFH for PCI used in OASIS 5: 47 IU/kg 0.45 0.18 1.11 1.11 0.34 0.12 0.95 0.95 0.48 0.20 1.17 0.42 0.24 0.71 0.71 Yusuf S. et al. N Engl J Med. 2006;354:2829

OASIS 5 PCI: Net Clinical Benefit Favours Fondaparinux in Invasively Managed Patients Death/MI/Stroke/Major Bleeding 12 10 RR 0.78 P=0.004 RR 0.76 P=0.035 Death, MI, Stoke, Major Bleeding (%) 8 6 4 2 Enoxaparin Fondaparinux 0 ALL PCI EARLY PCI < 24h Mehta et al. JACC 2006;abstract 821-5 Mehta et. al. JACC 2007, in press

Conclusions for PCI 1. Patients who underwent an early invasive strategy in OASIS 5 trial had superior net benefit with fondaparinux compared to enoxaparin 2. Fondaparinux is safe and effective as upstream therapy in patients undergoing PCI and reduces bleeding by half compared to enoxaparin 3. Catheter thrombus occurs very rarely in comparison with death or re-mi and appears to be avoided with standard UFH for the PCI itself without increasing major bleeding 4. Adjunctive UFH (50 IU/kg) with or without GP IIb/IIIa antagonist is recommended as PCI anticoagulation

Low vs. Standard Dose Unfractionated Heparin for Percutaneous Coronary Intervention in Acute Coronary Syndromes Patients treated with Fondaparinux: the FUTURA/OASIS 8 Randomised Trial Sanjit S. Jolly on behalf of FUTURA/OASIS 8 Trial Group

FUTURA Trial Study Objectives Primary Objective: To determine whether Low fixed dose vs. Standard ACT guided unfractionated heparin during PCI reduces the composite of peri-pci* major, minor bleeding and vascular access site complications in ACS patients treated with fondaparinux Secondary Objective: To determine if major bleeding rates in FUTURA (with unfractionated heparin added to fondaparinux) are higher than OASIS 5 PCI (with Fondaparinux used alone) *Peri-PCI defined within 48 hours following PCI

Study Design Adjunctive therapy during PCI Coronary Angiography/PCI to be performed within 72 hours Double Blind With at least 2 of following: Age>60 elevated biomarkers ECG changes Patients were not eligible if required urgent coronary angiography (<120 min) due to clinical instability Registry *ACT Targets consistent with current guidelines

Outcomes to 30 days 0.05 Major Bleed at 30 days 0.05 Death/MI/TVR at 30 days 0.04 0.03 Low dose 2.2% vs. Standard dose 1.8%, HR 1.20 (95% CI 0.64-2.23, p=0.57) 0.04 0.03 0.02 0.02 Low dose 4.5% vs. Standard dose 2.9% HR 1.56 (95% CI 0.98-2.48, p=0.06) No. at Risk 0.01 0.0 Standard Dose Low Dose 0 Standard Dose Low Dose 3 6 9 12 15 18 21 24 27 30 Days 1002 986 981 980 980 978 1024 1002 1001 998 997 994 No. at Risk 0.01 0.0 Standard Dose Low Dose Standard Dose Low Dose 0 3 6 9 12 15 18 21 24 27 30 Days 1002 980 975 975 974 971 1024 997 988 982 981 978 Subgroup analysis showed consistent results for primary outcome and for death/mi/tvr for pre-specified subgroups of: Age, Sex, GP IIb/IIIa, BMI, CrCl, Arterial access site

Conclusions No significant difference in major/minor bleeding or vascular complications between Low fixed dose and Standard dose unfractionated heparin While low dose heparin reduced minor bleeding there was a trend towards reduced efficacy The use of unfractionated heparin for PCI on a background of fondaparinux did not increase major bleeding when compared to fondaparinux alone and lower than that previously observed with enoxaparin

Implications ACS patients treated with fondaparinux can undergo PCI safely with unfractionated heparin No evidence to depart from guideline recommended standard dose regimen of unfractionated heparin during PCI Adding unfractionated heparin during PCI to fondaparinux preserves the benefits and safety of fondaparinux (ie. reduced bleeding) while minimizing catheter thrombus

ESC 2011 Guidelines in ACS in patients without presenting persistent ST-segment elevation Fondaparinux (2.5mg subcutaneously daily) is recommended as having the most favourable efficacy safety profile with respect to anticoagulation GRADE 1 A ESC Guidelines European Heart Journal doi:10.1093/eurheart/ehr236

ESC 2011 Guidelines in ACS in patients without presenting persistent ST-segment elevation Fondaparinux Contraindicated in severe renal failure (CrCl<20mL/min). Drug of choice in patients with moderately reduced renal function (CrCl 30 60 ml/min) ESC Guidelines European Heart Journal doi:10.1093/eurheart/ehr236

How Should Fondaparinux Be Used in Patients with UA/NSTEMI? Administer fondaparinux (2.5 mg sc od) for up to 8 days or until hospital discharge if earlier If a patient needs to undergo an invasive procedure during the treatment period, the following is recommended: PCI: UFH should be used during the procedure CABG surgery: fondaparinux where possible should not be given during the 24 h before surgery and may be restarted 48 h post-operatively

BIVALIRUDIN

ACUITY Ischemic Composite Endpoint Cumulative Events (%) 15 10 5 0 Estimate P UFH/Enoxaparin + IIb/IIIa (N=4603) 7.3% (log rank) Bivalirudin + IIb/IIIa (N=4604) 7.7% 0.37 Bivalirudin alone (N=4612) 7.8% 0.30 0 5 10 15 20 25 30 35 Days from Randomization Stone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16.

ACUITY Major Bleeding Endpoint Cumulative Events (%) 15 10 5 0 Estimate P UFH/Enoxaparin + IIb/IIIa (N=4603) 5.7% (log rank) Bivalirudin + IIb/IIIa (N=4604) 5.3% 0.41 Bivalirudin alone (N=4612) 3.0% <0.0001 0 5 10 15 20 25 30 35 Days from Randomization Stone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16.

ACUITY Net Clinical Outcome 15 Cumulative Events (%) 10 5 0 Estimate P UFH/Enoxaparin + IIb/IIIa (N=4603) 11.7% (log rank) Bivalirudin + IIb/IIIa (N=4604) 11.8% 0.89 Bivalirudin alone (N=4612) 10.1% 0.014 0 5 10 15 20 25 30 35 Days from Randomization Stone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16.

ACUITY Mortality at One Year Mortality (%) 5 4 3 2 Bivalirudin+GPI vs. Hep+GPI HR [95% CI] = 0.99 (0.80-1.22) Bivalirudin alone vs. Hep+GPI HR [95% CI] = 0.95 (0.77-1.18) 30 day Estimate P (log rank) 1 year Estimate P (log rank) p=0.90 1 0 UFH/Enoxaparin + IIb/IIIa Bivalirudin + IIb/IIIa Bivalirudin alone 1.4% 1.6% 1.6% 0.53 0.39 4.4% 4.2% 3.8% 0.93 0.66 0 30 60 90 120 150 180 210 240 270 300 330 360 390 Days from Randomization Stone GW, ACC 2007

ACUITY and ISAR-REACT 4 trials, randomized a total of 3,798 NSTEMI patients undergoing PCI to bivalirudin or heparin (unfractionated or enoxaparin) plus a GPI (eptifibatide, tirofiban, or abciximab). Table 1. Thirty-Day Outcomes MACE NACE Mortality MI TVR Bivalirudin (n = 1,928) 10.6% 13.4% 1.3% 8.7% 1.7% Heparin + GPI (n = 1,870) 10.2% 14.7% 1.1% 8.7% 1.9% OR (95% CI) 1.04 (0.85-1.27) 0.90 (0.76-1.06) 1.26 (0.70-2.25) 1.00 (0.80-1.24) 0.91 (0.57-1.47) Adnan Kastrati, et al, Circulation 2012

ACUITY and ISAR-REACT 4 trials, randomized a total of 3,798 NSTEMI patients undergoing PCI to bivalirudin or heparin (unfractionated or enoxaparin) plus a GPI (eptifibatide, tirofiban, or abciximab). Table 2. Bleeding Outcomes at 30 Days Bivalirudin (n = 1,928) Heparin + GPI (n = 1,870) P Value Major Bleeding 3.4% 6.3% < 0.001 TIMI Major Bleeding 1.3% 2.4% 0.02 TIMI Minor Bleeding 4.8% 7.5% < 0.001 Adnan Kastrati, et al, Circulation 2012

Bivalirudin: A Guidelines-Supported Alternative to UFH/LMWH in ACS Advantages of the direct thrombin inhibitor bivalirudin No requirement for antithrombin III Inhibits thrombin-mediated platelet activation Effective on clot-bound thrombin No interactions with PF- 4 Plasma half-life 25 minutes No requirement for anticoagulant monitoring Clinical results with bivalirudin in PCI Similar protection from ischemic events as UFH + GP IIb/IIIa inhibitors, with markedly reduced bleeding 1 Not previously tested in contemporary ACS patients REPLACE 2. Lincoff AM et al. JAMA 2003;289:853-863.

SWITCH: Study Design Open-label, prospective, 3-arm 3 study 91 ACS patients undergoing PCI (3 US sites) 30 30 31 LMWH 1mg/kg SC 0-44 h before PCI LMWH 1mg/kg SC 4-88 h before PCI LMWH 1mg/kg SC 8-12 h before PCI Arms Switched Bivalirudin during PCI 0.75 mg/kg bolus 1.75 mg/kg/h IV infusion Primary Endpoint BLEEDING Waksman J Invasive Cardiol 2006;18:370-375.

Results: Study Drug-Related Bleeding Events All, % N=91 Group 1,% n=30 Group 2,% N=30 Group 3,% N=31 p value All Major Bleed 7.7 (7) 13.3 (4) 3.2 (1) 6.5 (2) 0.39 Transfusion 2 units 4.4 (4) 3.2 (1) 3.2 (1) 6.5 (2) 1.0 Intracranial Bleed 0 (0) 0 (0) 0 (0) 0 (0) -- Retroperitoneal Bleed 0 (0) 0 (0) 0 (0) 0 (0) -- Spontaneous Hematuria or 1.1 (1) 3.2 (1) 0 (0) 0 (0) 0.66 Hematemesis Drop in Hg > 4g/dL, no site 2.2 (2) 6.7 (2) 0 (0) 0 (0) 0.21 Drop in Hg 3 g/dl 0 (0) 0 (0) 0 (0) 0 (0) -- All Transfusions 4.4 (4) 6.7 (2) 0 (0) 6.5 (2) 1.0 Minor Bleed 4.4 (4) 6.7 (2) 6.7 (2) 0 (0) 0.39

SWITCH: Conclusions Switching from LMWH to bivalirudin during PCI for patients with ACS was safe Switching was not associated with major bleeding complications regardless of when LMWH was administered The use of bivalirudin as the sole antithrombin agent during PCI can be extended for patients who were pretreated with enoxaparin 8 hours post the last dose of LMWH

How to Switch Science to Practice From UFH to Bivalirudin Discontinue UFH for 30 minutes before starting bivalirudin for PCI From LMWH to Bivalirudin Discontinue LMWH for 8 hours before starting bivalirudin for PCI Gibson CM, Am J Cardiol. 2007 Jun 15;99(12):1687-90.

ΑΝΤΙΠΗΚΤΙΚΑ ΣΤΑ ΟΣΣ ΟΞΕΙΑ ΦΑΣΗ Ηπαρίνη Ηπαρίνη ΧΜΒ Βιβαλιρουδίνη ΜΑΚΡΟΧΡΟΝΙΑ ΧΟΡΗΓΗΣΗ Κουμαρινικά

CHA 2 DS 2 -VASc Stroke Risk Score HASBLED Hemorrhage Risk Score

Where does bleeding risk assessment fit in? Bleeding risk varies significantly amongst individuals Overlap of bleeding risk factors and stroke risk factors Multiple bleeding risk assessment tools

Pisters R et al. Chest 2010;138:1093 100

Major bleeding rates by HAS-BLED score in the overall SPORTIF cohort Adapted from Lip GYH et al. J Am Coll Cardiol 2011; 57: 173 80

HASBLED often misunderstood HASBLED 3 = increased bleeding risk not meant to be a contraindication to anticoagulation per se increased caution and monitoring Emphasizes modifiable risk factors Adds perspective to specific bleeding risk factors Highlights individualised stroke vs bleeding risk assessment Manolis A, Kallistratos M, Poulimenos L. Curr Hypertens Rep. 2012;14(4):350-9

Hb drop of 2g/dl Transfusion of 2 U Symptomatic bleeding in critical organ Fatal haemorrhage Intracranial haemorrhage Hb drop of 5g/dl Transfusion of 4 U Inotropic agent support Surgery

Triple antithrombotic therapy ESC/EACTS GUIDELINES 2011 Should only be given if a compelling indication exists (AF with CHADS score 2, mechanical valves, recent/recurrent Hx of deep venous thrombosis, PE) Only for the shortest period with frequent INR measurement (Target 2-2.5) Avoid DES (to restrict the duration to 1 month)

7 μήνες μετά από οξύ στεφανιαίο σύνδρομο (NSTEMI) και εμφύτευση επικαλυμμένου (DES) stent σε ασθενή με κολπική μαρμαρυγή, με CHA2DS2-VASc score 3 και HASBLED score 2, η καταλληλότερη αντιθρομβωτική αγωγή είναι: A. Ανταγωνιστής βιταμίνης Κ (VKA) με επίπεδα INR 2-3 και κλοπιδογρέλη 75mg/ημερησίως. B. Ανταγωνιστής βιταμίνης Κ (VKA) με επίπεδα INR 2-2.5 και κλοπιδογρέλη 75mg/ημερησίως. C. Ανταγωνιστής βιταμίνης Κ (VKA) με επίπεδα INR 2.5-3,ασπιρίνη 100mg και κλοπιδογρέλη 75mg/ημερησίως. D. Ανταγωνιστής βιταμίνης Κ (VKA) με επίπεδα INR 2-2.5,ασπιρίνη 100mg και κλοπιδογρέλη 75mg/ημερησίως. E. Ανταγωνιστής βιταμίνης Κ (VKA) ως μονοθεραπεία

7 μήνες μετά από οξύ στεφανιαίο σύνδρομο (NSTEMI) και εμφύτευση επικαλυμμένου (DES) stent σε ασθενή με κολπική μαρμαρυγή, με CHA2DS2-VASc score 4 και HASBLED score 2, η καταλληλότερη αντιθρομβωτική αγωγή είναι: A. Ανταγωνιστής βιταμίνης Κ (VKA) με επίπεδα INR 2-3 και κλοπιδογρέλη 75mg/ημερησίως. B. Ανταγωνιστής βιταμίνης Κ (VKA) με επίπεδα INR 2-2.5 και κλοπιδογρέλη 75mg/ημερησίως. C. Ανταγωνιστής βιταμίνης Κ (VKA) με επίπεδα INR 2.5-3,ασπιρίνη 100mg και κλοπιδογρέλη 75mg/ημερησίως. D. Ανταγωνιστής βιταμίνης Κ (VKA) με επίπεδα INR 2-2.5,ασπιρίνη 100mg και κλοπιδογρέλη 75mg/ημερησίως. E. Ανταγωνιστής βιταμίνης Κ (VKA) ως μονοθεραπεία

3 μήνες μετά εμφύτευση επικαλυμμένου BMS σε ασθενή με εκλεκτική PCI, λόγω ασταθούς στηθάγχης, και μεταλική βαλβίδα, με CHA2DS2-VASc score 3 και HASBLED score 2, η καταλληλότερη αντιθρομβωτική αγωγή είναι: A. Ανταγωνιστής βιταμίνης Κ (VKA) με επίπεδα INR 2-3 και κλοπιδογρέλη 75mg/ημερησίως. B. Ανταγωνιστής βιταμίνης Κ (VKA) με επίπεδα INR 2-2.5 και κλοπιδογρέλη 75mg/ημερησίως. C. Ανταγωνιστής βιταμίνης Κ (VKA) με επίπεδα INR 2.5-3,ασπιρίνη 100mg και κλοπιδογρέλη 75mg/ημερησίως. D. Ανταγωνιστής βιταμίνης Κ (VKA) με επίπεδα INR 2-2.5 και ασπιρίνη 100mg ημερησίως. E. Ανταγωνιστής βιταμίνης Κ (VKA) ως μονοθεραπεία

Σε ασθενή με NSTEMI και κάθαρση κρεατινίνης 30-60 ml/h θα πρέπει να προτιμάται A. fondaparinux B. enoxaparine C. tinzaparine D. Nadroparine E. cilostasol

Ασθενής με NSTEMI και συντηρητική προσέγγιση θα πρέπει να λαμβάνει αντιπηκτική αγωγή από την εισαγωγή του στο νοσοκομείο: A. για το 1 ο 24ωρο B. για 2 ημέρες C. για 4 ημέρες D. μέχρι το εξιτήριο του E. για 1 μήνα

Σε περίπτωση χρήσης fondaparinux κατά την PCI θα πρέπει να χορηγείται A. Μη κλασματοποιημένη ηπαρίνη (UFH) 40 IU/kg B. UFH 85 IU/kg C. UFH 40 μg/kg/min D. bivalirudin E. Τίποτα από τα ανωτέρω

Ασθενής με NSTEMI και κολπική μαρμαρυγή που θα υποβληθεί σε αγγειοπλαστική, έχει CHA2DS2-VASc score 5 και HASBLED score 4: A. θέτει σοβαρή υποψηφιότητα για χρήση bare metal stents B. δεν θα πρέπει να λαμβάνει ασενοκουμαρόλη C. καλύτερα να λαμβάνει τικαγρελόρη D. Επαρκεί ο συνδυασμός ασπιρίνης, κλοπιδογρέλης E. Τίποτα από τα ανωτέρω