Management of patients with recent ACS undergoing surgery: bridging with GPIIb/IIIa Inhibitors

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1 Management of patients with recent ACS undergoing surgery: bridging with GPIIb/IIIa Inhibitors Stefano Savonitto Division of Cardiology Ospedale A. Manzoni Lecco - Italy

2 Rates of postoperative MACE (D+MI+revasc) According to prior MI US national retrospective cohort study stent implant. (48%DES, 52% BMS), patients (22.5%) underwent NCS 1980 MACE (4.7%). Time between stent and surgery was associated with MACE (P <.001). Time effect MACE rate: 5.1% BMS and 4.3% DES The 3 factors most strongly associated with MACE were nonelective surgery (adj OR, 4.77), MI in the 6 months preceding surgery (AOR, 2.63), revised cardiac risk index >2 (AOR, 2.13). APT withdrawal effect? Hawn MT. JAMA 2013;310:1462

3 Predictors of reoperation in ACS patients undergoing CABG Clopidogrel <5 days Pre-op aspirin Pre-op GPI Prior CABG Odds ratio 95% CI P-value Berger JS. JACC 2008;52:1693

4 Noncardiac surgery after stent implantation Antiplatelet therapy and risk of bleeding Van Kuijk P. Am J Cardiol 2009;104:1229

5 Predictors of stent thrombosis the dutch registry: 437 out of 21,009 pts (2.1%) Van Werkum JW. JACC 2009;53:1399

6 It is not just a matter of stent thrombosis: it s coronary risk Overall risk of ST 2.0%, with 4 definite and 7 probable events. Overall risk of the combined EP of death, nonfatal MI, or ST was 9.0%. Anwaruddin S. J Am Coll Cardiol Intv 2009;2:542

7 Multifactorial causal mechanisms of early post-operative cardiac events

8 Reduced effect of Clopidogrel administered via nasogastric tube to intubated patients Critically-ill patients with STEMI often present with insufficient gastroduodenal motility, liver hypoperfusion, and higher levels of circulating catecholamines. All of these factors can lead to reduced efficacy of clopidogrel, which is only available as a p.o. medication. The aim of the study was to compare clopidogrel effectiveness in unstable STEMI patients on mechanical ventilation with stable STEMI patients. Dosage: 600 mg + 75 mg Osmancik P, Catheterization CV Interv 2010;75:158

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10 Platelet aggregation patways and inhibitors LMWH fondaparinux Arachidonic acid Adhesion molecules, vwf collagen thrombin heparin hirudin epinephrine Ticlopidine Clopidogrel Prasugrel Ticagrelor ADP Aspirin TXA 2 synt inhib TxA 2 blockers agonists GP IIb/IIIa expression GPIIb/IIIa inhibitors Platelet aggregation + Fibrinogen

11 Reversibility of platelet inhibition Oral drug aspirin clopidogrel prasugrel ticagrelor Reversibility irreversible irreversible irreversible reversible Time to surgery 5-7 days 5-7 days >7 days 5 days i.v. drug abciximab tirofiban eptifibatide Reversibility irreversible reversible reversible Time to surgery 3-5 days 4 hours (8 hours if CrCl <30 ml) 4 hours

12 Phase 2 protocol (Simon s two-stage design) for urgent surgery early after DES (EudraCT No ) Stop Plavix Inclusion criteria Patients within 6-12 months of DES implantation + high-risk for surgical bleeding, so that the surgeon would not operate on clopidogrel Start tirofiban 12 months in the case of high-risk of ST: stent implantation due to an ACS diabetes renal insufficiency severe LV dysfunction DES in LMCA, proximal LAD, bifurcation Stop tirofiban surgery Resume tirofiban** Resume Plavix mg*** Exclusion criteria Allergy to tirofiban Thrombocytopenia < Stroke < 30 days or prior ICH Intracranial disease Uncontrolled hypertension Unable to sign consent form ASA continued throughout the study Low-dose LMWH for DVT prevention Day h* 0 4h follow-up until discharge *8h in pts with egfr <30 ml/min **if oral admin not possible *** as soon as oral admin possible Tirofiban: 0.4 mg/kg/min over 30, followed by 0.1 mg/kg/min Or 0.05 mg/kg/min if egfr <30 ml/min Primary EP: the composite of Death, MI, stent thrombosis, haemostatic reoperation Secondary EP: TIMI major bleeding Savonitto S. Br J Anaesth 2010;104:285

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14 40 pts/8 deaths = 20% Kaluza GL. JACC 2000;35:1288

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19 Surgical category Cardiovasc, N= 32 Urologic N= 13 Gastrointest N= 23 Type of surgery DES-surg delay CABG= 18, Valvuloplasty=1 Aortic aneur = 5 post-mi VSD= 3 AVR = 2 TEA periph= 2 Fix.epicardial lead=1 Kidney K =3 Prostate K=2 Bladder K=5 Urethra K =3 Gastric K=3 Colon K=14 Pancreas K=2 Cholecyst=4 Mixed Uterus K=1 Breast K=1 N= 14 Eye surgery=3 Femoral Fr=2 Hip arthropl.=1 Pheocromo=1 Larynx K=1 Tracheotomy=1 Salivary stent=1 Lymphoma=1 Titolo: bridging with Leg GPI amputat.=1 Autore: Lung K= 1 stefano savonitto Summary of first 82 cases (y ) 3,1-12 months 3, 2-12 months 4, 1-12 months 4, 1-12 months Tirofiban pre-op Tirofiban post-op Primary EP Bleeding (TIMI criteria) minor bleed 1 major bleed 16 transfusions minor bleed 4 transfusions major bleed 3 minor bleed 9 transfusions 1 severe thr.penia minor bleed 4 transfusions

20 A case-control study on 314 pts with surgery after stenting Percentage Bridge N=87 Standard N=227 Adjusted OR % CI p= Adjusted OR % CI p= Adjusted OR % CI p= Total NACE 3.4 NACE in 34 pts With stent to surgery < 60 days De Servi S, submitted 10.3 NACE in 104 pts With stent to surgery > 60 days

21 Rassi AN. Am J Cardiol 2012;110:485

22 Need for transfusion (%) Cleveland clinic eptifibatide (N=100) Niguarda/Legnano Tirofiban (N=82) % 66% 67% 76% 40% Eptifibatide (N=29) Epti + ASA (N=41) Epti + UFH (N=9) Epti + ASA+ UFH (N=21) Tirofiban + ASA (N=82) Rassi AN. Am J Cardiol 2012;110:485

23 Bleeding/tamponade with return to operating room (%) % Bridged group (N=68) 2.9% Control group (N=68) Rassi AN. Am J Cardiol 2012;110:485

24 Preoperative bridging with GPIIb/IIIa RB (Southwestern Medical Center, Dallas, TX) 67 patients undergoing non-cardiac (n=51) or cardiac (n=16) surgery after DES implantation between 2008 and 2010, a median of 14 months (NCS) and 9 months (CS) after stenting. GPI used for a mean of 7 days prior to surgery and withdrawn 6 hours prior to surgery, but not postoperatively clopidogrel was started as early as possible after surgery. In the NCS group, 2 pts suffered acute ST in the immediate post-operative period (3.9%, 95% CI 0.5%- 13.5%). In the CS group, one pt had probable ST one hour after surgery. Alshawabkeh LI. Eurointervention 2013;9:204

25 A quantitative analysis of i.v. bridge therapy with surgery after stening Outcome based upon bridging molecule Morici N. Intern Emerg Med 2014;9:225

26 A quantitative analysis of i.v. bridge therapy with surgery after stening Outcome based upon bridging molecule Morici N. Intern Emerg Med 2014;9:225

27 A quantitative analysis of i.v. bridge therapy with surgery after stening Outcome based upon type of surgery Morici N. Intern Emerg Med 2014;9:225-35

28 Times they are a changing Dylan B, 1964 Piccolo R. Lancet 2015;386:702

29 Lo N. Am J Cardiol 2014;114:230

30 Current place of GPI bridging therapy in practice Guidelines

31 Heart, Lung and Circulation 2010;19:2 10

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38 Perioperative antiplatelet drugs 100%- 90%- aspirin P2Y 12 inhibitor GPI bridge 80%- 70%- 60%- 50%- 40%- 30%- 20%- 10%- 0% <1 month (n=20) >1-6 months (n=116) months (n=100) >12 months (n=608) Time interval from stenting to surgery

39 Adverse events 25%- 20%- NACE MACE BARC 3-5 bleeds 15%- 10%- 19 5%- 0% <1 month (n=20) 5 16 >1-6 months (n=116) months (n=100) >12 months (n=608) Time interval from stenting to surgery

40 The SAS Registry: ischemic and bleeding endpoints

41 Event rates for patients undergoing CABG (< 72 h of GP IIb/IIIa discontinuation) cumulative incidence (%) 35% 25% 15% RRR 30% p = % 23.8% placebo eptifibatide days from randomization Marso SP. Circulation 2000;102:2952

42 ISCHEMIC ENDPOINTS AT 30 DAYS IN PATIENTS UNDERGOING CABG DURING HOSPITALIZATION in EPILOG and EPISTENT % PATIENTS Death MI QMI NQMI Death or MI Death or QMI Placebo (n=38) Reopro (n=44) Lincoff AM. Ann Thorac Surg 2000;70:516

43 Transfusions from time of CABG Characteristic Any transfusion Ticagrelor (n=632) Transfusions within 7 days post-cabg Clopidogrel (n=629) Hazard/Odds Ratio (95% CI) 0.98 (0.85, 1.14) p-value 0.83 PRBC or whole blood* (0.88, 1.20) 0.69 Platelets (0.67, 1.16) 0.37 Fresh frozen plasma (0.84, 1.31) 0.67 Transfusions post CABG-related bleeding >4 units blood >5 units whole blood/ PRBC (2 days) (0.83, 1.53) 1.25 (0.70, 2.23) Chest tube output >2L 1.24 (0.61, 2.52) (24 hours) 0.62 *Median (range) units transfused within 7 days post-cabg: tic 3.0 ( ) vs. clop 3.0 ( ); p= Ticagrelor better Clopidogrel better Held C, JACC 2011;57:672

44 Time from CABG to CV death 8 Clopidogrel (n=629) K-M estimated rate (%) Ticagrelor (n=629) HR: 0.52 (95% CI = ), p< Months from CABG procedure Held C. JACC 2011;57:672

45 Bleeding and mortality after isolated CABG clopidogrel vs prasugrel mean 12-h chest tube blood loss ( ml vs ml; p 0.050) All-cause mortality Smith PK. JACC 2012; 60:388-96

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