IV CONVENTION UTIC LOMBARDE 8-9 Aprile 2011 Gestione del rischio emorragico nella chirurgia non cardiaca maggiore Maria Rosa Conte Ospedale Mauriziano -Torino 1

Age (years) Number of procedures(in thousands) % change Guidelines for pre-operative cardiac risk assessment and perioperative cardiac management in non-cardiac surgery The Task Force for Preoperative Cardiac Risk Assessment and Perioperative Cardiac Management in Non-cardiac Surgery of the European Society of Cardiology (ESC) and endorsed by the European Society of Anaesthesiology (ESA) Change in numbers of discharges for surgical procedures by age for the time periods 1994/95 and 2004/05 as reported from the 2005 US National Hospital Discharge Survey (non-federal short-stayhospitals) Age (years) Number of procedures(in thousands) % change 1994/95 2004/05 18–44 7311 7326 + 2.1 45–64 4111 5210 + 26.7 65–74 3069 3036 - 1.1 75 and over 3479 4317 + 24.1 18 and over 17969 19889 + 10.7 4317 þ24.1 969 19 889 þ10.7

Impact of the ageing population Within the next 20 years, the acceleration in ageing of the population will have a major impact on perioperative patient management. It is estimated that elderly people require surgery four times more often than the rest of the population. Although exact data regarding the number of patients undergoing surgery in Europe are lacking, it is estimated that this number will increase by 25% by 2020, and for the same time period the elderly population will increase by .50%. The total number of surgical procedures will increase even faster because of the rising frequency of interventions with age.

Incidence of surgery within 1 year after coronary stenting 10- 8- 6- 4- 2- 0- Noncardiac 8.6% Noncardiac Noncardiac 2.0% minor Cardiac (20%) + Noncardiac Noncardiac 5.0% 4.4% 4.4% major 3.8% Austrian Vicenzi MN BJA 2006 Cleveland Anwaruddin S JACC Intv 2009 New Zealand To ACY Circ CV Intv 2009 Scottish Cruden N Circ CV Int 2010 EVENT REGISTRY Berger PB JACC Intv 2010 4

In patients with stable CAD, Probability of surgery higher than probability of D+MI CNR-OD 1 study Events per year (%) 1083 pts with stable CAD followed for 66+11 months, pre-PCI era Incidence of surgery first year after stent (%) 10- 8- 6- 4- 2- 0- 10- 8- 6- 4- 2- 0- 8.6 5.0 4.4 3.8 1.5 1.0 Cardiovascular death Myocardial Infarction Austrian N=2000 Cleveland N=12,794 Scottish N=1,953 New Zealand Brunelli C. Eur Heart J 1989 Vicenzi MN. BJA 2006; Anwaruddin S. JACC Intv 2009 Cruden N. Circ CV Int 2010; To ACY. Circ CV Interv 2009 5

Patients caratheristics

Circ Cardiovasc Intervent. 2009;2:213-221. 11150 patients (age, 62+-11 years;30% women) who underwent PCI from 1996 to 2001 (New Zealand), 5-year follow-up: 26% of the population underwent at least 1 noncardiac surgical procedure (23% orthopedic, 20% abdominal, 12% urologic, 10% vascular, 35% others) Circ Cardiovasc Intervent. 2009;2:213-221.

The main clinical predictors of noncardiac surgery were advanced age, previous noncardiac surgery, osteoarthritis, and peripheral vascular disease. Noncardiac surgery is required frequently after PCI, whereas bleeding is less common. Before implanting a drug- eluting or bare-metal stent, individual patient risk stratification by the interventional cardiologist should include assessment of whether there is an increased likelihood of needing noncardiac surgery or developing bleeding.

Clinical presentation at the time of PCI

Perioperative death and ischemic cardiac events occurred more frequently when surgery was in patients revascularized after an acute coronary syndrome (65% versus 32% - elective indication - ; P=0.037). (acute coronary syndrome [triangles] vs stable coronary artery disease [diamonds]) Patients undergoing noncardiac surgery after recent coronary stent implantation are at increased risk of perioperative myocardial ischemia, myocardial infarction, and death, particularly after an acute coronary syndrome. For at least 2 years after percutaneous coronary intervention, cardiac outcomes after noncardiac surgery are similar for both drug-eluting and bare-metal stents.

Time course and incidence of ST after a NSTEACS Does not differ between BMS and DES Definite/Probable ST: DES Only (N=5743) Definite/Probable ST: BMS Only (N=6461) 2.31% 2.41% 2.5 2.5 2 2 % of Subjects 1.5 1.5 1 Clopidogrel-treated patients Clopidogrel-treated patients 1 0.5 0.5 50 100 150 200 250 300 350 400 450 DAYS 50 100 150 200 250 300 350 400 450 DAYS Wiviott SD. Lancet 2008;371:1353 13 13

TIMING

Circ Cardiovasc Interv. 2010;3:236-242.) Scottish Coronary Revascularisation Register From April 2003 and March 2007,1953 post-PCI patients underwent noncardiac surgery. Of these, 570 (29%) were treated with at least 1 drug-eluting stent and 1383 (71%) with bare-metal stents only. Circ Cardiovasc Interv. 2010;3:236-242.)

Timing of noncardiac surgery in cardiac-stable/ asymptomatic patients with prior PCI 2009 ESC Guidelines on perioperative evaluation for noncardiac surgery 17

Guidelines for pre-operative cardiacmanagement in non-c Recommendations on timing of non-cardiac surgery in cardiac-stable/asymptomatic patients with prior revascularization Recommendations Class Level It is recommended that patients with previous CABG in the last 5 years be sent I C for non-cardiac surgery without further delay It is recommended that non-cardiac surgery be performed in patients with recent bare I B metal stent implantation after a minimum 6 weeks and optimally 3 months following the intervention be performed in patients with recent I B drug-eluting stent implantation no sooner than 12 months following the intervention Consideration should be given to postponing non-cardiac surgery in patients with recent II a B balloon angioplasty until at least 2 weeks following the intervention

DAT MANAGEMENT

Class I Class IIb 20

Occurrence of early and late angiographically- documented stent thrombosis in the Rotterdam and Bern registries 0.6% per year 30D 3y Independent predictors HR 95%CI ACS at presentation 2.3 1.3-4.0 Diabetes 2.0 1.1-3.8 Daemen J, Lancet 2007;369:667 21

Predictors of stent thrombosis the dutch registry: 437 out of 21,009 pts (2.1%) Van Werkum JW. JACC 2009;53:1399 22

Clopidogrel discontinuation and incidence of stent thrombosis after PCI in the ISAR studies Cumulative incidence of stent thrombosis in patients who continued (black) and those who discontinued clopidogrel (red). Patients switched from one group to the other as soon as they stopped taking clopidogrel. Schulz S. Eur Heart J 2009;30:2714 23 23

Clinical outcome of stent thrombosis At 30-day and 180-day follow-up Airoldi F. Circulation 2007;116:745-54 24

NCS after percutaneous coronary intervention Stent Thrombosis risk Timing dell’impianto Stent SCA o coronaropatia stabile Tipo di STENT Diabete Lunghezza dello Stent Biforcazioni / lesioni ostiali… BLEEDING RISK Female sex Diabetes, Chronic renal impairment bleeding…… SURGICAL RISK Ch aortica e vascolare maggiore BLEEDING SURGICAL RISK intracranial spinal Extraocular TURP

con necessità di anestesia retro bulbare RISCHIO EMORRAGICO CHIRURGIA OCULARE RISCHIO EMORRAGICO Cataratta Trabeculectomia Glaucoma Basso Chirurgia complessa su retina Chirurgia complessa su palpebra Chirurgia complessa su ghiandole lacrimali Chirurgia complessa a livello orbitario con necessità di anestesia retro bulbare Intermedio Alto Ickx et al. Can J Anesth 2006; 53: 6; S113-22 Thachil J. et al. British Journal of Surgery 2008; 95: 1437–1448.

RISCHIO EMORRAGICO PROCEDURE UROLOGICHE Cistoscopia Litotrissia Basso Litotrissia Biopsia prostatica Biopsia renale Intermedio Alto Ickx et al. Can J Anesth 2006; 53: 6; S113-22 Thachil J. et al. British Journal of Surgery 2008; 95: 1437–1448.

Recommendation/statement on surgical risk estimate Recommendation/statement Class Level Laparoscopic procedures demonstrate a cardiac stress similar to open procedures and it is I A recommended that patients be screened prior to intervention accordingly

PROCEDURE ENDOSCOPICHE GASTROINTESTINALI (GI) RISCHIO EMORRAGICO PROCEDURE ENDOSCOPICHE GASTROINTESTINALI (GI) RISCHIO EMORRAGICO del tratto gastrointestinale superiore del tratto gastrointestinale inferiore ERCP senza sfinterectomia Inserzione di stent biliare senza sfinterectomia Endosonografia senza incannulazione Enteroscopia “push” dell’intestino tenue Capsula endoscopica con o senza biopsia Basso <1% Polipectomia Coagulazione laser Sfinterectomia endoscopica Dilatazione pneumatica Stenting esofageo Posizionamento di PEG Trattamento di varici ERCP con sfinterectomia Resezione della mucosa o dissezione sub mucosa per via endoscopica Endoscopia ad ultrasuoni con ago aspirato Alto ≥1% Ickx et al. Can J Anesth 2006; 53: 6; S113-22 Thachil J. et al. British Journal of Surgery 2008; 95: 1437–1448. Kwok A. et al. Am J Gastroenterol online pubblication, 11 August 2009; doi:10.1038/ajg.2009.469

How to manage post-stent DAT & NCS?

British Journal of Anaesthesia 105 (S1): i3–i15 (2010) Relative contributions of key hazards associated with major adverse cardiovascular events in patients with coronary stents. These form the framework for clinical decision-making. British Journal of Anaesthesia 105 (S1): i3–i15 (2010)

Noncardiac surgery after stent implantation: Antiplatelet therapy and risk of bleeding Van Kuijk P. Am J Cardiol 2009;104:1229 32

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Clopidogrel was discontinued 5 days before surgery, and hospital admission was planned for the day after the last clopidogrel intake (4 days before surgery), when i.v. tirofiban infusion was started according to the schedule approved for patients with ACS: that is, 0.4 mg kg21 min21 over 30 min, followed by 0.1 mg kg21 min21.15 The tirofiban dose was reduced by 50% if creatinine clearance was ,30 ml min21. The infusion was stopped 4 h before surgery (8 h in the case of creatinine clearance ,30 ml min21), resumed at the same schedule (including the 30 min bolus) 2 h after the end of surgery, and continued for up to 6 h after the resumption of clopidogrel, unless oral administration could be resumed on the same day as surgery. After surgery, clopidogrel was reintroduced using a loading dose of 300 mg (four tablets) as soon as the patient could resume oral administration, and then continued at a once daily dose of 75 mg. Aspirin (75–100 mg once a day) was ideally to be continued throughout the perioperative period Results: There were no cases of death, myocardial infarction, stent thrombosis, or surgical re-exploration due to bleeding during the index admission, with a risk estimate of 0–11.6% (one-tail 97.5% CI). There was one case of thrombolysis in myocardial infarction (TIMI) major and one of TIMI minor bleeding in the postoperative phase; another four patients were transfused without meeting the TIMI criteria for major or minor bleeding. Br J Anaesth 2010; 104: 285–91

Phase 2 protocol (Simon’s two stage design) for urgent surgery early after DES Inclusion criteria Exclusion criteria Patients within 6-12 months of DES implantation 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 · Allergy to tirofiban – eptifibatide · Thrombocytopenia <100.000 · Stroke < 30 days or prior ICH · Intracranial disease · Uncontrolled hypertension · Unable to sign consent form + high-risk for surgical bleeding, “so that the surgeon would not operate on clopidogrel” surgery Stop Plavix Start bridge Stop bridge Resume Bridge** Resume Plavix 300+75 mg*** Aspirin continued throughout Low-dose LMWH for DVT prevention T Day -5 -4 -3 -2 -1 4h* 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 Primary EP: the composite of Death, MI, stent thrombosis, haemostatic reoperation Savonitto S. Br J Anaesth 2010;104:285-91 38

For urgent surgery early after DES: current status Phase 2 bridge study For urgent surgery early after DES: current status PATIENTS ENROLLED 56 cardiac 19 urinary tract 7 gastrointestinal 18 mixed surgery 12 PRIMARY ENDPOINT* 0 (97.5% C.I. 6.4%) BLEEDING** EVENTS major 2 minor 3 transf 12 SEVERE§ THROMBOCITOPENIA 1 Urgent surgery after DES.. Savonitto De Servi * The composite of death+MI+stent thrombosis+haemostatic reoperation **Bleeding according to TIMI criteria: major means Hb decrease >5 g/dL, minor means Hb decrease >3 but <5 g/dL, after correction for transfusion (1 g ofHb for each U transfused); § platelet count <20,000. 39

Early surgery after stent implantation: Anesthesiologist warning

Heart, Lung and Circulation 2010;19:2–10 41

CONCLUSIONI I con l’ aumentare dell’eta’ un crescente numero di pazienti va incontro ad interventi di chirurgia non cardiaca al momento dell’impianto di uno Stent (che richiede una DAPT da un minimo di 1 mese ad un massimo di 12-15 mesi ) devono essere considerati con attenzione il rischio emorragico ed le patologie associate la trombosi di Stent è un evento drammatico con elevata mortalità ed è principalmente determinato dalla interruzione prematura della DAPT Nei pazienti portatori di Stent coronarici l’intervento chirurgico dovrebbe essere differito a 3 mesi in caso di BMS e 12 mesi in caso di DES

In caso di intervento non differibile ad elevato rischio emorragico in pazienti con elevato rischio trombotico la bridge strategy con agenti antipiastrinici ev a breve durata d’azione si e’ dimostrata efficace nella prevenzione della ST senza aumentare significativamentel e emorragie. l’impiego di tale strategia e’ tuttavia ancora controverso e non indicato dalle linee guida con livello elevato di evidenza Nei pazienti con eccessivo sanguinamento peri-operatorio sono indicati trasfusioni di piastrine e agenti pro emostatici Nuovi farmaci quali il Ticagrelor ( breve emivita ) potrebbero in futuro costituire un alternativa all’impiego degli inibitori del II b- III a ( piccole molecole ).

Ticagrelor vs clopidogrel: time course of IPA by 20 M/L ADP Gurbel P. Circulation 2009, published online Nov 19

Reversibility of platelet inhibition Oral drug aspirin clopidogrel prasugrel ticagrelor Reversibility irreversible reversible Time to surgery 5-7 days 3 days? i.v. drug abciximab tirofiban eptifibatide Reversibility irreversible reversible Time to surgery 3-5 days 4 hours (8 hours if CrCl <30 ml) 46

GESTIONE ANTIAGGREGANTI IN PROCEDURE ENDOSCOPICHE GI Kwok A. et al. Am J Gastroenterol online pubblication, 11 August 2009; doi:10.1038/ajg.2009.469

Response to clopidogrel 300 mg Healthy volunteer crossover study IPA (20 M ADP) at 24 hours 100 80 60 Inhibition of platelet aggregation (%) 40 20 N=64 –20 Response to clopidogrel 300 mg Response to prasugrel 60 mg Brandt J et al. AHJ 2006

325 patients with stable CVD taking ASA 325 mg >7days Prevalence of ASA Resistance 325 patients with stable CVD taking ASA 325 mg >7days ASA-R: mean aggregation ≥70% with µM 10 ADP & ≥20% with 0.5 mg/ml AA Gum PA et al. Am J Cardiol 2001;88:230-235

La sospensione degli Antiaggreganti Sospensione ASA in 50 La sospensione degli Antiaggreganti Sospensione ASA in 50.279 coronaropatici Aumentato Rischio Trombotico Biondi-Zoccai GGL, et al. Eur Heart J 2006 27:2667-2674

SEMIN CARDIOTHORAC VASC ANESTH 2010 14: 256

Conclusions on DAPT and surgical risk For surgical and endoscopic procedures at HR of bleeding, DAPT represents a serious issue. Withdrawal of DAPT + post-surgical haemostatic activation + malignancy increase severalfold the risk of ST and death, THE POST-OPERATIVE FASE BEING THE MORE DANGEROUS. Based on the results of our ongoing experience, we propose that a “bridge strategy” using short-acting i.v. antiplatelet agents confers protection against perioperative CV events that goes beyond the prevention of ST, without increasing the risk of surgical bleeding. Among the new P2Y12 antagonist, the reversible blocker ticagrelor might reduce by 1-2 days the duration of pre- operative withdrawal, but it’s use in the early post-op days should be studied, and sofar it hasn’t been shown to reduce bleeding compared to clopidogrel. The concept of “platelet anaesthesia” should be further explored 57

Early surgery after stent implantation: Step 2: risk stratification for stent thrombosis 58

Heart, Lung and Circulation 2010;19:2–10 59

Pazienti con STENT coronarici che devono essere sottoposti a chirurgia non cardiaca Tutti gli stent coronarici richiedono un periodo di DAPT post- impianto: 4 settimane i BMS, 6-12 mesi i DES. Ciò al fine di prevenire la trombosi di stent (morte-infarto nel 50-70% dei casi) La terapia antiaggregante aumenta il rischio emorragico in chirurgia generale, laparoscopica, e durante procedure endoscopiche La sospensione della terapia antiaggregante prima che sia finito il periodo di vulnerabilità espone al rischio di trombosi di stent, aumentato dall’ effetto pro-trombotico della chirurgia surgery, either elective or urgent, poses a largely unsolved problem for patients on dual antiplatelet therapy and their treating physicians. Schulz S. Eur Heart J 2009;30:2714 61