Mayor lung resection in the presence of anti-platelet therapy. Hans-Beat Ris Service de Chirurgie Thoracique CHUV, Lausanne

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1 Mayor lung resection in the presence of anti-platelet therapy Hans-Beat Ris Service de Chirurgie Thoracique CHUV, Lausanne

2 THORACIC SURGERY IN THE PRESENCE OF ANTI-PLATELET THERAPY Charybdis: Thrombosis Myocardial infarction Scylla: Risk of hemorrhage Delay of surgery sailing between Scylla and Charybdis Published data for non-cardiac thoracic surgery are relatively scarce Homer, The Odyssey, 8 th century BC

3 ANTI-PLATELET THERAPY Anti-platelet therapy reduces the risk of serious vascular events in high-risk patients RISK REDUCTION Non-fatal myocardial infarction (MI) 33% Non-fatal stroke 25% Vascular mortality 17% Antithrombotic Trialists Collaboration BMJ 2002;324:71-86

4 ANTI-PLATELET THERAPY Frequently prescribed medication for a variety of conditions: Primary prevention Coronary artery disease (CAD) Peripheral artery occlusive disease (PAD) Cerebrovascular disease (CVD) Atrial fibrillation (AF) Prevention of venous thromboembolism Eikelboom JW, Chest 2012;141:89-119

5 ACTION OF ANTI-PLATELET AGENTS Irreversible COX-1 inhibitor: Aspirin 1 Reversible COX-1 inhibitor: NSAID TXA 2 Reversible PAR-1 inhibitor: Vorapaxar Thrombin ADP Irreversible ADP inhibitor: Clopidogrel 1 Prasugrel Reversible ADP inhibitor: Ticagrelor, Cangrelor Kengrexal, Elinogrel α-granule GP Ib/V/IX GP IIb/IIIa TXA 2 ADP vwf Fibrinogen Reversible GP IIb/IIIa inhibitor: Abciximab Eptifibatide, Tirofiban 1 Termination of drug activity for irreversible inhibitors relies on platelet renewal (10%/day) Chassot PG In: Perioperative Hemostasis. Eds Marcucci&Schoettker, Springer 2015

6 NON-CARDIAC SURGERY AND ANTI-PLATELET THERAPY (ASPIRIN) Randomized controlled trial (n=10500) Patients at risk for vascular complications 1 having non-cardiac surgery Exclusion criteria: Bare-metal stents < 6 weeks before surgery Drug-eluting stents < 12 monts before srugery 1 Patients with > 3 of the following risk criteria: mayor / emergency surgery; age>70y; diabetes; creatinine >2mg/dl; history of congestive heart failure / TIA / hypertension / smoking Devereaux PJ et al, POISE-II TRIAL, NEJM 2014;370 :

7 NON-CARDIAC SURGERY AND ANTI-PLATELET THERAPY (ASPIRIN) Inititation stratum: Continuation stratum: No asprin before surgery (n=5628) Aspirin before surgery stop 3d preop (n=4382) Randomization: 200mg aspirin vs placebo just before surgery Inititation stratum: Continuation stratum: Continued medication 100mg/d for 30 days Continued medication 100mg/d for 7 days aspirin as before Devereaux PJ et al, POISE-II TRIAL, NEJM 2014;370 :

8 NON-CARDIAC SURGERY AND ANTI-PLATELET THERAPY (ASPIRIN) ASPIRIN PLACEBO N=4998 N=5012 Age 69y 69y Male 52% 54% Coronary artery disease 23% 22% Peripheral artery disease 9% 9% Stroke 5% 6% Dialysis 1% 1% Major vascular surgery 5% 5% Coronary bypass grafting 5% 5% Percutaneous coronary intervention (PCI) 5% 5% Bare metal stent (BMS) 3% 3% Drug-eluting stent (DES) 1% 1% Devereaux PJ et al, POISE-II TRIAL, NEJM 2014;370 :

9 NON-CARDIAC SURGERY AND ANTI-PLATELET THERAPY (ASPIRIN) ASPIRIN PLACEBO HR [95%CI] P PRIMARY OUTCOME or nonfatal MI 7.0% 7.1% 1.0 [ ] ns SECONDARY OUTCOMES from any cause 1.3% 1.2% 1.1 [ ] ns Myocardial infarction 6.2% 6.3% 1.0 [ ] ns Pulmonary embolism 1 0.7% 0.6% 1.1 [ ] ns Deep vein thrombosis 1 0.5% 0.7% 0.7 [ ] ns Arterial thrombosis 0.3% 0.3% 0.9 [ ] ns Major bleeding 4.6% 3.8% 1.2 [ ] Postoperative prophylactic anticoagulation 65% aspirin group / 65% placebo group Devereaux PJ et al, POISE-II TRIAL, NEJM 2014;370 :

10 NON-CARDIAC SURGERY AND ANTI-PLATELET THERAPY (ASPIRIN) PRIMARY OUTCOME AT 30 DAYS % Patients with death / nonfatal MI Days since randomization Devereaux PJ et al, POISE-II TRIAL, NEJM 2014;370 :

11 NON-CARDIAC SURGERY AND ANTI-PLATELET THERAPY (ASPIRIN) % Patients with major bleeding 7 6 p< Aspirin Placebo Surgery day 1 day 2 day 3 day 4 day 5 day 6 day 7 day 8 Devereaux PJ et al, POISE-II TRIAL, NEJM 2014;370 :

12 NON-CARDIAC SURGERY AND ANTI-PLATELET THERAPY (ASPIRIN) SOUBGROUP ANALYSIS OF PRIMARY OUTCOME Primary outcome similar in the initiation / continuation stratum 2 Thoracic surgery 6% aspirin group, 6% placebo group Devereaux PJ et al, POISE-II TRIAL, NEJM 2014;370 :

13 NON-CARDIAC SURGERY AND ANTI-PLATELET THERAPY (ASPIRIN) «The administration of aspirin before non-cardiac surgery and during the early postoperative period had no significant effect on the rate of death or nonfatal myocardial infarction but increased the risk of major bleeding This applies to patients who were not already on aspirin as well as to those who were on a long-term aspirin regimen» Devereaux PJ et al, POISE-II TRIAL, NEJM 2014;370 :

14 THORACIC SURGERY AND ANTI-PLATELET THERAPY (APA) Retrospective study VATS lobectomy (n=164) Preoperatively interrupted APA 2 n=106 Continued APA n=58 1 VATS lobectomy + mediastinal lymph node dissection for NSCLC 2 median duration of APA interruption: 9 (2-50) days Yu WS, J Thorac Dis 2015;7:

15 THORACIC SURGERY AND ANTI-PLATELET THERAPY (APA) CONTINUED INTERRUPTED n=58 n=106 Age 69y 70y ns Male 67% 69% ns Smoking 67% 59% ns Aspirin 76% 80% ns Aspirin+clopidogrel 19% 6% p=0.008 Indication for APA CAD 48% 27% p=0.007 PCI 24% 9% p=0.006 TIA/stroke 26% 21% ns AF 9% 7% ns Primary prevention 26% 57% p<0.001 Yu WS, J Thorac Dis 2015;7:

16 THORACIC SURGERY AND ANTI-PLATELET THERAPY (APA) CONTINUED INTERRUPTED n=58 n=106 Conversion thoracotomy 5% 4% ns Intraoperative transfusion 3% 2% ns Intraoperative bleeding > 500cc 9% 3% ns 30d-mortality 2% 1 0% ns 30d-morbidity 22% 13% ns 30d-transfusions 9% 3% ns 30d-reoperation rate (bleeding) 0 1% ns 1 Broncho-pleural fistula (n=1) Yu WS, J Thorac Dis 2015;7:

17 THORACIC SURGERY UNDER ANTI-PLATELET THERAPY SINGLE VS DUAL APA REGIMEN % Patients 40% p<0.05 p=ns 35% p< % 25% p< % 15% Aspirin+clopidogrel (n=11) single APA (n=47) 10% 5% 0% >500ml blood loss postop transfusion postop bleeding postop morbidity Yu WS, J Thorac Dis 2015;7:

18 THORACIC SURGERY AND ANTI-PLATELET THERAPY (APA) «Anti-platelet agents can be safely administered in patients at risk of cardiac events undergoing thoracoscopic lobectomy for lung cancer However, patients receiving both, clopidogrel and aspirin, have an increased risk of postoperative bleeding and transfusion requirements» Yu WS, J Thorac Dis 2015;7:

19 SURGERY IN THE PRESENCE OF CORONARY ARTERY DISEASE /STENTS Withdrawal of anti-platelet therapy increased risk of perioperative MI Dual anti-platelet therapy increased risk of perioperative bleeding Sword of Damocles, Dionysus II of Syracuse, 4 th century BC

20 SURGERY IN THE PRESENCE OF CORONARY ARTERY DISEASE Myocardial infarction is a common vascular complication after surgery in patients at risk for CAD (mortality rate of 15-25%) Botto f, Anesthesiology 2014;120: Surgery leads to platelet activation, hypercoagulabitity and shear stress risk of coronary artery thrombosis / MI Naesh O, Thromb Haemost 1985;54: Devereaux PJ, JAMA 2012;307: Perioperative anti-platelet therapy inhibits platelet aggregation and may prevent perioperative MI Robless P, Br J Surg 2001;88:

21 SURGERY IN THE PRESENCE OF CORONARY ARTERY STENTS Surgery exposes thrombogenic material to a prothrombotic milieu Risk of in-stent thrombosis of not re-endothelialized stents in the absence of anti-platelet agents Risk of myocardial infarction 35% Mortality rate 20-40% Chassot PG, Br J Anaesth 2007;99:316-28a

22 MORTALITY FOR NON-CARDIAC SURGERY IN PATIENTS WITH CA STENTS AND PERIOPERATIVE INTERRUPTION OF DUAL ANTI-PLATELET THERAPY Mortality (%) due to in-stent thrombosis / MI Bare metal stents / Bypass surgery Drug eluting stents Time since stenting (months) Chassot PG In: Perioperative Hemostasis. Eds Marcucci&Schoettker, Springer 2015

23 SURGERY IN THE PRESENCE OF CORONARY ARTERY STENTS AHA RECOMMENDATIONS 1. Live-long aspirin administration 2. Uninterrupted dual anti-platelet therapy (clopidogrel + aspirin) until stent re-endothelialization at least 6 weeks for bare metal stents at least 12 months for drug eluting stents Grines CL, AHA Recommendations, Circulation 2007;115:813-8

24 THORACIC SURGERY IN PATIENTS WITH CLOPIDOGREL FOR CAD Patients with thoracic surgery and clopidogrel for CAD (n=33) + Patients thoracic surgery but without clopidogrel (controls, n=132) 1 30d-major cardiac events (MACE) 30d-mortality 30d-morbidity Estimated blood loss 1 Propensity score matching age / gender / procedures / coronary artery disease / coronary artery stent / diabetes / smoking Cerfolio RJ, J Thorac Cardiovasc Surg 2010;140:970-6

25 THORACIC SURGERY IN PATIENTS WITH CLOPIDOGREL FOR CAD CLOPIDOGREL (N=33) CONTROLS (N=132) Age 68y 67y ns Male 87% 73% ns Smoking 45% 44% ns Coronary artery disease 100% 100% ns Diabetes mellitus 21% 15% ns Peripheral artery disease 9% 4% ns Coronary stents 1 64% 33% ns +Aspirin 23% 39% ns 1 Drug eluting stents: Clopidogrel group 19/21; control group 39/43 Cerfolio RJ, J Thorac Cardiovasc Surg 2010;140:970-6

26 THORACIC SURGERY IN PATIENTS WITH CLOPIDOGREL FOR CAD % Patients 35% p=ns 30% 25% 20% 15% 10% p=ns p=ns p=ns Clopidogrel+aspirin (n=14) Clopidogrel alone (n=19) Controls (n=132) 5% 0% Reoperation (bleeding) 1 Postoperative morbidity Postoperative MACE Mortality 1 Reoperation for bleeding in 2/2 patients with redo-thoracotomy under aspirin + clopidogrel Cerfolio RJ, J Thorac Cardiovasc Surg 2010;140:970-6

27 MYOCARDIAL INFARCTION AFTER LOBECTOMY IN PATIENTS WITH CORONARY ARTERY STENTS % Patients 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Clopidogrel (n=8) p<0.05 No clopidogrel (n=14) Perioperative MI 1 1 Mortality in patients with perioperative MI 40% Cerfolio RJ, J Thorac Cardiovasc Surg 2010;140:970-6

28 THORACIC SURGERY IN PATIENTS WITH CLOPIDOGREL FOR CAD «Pulmonary resection can be performed safely in patients who are receiving both clopidogrel and aspirin except for redo-thoracotomy (risk of clinically significant bleeding) Significant reduction of perioperative myocardial infarction can be obtained by continuing clopidogrel in patients with coronary artery stents» Cerfolio RJ, J Thorac Cardiovasc Surg 2010;140:970-6

29 LUNG RESECTION WITHIN 3 MONTHS OF CA STENTING PERIOPERATIVE IN-STENT THROMBOSIS AND BLEEDING Patients undergoing lobectomy / pneumonectomy via thoracotomy within 3 months of coronary artery stenting (n=33) 30d-morbidity 30d-mortality In-stent thrombosis / MI Hemorrhage Brichon PY, Eur J Cardiothorac Surg 2006;30:793-6

30 LUNG RESECTION WITHIN 3 MONTHS OF CA STENTING PERIOPERATIVE IN-STENT THROMBOSIS AND BLEEDING CA stenting Bare metal stents 100% 1 / 2 / 4 stents 72% / 22% / 6% Clopidogrel + aspirin after stenting for 6 weeks 100% Clopidogrel stop 7-10d before surgery 100% Peri-/postoperative heparin + aspirin 66% Peri-/postoperative heparin 34% Lobectomy / pneumonectomy 84% / 16% Brichon PY, Eur J Cardiothorac Surg 2006;30:793-6

31 LUNG RESECTION WITHIN 3 MONTHS OF CA STENTING PERIOPERATIVE IN-STENT THROMBOSIS AND BLEEDING 30d-mortality 9% 1 30d-morbidity 25% Bleeding complications 9% 2 In stent thrombosis 9% 3 1 ARDS (n=2), MI after in-stent thrombosis (n=1) 2 Hemothorax (n=2), retroperitoneal hematoma (n=1) requiring transfusions 3 non-fatal (n=2), fatal (n=1), all patients treated according the AHA guidelines Brichon PY, Eur J Cardiothorac Surg 2006;30:793-6

32 FATAL MYOCARDIAL INFARCTION AFTER LOBECTOMY AND CA STENTING DESPITE FOLLOWING AHA RECOMMENDATIONS CA stenosis LAD / diagonal branch Stenting LAD 2 bare metal stents 6 weeks dual anti-platelet therapy 1 Marcucci C, Br J Anaesth 2004;92:743

33 FATAL MYOCARDIAL INFARCTION AFTER LOBECTOMY AND CA STENTING DESPITE FOLLOWING AHA RECOMMENDATIONS LUL lobectomy (heparin+aspirin) In-stent thrombosis Failed PCI revascularization Fatal myocardial infarction 1 Marcucci C, Br J Anaesth 2004;92:743

34 FATAL MYOCARDIAL INFARCTION AFTER LOBECTOMY AND CA STENTING DESPITE FOLLOWING AHA RECOMMENDATIONS «Major lung resection performed after coronary artery stenting may be complicated by perioperative in-stent thrombosis even if AHA recommendations are followed» Brichon PY, Eur J Cardiothorac Surg 2006;30:793-6

35 Patients on aspirin ( mg/d) and clopidogrel (75 mg/d) Patients on aspirin ( mg/d) or clopidogrel alone (75 mg/d) Primary prevention Secondary prevention High-risk cardiac <6 weeks PCI/BMS <3 mts MI / ACS <12 mts DES >12 mts high-risk stents Low-risk cardiac All surgery Stop 5 days before surgery All surgery Vital /urgent / cancer surgery Bleeding risk Elective surgery Delay surgery Stop clopidogrel Maintain aspirin Surgery under continuous treatment Stop clopidogrel + substitute Maintain aspirin Restart clopidogrel <24h CHUV algorithm: Chassot PG In:Perioperative Hemostasis. Eds Marcucci&Schoettker. Springer 2015

36 MAYOR LUNG RESECTION ANDANTI-PLATELET THERAPY Retrospective study anatomical resections CHUV Three groups according to perioperative APA treatment: Prophylactic LMWH 1 n=382 Aspirin + LMWH n=99 Aspirin + Clopidogrel (CA stents) n=17 30d-mortality 30d-morbidity Myocardial infarction Hemothorax requiring reoperation 1 Clexane 40mg sc CHUV algorithm

37 MAYOR LUNG RESECTION 1 AND ANTI-PLATELET THERAPY VATS 305 Thoracotomy 189 Segmentectomy 61 Lobectomy 360 Bilobectomy 7 Sleeve (bi)lobectomy 52 Pneumonectomy 14 1 Mediastinal lymph node dissection in case of NSCLC CHUV algorithm

38 MAYOR LUNG RESECTION ANDANTI-PLATELET THERAPY LMWH (n=382) Aspirin+LMWH (n=99) Aspirin+Clopidogrel (n=17) 30d-Mortality 30-Morbidity Myocardial infarction 0.2% 15% 0.5% 2% 0% 6% 1% 3% 6% 18% 18% 6% Hemothorax CHUV algorithm

39 THORACIC SURGERY AND ANTI-PLATELET THERAPY Scylla Hemorrhage Charybdis Stent thrombosis Odysseus preferred Scylla over Charybdis 2012 STS GUIDELINES UPDATE FOR THORACIC SURGERY 1. Continuing anti-platelet monotherapy during thoracic surgery is feasible 2. Continuing dual anti-platelet therapy can be feasible unless the risk of bleeding is prohibitive Ferraris VA, Ann Thorac Surg 2012;94:

40 Thank you for your attention

41 PERIOPERATIVE IN-STENT THROMBOSIS AFTER LUNG RESECTION PERFORMED WITHIN 3 MONTHS OF CORONARY ARTERY STENTING Age 64y (46-82) Male 91% Persistent smoking 34% Diabetes mellitus 16% Peripheral arterial disease 31% Hypertension 56% History of Coronary artery disease 53% MI 44% previous CABG 6% previous PCI 28% Brichon PY, Eur J Cardiothorac Surg 2006;30:793-6