The patient with Drug Eluting Stent (DES): when to operate and how to bridge antiplatelet therapy

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1 The patient with Drug Eluting Stent (DES): when to operate and how to bridge antiplatelet therapy B. Preckel, MD, MA, DEAA Professor of Anesthesiology Academic Medical Center AMC University of Amsterdam The Netherlands

2 The patient with Drug Eluting Stent (DES): when to operate and how to bridge antiplatelet therapy B. Preckel, MD, MA, DEAA Professor of Anesthesiology Academic Medical Center AMC No Disclosures University of Amsterdam The Netherlands

3 The old problem: - stents (BMS, DES) - dual antiplatelet therapy (DAPT) - operation - bleeding - ischaemia

4 Defining the fine balance between ischemic and bleeding risk remains a challange in stented patients undergoing surgery treated with antiplatelet therapy

5 Three questions to be answered: - how long is dual antiplatelet therapy necessary (DAPT) - how to bridge interruption of dual antiplatelet therapy - how to treat patients with stent thrombosis

6 stent generations: - Bare Metal Stents (BMS), Drug Eluting Stents (DES), first generation: Sirolimus-eluting stent Paclitaxel-eluting stent - second generation: Everolimus-eluting stent - third generation: Biolimus-eluting stent ( biological degradable)

7 Drug Eluting Stents (DES) Re-stenosis Morice MC et al., NEJM 2002;346 Curfman GD et al., NEJM 2007;356:

8 Risk factors for stent restenosis Byrne RA et al., Eur Heart J 2015

9 Drug Eluting Stents (DES) Morice MC et al., NEJM 2002;346

10 Stent type and re-stenosis Byrne RA et al., Eur Heart J 2015

11 Finn AV et al. Arteriosler Thromb Vasc Biol 2007;27:

12 DAPT: BMS 1-3 months Sirolimus: 2-3 months Paclitaxel: 6 months Finn AV et al. Arteriosler Thromb Vasc Biol 2007;27:

13 Timing of Stent Thrombosis Byrne RA et al., Eur Heart J 2015

14 Drug Eluting Stents (DES) Risk for late stent thrombosis Morice MC et al., NEJM 2002;346 Lagerqvist B et al., NEJM 2007;356:

15 Drug Eluting Stents (DES) Stent thrombosis: 0.5% to 3.1% Myocardial infarction: 25% to 65% Death: 45% to 75% Very late stent thrombosis also after BMS: however, only after interruption of aspirin therapy (Ferrari et al., JACC 2005;45: )

16 Drug Eluting Stents (DES) Risk factors for stent thrombosis: - incomplete endothelialisation - early discontinuation of DAPT (aspirin, clopidogrel): Risk increases fold Jeremias et al., Circulation 2004;109: , Iakovou et al., JAMA 2004;293: withdrawal of aspirin high age, diabetes, low ejection fraction, kidney failure

17 Guidelines 2007 Hall R et al, Anesth Analg 2011;112: Fleisher LA et al., Circulation 2007

18 Duration of Dual AntiPlatelet Therapy (DAPT): 1 up to 12 months versus > 12 months months versus 12 months

20 DAPT: How long? Mauri L et al. NEJM 2014

22 DAPT: How long? Brener SJ Circulation 2015

24 Prolonged duration of DAPT: up to 12 months versus > 12 months Byrne RA et al., Eur Heart J 2015

25 Prolonged duration of DAPT: up to 12 months versus > 12 months Palmerini T et al. Lancet 2015;385:

26 DAPT: How long? Becker RC et al. Circulation 2015

27 Stent type and re-stenosis Byrne RA et al., Eur Heart J 2015

29 DAPT: How long? Palmerini T et al. Lancet 2015;385:

30 Montalescot G et al., JACC 2015

31 Three questions to be answered: - how long is dual antiplatelet therapy necessary (DAPT) - how to bridge interruption of dual antiplatelet therapy - how to treat patients with stent thrombosis Recommendations of the European Society of Cardiology: Drug Eluting Stent in patients with stable CAD: DAPT for 6 months, even shorter if the risk of bleeding is high (peri-operative?) longer if the risk of ischemia is high and bleeding risk is low Drug Eluting Stent in patients with acute coronary syndrome (ACS): DAPT for 12 months regardless of stent type Windecker S et al., Eur Heart J 2014;35:

32 Three questions to be answered: - how long is dual antiplatelet therapy necessary (DAPT) - how to bridge interruption of dual antiplatelet therapy - how to treat patients with stent thrombosis Recommendations of the European Society of Cardiology: Drug Eluting Stent in patients with stable CAD: DAPT for 6 months, even shorter if the risk of bleeding is high (peri-operative?) longer if the risk of ischemia is high and bleeding risk is low Drug Eluting Stent in patients with acute coronary syndrome (ACS): DAPT for 12 months regardless of stent type Windecker S et al., Eur Heart J 2014;35:

33 Bridging Dual Antiplatelet therapy: What do you do? About 6 weeks ago five everolimus eluting stents (EES) were implanted into a chronic total occlusion (CTO) of the RCA in a 53-year old diabetic woman. She is now admitted for D&C for endometrial cancer. We have been asked about bridging her with antiplatelet/anticoagulant therapy during the perioperative period. Surgery is planned for 4 days from now. Kern JM et al., Cath Cardiovasc Interv 2014;83:

34 Bridging Dual Antiplatelet therapy: What do you do? About 6 weeks ago five everolimus eluting stents (EES) were implanted into a chronic total occlusion (CTO) of the RCA in a 53-year old diabetic woman. She is now admitted for D&C for endometrial cancer. We have been asked about bridging her with antiplatelet/anticoagulant therapy during the perioperative period. Surgery is planned for 4 days from now. 1. continue with ASA, hold Plavix for 4 5 days, and start eptifibatide infusion today. The eptifibatide will be continued until 6 hr before surgery. Enoxaparin has also been recommended for DVT prophylaxis. Costs about USD 2. continue with ASA, hold Plavix for 4 5 days, and start enoxaparin anticoagulation BID with the last dose being administered the night before surgery. Plavix will be restarted as soon as practical after surgery. Costs about USD Kern JM et al., Cath Cardiovasc Interv 2014;83:

35 Roffi M et al. Eur Heart J 2015

36 Bridging: Heparin? Arteriel thrombosis depends on platelet function, not on coagulation cascade Unfractionated heparin facilitates activation of platelets Heparin binds to the GP IIb/IIIa receptor, thereby possibly introducing a prothrombotic effect Wallentin L et al., Eur Heart J 2009;30: Hirsh J et al., Chest 2001;119:64-94

37 For patients with a very high risk of stent thrombosis, bridging therapy with intravenous, reversible glycoprotein inhibitors, such as eptifibatide or tirofiban, should be considered... The use of low-molecular-weight heparin (LMWH) for bridging in these patients should be avoided. Dual anti-platelet therapy should be resumed as soon as possible after surgery and, if possible, within 48 hours. Kristensen SD et al., EJA 2014

38 Alshawabkeh et al. EuroIntervention 2013

41 Bridging DAPT: GP IIb/IIIa receptor antagonists Capodanno D et al., Circulation 2013;128:

42 Three questions to be answered: - how long is dual antiplatelet therapy necessary (DAPT) - how to bridge interruption of dual antiplatelet therapy - how to treat patients with stent thrombosis Recommendations of the ESC and ESA: ü intravenous, reversible glycoprotein inhibitors, such as eptifibatide or tirofiban, should be considered ü Cangrelor, a new reversible intravenous P2Y12-inhibitor, has been shown to provide effective platelet inhibition but is not yet available ü low-molecular-weight heparin (LMWH) for bridging should be avoided ü Dual anti-platelet therapy should be resumed as soon as possible Kristensen SD et al., EJA 2014

45 Acute thrombosis of right coronary artery stent (RCA) Alshawabkeh et al. EuroIntervention 2013

46 Acute thrombosis of right coronary artery stent (RCA): successful DES placing Alshawabkeh et al. EuroIntervention 2013

47 Three questions to be answered: - how long is dual antiplatelet therapy necessary (DAPT) - how to bridge interruption of dual antiplatelet therapy - how to treat patients with stent thrombosis Recommendations : ü High risk patients to be operated in centers with 24h/7d PCI possibilities ü Risk of stent thrombosis highest early AFTER surgery: 24 h PACU/ICU ü Multidisciplinary treatment of high risk patients pre-, intra-, and postoperatively

48 The future: Biodegradable stents, DAPT for only 1 month? Cangrelor, intravenous ultra short acting, reversible P2Y 12 inhibitor Is there a doctor?

49 Registration opens: 18 November 2015 Abstract submissions: 1 Nov - 15 Dec 2015 registration@esahq.org

50 The patient with stent and DAPT: interdisciplinary approach Is there a doctor?

51

52 P2Y 12 inhibitors Roffi M et al. Eur Heart J 2015

58 Sanon S et al. Am J Cardiol 2014;114:

59 Roffi M et al. Eur Heart J 2015

60 Incidence of Stent Thrombosis dependent on Stent Generation Byrne RA et al., Eur Heart J 2015

61 Postop. Blutungsinzidenz unter Plättchenaggregationshemmung mittlerer Anstieg des Blutverlustes Aspirin: 2,5-20% Aspirin + Clopidogrel: 30-50% Transfusionsrate erhöht +30% Aber: keine erhöhte operative Letalität (außer NC)

62 Drug Eluting Stents (DES) Akuter Entzug der Plättchenaggregationshemmer excessive Thromboxan A2 Aktivität, reduzierte Fibrinolyse pro-thrombotischer Effekt größer als unter physiologischen Bedingungen operative Eingriffe unter so viel TZAH durchführen wie eben möglich Chassot PG et al., BJA 2007;99:

63 Oprea et al., BJA 2013

64 Thrombozyten-Aggregations-Hemmer Acetylsalicylsäure: Prasugrel (2009) Clopidogrel: Ticagrelor (2010) Ticagrelor (2010)

65 Oprea et al., BJA 2013 Oral Antiplatelets

66 Pharmakodynamik/-kinetik der Thienopyridine Schömig A, NEJM 2009;361:

67 Warum neue Thienopyridine? Variabilität der Plättchenhemmung durch Clopidogrel - Langsamer Wirkungseintritt - Responder Non-Responder - Genetische Variabilität - Beeinflussung der Metabolisierung (Aktivierung) durch andere Medikamente Serebruany VL et al., JACC 2005;45:246-51

68 Clopidogrel: Verzögerter Wirkungseintritt Gurbel RA Circulation 2009;120:

69 Darvish-Kazem S et al., Chest 2013

70 Darvish-Kazem S et al., Chest 2013

71 When should elective non-cardiac surgery be done in patients with a coronary stent? Which anti-platelet agents should be stopped or continued around the time of surgery? When should anti-platelet therapy be stopped and resumed before and after surgery? Is bridging needed around the time of surgery?...there were no practice guidelines that conferred a strong recommendation that was associated with high- or moderate-quality evidence, e.g. grade 1A or 1B Darvish-Kazem S et al., Chest 2013

72 worst-case Szenario Tanaka KA BJA 2014;112: Patient hat im Katheterlabor eine Initialdosierung Clopidogrel/Ticagrelor erhalten, dennoch ist die PCI gescheitert und eine Bypass-Operation ist erforderlich Hautschnitt 1-2 Stunden nach Antikoagulation

73 Clopidogrel: Verzögerter Wirkungseintritt Gurbel RA Circulation 2009;120:

74 Dringliche/Notfalleingriffe Gurbel RA Circulation 2009;120:

75 Unterbrechung der Dualen Plättchenaggregations-Hemmung? - Aspirin nicht stoppen - Clopidogrel: 5 Tage vor chirurgischem Eingriff stoppen - Ticagrelor: - USA: 5 Tage vor chirurgischem Eingriff stoppen - Europa: 7 Tage vor chirurgischem Eingriff stoppen

76 Plättchen-Transfusion? Individualisiertes TZ-Transfusionsschema erforderlich Fehlen/unzureichend zur Verfügung stehende Standardisierte Tests Plättchen-Zahl vs. Plättchen-Funktion Viele Studien untersuchen den ex-vivo Effekt von TZ-Transfusionen Einfluss frischer vs. älterer TZ-Konzentrate Andere Risikofaktoren: Hypofibrinogenämie, Vitamin-K abhängige Gerinnungsfaktoren Tanaka KA BJA 2014;112:780-84

77 Plättchen- Transfusion? Hansson EC et al., BJA 2014;112:570-5

78 Plättchen-Transfusion? Clopidogrel Halbwertzeit: 4h, aber irreversibler Antagonist! 12 h nach der letzten Einnahme TZ transfundieren Herbstreit F et al., Anaesthesia 2005;60:85

79 Bridging: TZ-Transfusionen? Thiele T et al., J Thromb Haemost 2012;10:968-71

80 Was fehlt uns eigentlich? Ein intravenöser Plättchenaggregationshemmer den wir an- und abschalten können Angiolillo DJ et al., JAMA 2012;307:

81 Oprea et al., BJA 2013 Intravenous Antiplatelets

82 Cangrelor for Bridging Stop Clopidogrel 29.1 (IQR h) vor Start Cangrelor Stop Cangrelor 1-6 h vor OP; 3.2 (IQR 2-5h) 0.75 µg/kg/min Plättchenreaktivität <240 PRU (VerifyNow P2Y12) Angiolillo DJ et al., JAMA 2012;307:

83 Cangrelor for Bridging Stop Clopidogrel 29.1 (IQR h) vor Start Cangrelor Stop Cangrelor 1-6 h vor OP; 3.2 (IQR 2-5h) 0.75 µg/kg/min Plättchenreaktivität <240 PRU (VerifyNow P2Y12) Kein erhöhtes Blutungsrisiko! Angiolillo DJ et al., JAMA 2012;307:

84 Cangrelor for Bridging

85 Cangrelor for Bridging

86 Bridging: Guidelines? Balance zwischen Ischämie und Blutung Morici N et al., Intern Emerg Med 2014;9:225-35

87 Neue Stents am Horizont - 2. Generation DES: 12 Monate Duale TZAH nicht besser im Vergleich zu 6 Monate - European CE Mark approval: - 3. Generation DES, Biologisch abbaubar - 2nd generation Xience Prime und Xience V Everolimus-eluting stents: duale TZAH für 3 Monate - Resolute Integrity Zotarolimus-elutig stent: duale TZAH für 1 Monat

88 Der Patient mit neuen Thrombozytenaggregationshemmern B. Preckel

89 Bridging Duale Plättchenaggregationshemmung Clopidogrel Stop ASS 100 Stationäre Aufnahme Clopidogrel 75 mg/tag OP Tirofiban 0,15 µg/kg/min Fraxiparin 0,3 ml s.c. Broad L et al., BJA 2007;98:19-22

90 Tokushige A et al., Circulation Cardiovasc Intervent 2012 perioperatives Risiko nach Stentimplantation

91 Tokushige A et al., Circulation Cardiovasc Intervent 2012 perioperatives Risiko nach Stentimplantation Aber: kein Unterschied zwischen BMS und DES!!

92 Erhöhtes Stent-Thrombose-Risiko nach Absetzen von Clopidogrel: Rebound Phänomen oder Entzug der Protektion Capodanno D et al., J Cardiovasc Trans Res 2014;7:82-90

93 Erhöhtes Stent-Thrombose-Risiko nach Absetzen von Clopidogrel: Rebound Phänomen oder Entzug der Protektion Capodanno D et al., J Cardiovasc Trans Res 2014;7:82-90

94 Bridging: GP Iib/IIIa Rezeptor Antagonisten? Clopidogrel Stop ASS 100 Stationäre Aufnahme Clopidogrel 75 mg/tag OP Tirofiban 0,15 µg/kg/min Fraxiparin 0,3 ml s.c. Broad L et al., BJA 2007;98:19-22

95 Rolle aktivierter Plättchen bei der Koagulation: - Initiierung und Progression der Atherosklerose - Entwicklung einer Atherothrombose - Endotheliale Reaktionen - Immunologische Reaktionen - Inflammatorische Reaktionen - Thrombotische Reaktionen

96 Endothelialer Schaden Exponierung von Kollagen an Blut und vwf PL Oberflächen-Glykoprotein-Rezeptoren interagieren mit Blut + vwf Subendotheliale Plättchen-Adhäsion Plättchen-Aktivierung Konformationsänderung der Plättchen Degranulation von Vesikeln,

97 Endothelialer Schaden Exponierung von Kollagen an Blut und vwf PL Oberflächen-Glykoprotein-Rezeptoren interagieren mit Blut + vwf Subendotheliale Plättchen-Adhäsion Plättchen-Aktivierung Konformationsänderung der Plättchen Degranulation von Vesikeln, Freisetzung von ADP, TxA2, Thrombin Konformationsänderung und Expression des GP IIb/IIIa Receptors Bindung andere PL durch Fibrinogen-Brücken Rekrutierung und Aktivierung benachbarter PL PL Aggregat, Wechselwirkung mit Fibrin und Thrombin Thrombus-Bildung

98 Blockade verschiedener Plättchen-Rezeptoren Meadows TA et al., Circ Res 2007;100: Oprea AD et al., BJA 2013;111(S1): i3-i17