when to operate and how to bridge antiplatelet therapy

Transcription

The patient with Drug Eluting Stent (DES):
B. Preckel, MD, MA, DEAA
Professor of Anesthesiology
Academic Medical Center AMC
University of Amsterdam
The Netherlands
[email protected]
The patient with Drug Eluting Stent (DES):
B. Preckel, MD, MA, DEAA
Professor of Anesthesiology
Academic Medical Center AMC
No Disclosures
University of Amsterdam
The Netherlands
[email protected]
B. Preckel, Academic Medical Center Amsterdam
The old problem:
- stents (BMS, DES)
- dual antiplatelet therapy (DAPT)
- operation
- bleeding
- ischaemia
Defining the fine balance between
ischemic and bleeding risk
remains a challange in stented patients undergoing
surgery treated with antiplatelet therapy
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
stent generations:
- Bare Metal Stents (BMS), 1994
- Drug Eluting Stents (DES), 2002
- first generation:
Sirolimus-eluting stent
Paclitaxel-eluting stent
- second generation: Everolimus-eluting stent
- third generation:
Biolimus-eluting stent
(„biological degradable)
Drug Eluting Stents (DES)
Re-stenosis ↓
Morice MC et al., NEJM 2002;346
Curfman GD et al., NEJM 2007;356:1059-1060
Risk factors for stent restenosis
Byrne RA et al., Eur Heart J 2015
Stent type and re-stenosis
Finn AV et al. Arteriosler Thromb Vasc Biol 2007;27:1500-10
DAPT: BMS 1-3 months
Sirolimus: 2-3 months
Paclitaxel: 6 months
Finn AV et al. Arteriosler Thromb Vasc Biol 2007;27:1500-10
Timing of Stent Thrombosis
Risk for late stent
thrombosis ↑
Lagerqvist B et al., NEJM 2007;356:1009-1019
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;45:456-459)
Risk factors for stent thrombosis:
- incomplete endothelialisation
- early discontinuation of DAPT
(aspirin, clopidogrel):
Risk increases 30-90 fold
Jeremias et al., Circulation 2004;109:1930-1932,
Iakovou et al., JAMA 2004;293:2126-30
- withdrawal of aspirin
high age, diabetes, low ejection fraction, kidney failure…
Guidelines 2007
Hall R et al, Anesth Analg 2011;112:292-318
Fleisher LA et al., Circulation 2007
Duration of Dual AntiPlatelet Therapy (DAPT):
① up to 12 months versus > 12 months
② 3-6 months versus 12 months
DAPT: How long?
Mauri L et al. NEJM 2014
DAPT: How long?
DAPT: How long?
Brener SJ Circulation 2015
DAPT: How long?
Prolonged duration of DAPT: up to 12 months versus > 12 months
Prolonged duration of DAPT: up to 12 months versus > 12 months
Palmerini T et al. Lancet 2015;385:2371-82
DAPT:
How long?
Becker RC et al. Circulation 2015
Stent type and re-stenosis
DAPT: How long?
Palmerini T et al. Lancet 2015;385:2371-82
Montalescot G et al., JACC 2015
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;35:2541-2619
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;35:2541-2619
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;83:748–752
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 12.668 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 2.640 USD
Kern JM et al., Cath Cardiovasc Interv 2014;83:748–752
Roffi M et al. Eur Heart J 2015
Bridging: Heparin?
Ø Arteriel thrombosis depends
on platelet function, not on
coagulation cascade
Ø Unfractionated heparin
facilitates activation of
platelets
Ø Heparin binds to the GP
IIb/IIIa receptor, thereby
possibly introducing a
prothrombotic effect
Wallentin L et al., Eur Heart J 2009;30:1964-77
Hirsh J et al., Chest 2001;119:64-94
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
Alshawabkeh et al. EuroIntervention 2013
Bridging DAPT:
GP IIb/IIIa receptor antagonists
Capodanno D et al., Circulation 2013;128:2785-98
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
Acute thrombosis of right coronary artery stent (RCA)
Acute thrombosis of right coronary artery stent (RCA): successful DES placing
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
The future:
Biodegradable stents, DAPT for only 1 month?
Cangrelor, intravenous ultra short acting, reversible P2Y12 inhibitor
Is there a
doctor?
Registration opens:
18 November 2015
Abstract submissions:
1 Nov - 15 Dec 2015
[email protected]
www.esahq.org
The patient with stent and DAPT: interdisciplinary approach
Is there a
doctor?
P2Y12 inhibitors
DAPT: How long?
Sanon S et al. Am J Cardiol 2014;114:1613-20
Incidence of Stent Thrombosis dependent on Stent Generation
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)
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;99:316-322
Oprea et al., BJA 2013
Thrombozyten-Aggregations-Hemmer
Acetylsalicylsäure:
Prasugrel (2009)
Clopidogrel:
Ticagrelor (2010)
Ticagrelor (2010)
Oral Antiplatelets
Pharmakodynamik/-kinetik der Thienopyridine
Schömig A, NEJM 2009;361: 1108-1111
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
Clopidogrel: Verzögerter Wirkungseintritt
Gurbel RA Circulation 2009;120:2577-85
Darvish-Kazem S et al., Chest 2013
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
Tanaka KA BJA 2014;112:780-84
„worst-case Szenario“
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
Clopidogrel: Verzögerter Wirkungseintritt
Dringliche/Notfalleingriffe
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
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
PlättchenTransfusion?
Hansson EC et al., BJA 2014;112:570-5
Plättchen-Transfusion?
Clopidogrel Halbwertzeit: 4h, aber irreversibler Antagonist!
12 h nach der letzten Einnahme TZ transfundieren
Herbstreit F et al., Anaesthesia 2005;60:85
Bridging: TZ-Transfusionen?
Thiele T et al.,
J Thromb Haemost
2012;10:968-71
Was fehlt uns eigentlich?
Ein intravenöser Plättchenaggregationshemmer den wir
an- und abschalten können
Angiolillo DJ et al., JAMA 2012;307:265-274
Intravenous Antiplatelets
Cangrelor for Bridging
Stop Clopidogrel 29.1 (IQR 1138 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)
Stop Clopidogrel 29.1 (IQR 1138 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!
Bridging: Guidelines?
Balance zwischen
Ischämie und Blutung
Morici N et al., Intern Emerg Med 2014;9:225-35
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
Der Patient mit neuen
Thrombozytenaggregationshemmern
B. Preckel
Bridging Duale Plättchenaggregationshemmung
Stationäre Aufnahme
Clopidogrel Stop
Clopidogrel 75 mg/Tag
ASS 100
-7
-5
-3 -2 -1 OP
1 2 3 4
5
Tirofiban 0,15 µg/kg/min Fraxiparin 0,3 ml s.c.
Broad L et al., BJA 2007;98:19-22
Tokushige A et al., Circulation Cardiovasc Intervent 2012
perioperatives Risiko nach Stentimplantation
Tokushige A et al., Circulation Cardiovasc Intervent 2012
perioperatives Risiko nach Stentimplantation
Aber: kein Unterschied zwischen BMS und DES !!
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
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
Bridging: GP Iib/IIIa Rezeptor Antagonisten?
Stationäre Aufnahme
Clopidogrel Stop
Clopidogrel 75 mg/Tag
ASS 100
-7
-5
-3 -2 -1 OP
1 2 3 4
5
Tirofiban 0,15 µg/kg/min Fraxiparin 0,3 ml s.c.
Broad L et al., BJA 2007;98:19-22
Rolle aktivierter Plättchen bei der Koagulation:
-
Initiierung und Progression der Atherosklerose
Entwicklung einer Atherothrombose
Endotheliale Reaktionen
Immunologische Reaktionen
Inflammatorische Reaktionen
Thrombotische Reaktionen
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,
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
Blockade verschiedener Plättchen-Rezeptoren
Meadows TA et al., Circ Res 2007;100:1261-75
Oprea AD et al., BJA 2013;111(S1): i3-i17

when to operate and how to bridge antiplatelet therapy

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