Marco Comeglio

UO Diagnostica ed Interventisticadel Cuore e dei Vasi

USL 3 Pistoia

Come gestire la terapia Come gestire la terapia antiaggregante e anticoagulante antiaggregante e anticoagulante nei pazienti in attesa di chirurgia nei pazienti in attesa di chirurgia

non cardiaca?non cardiaca?

Risk Stratification forRisk Stratification forPerioperative TE in patients on OATPerioperative TE in patients on OAT

Mod from Douketis et al. Chest 2008

HEMORRHAGIC RISK IN NON CARDIAC SURGERYHEMORRHAGIC RISK IN NON CARDIAC SURGERY

RISKRISK BLOODBLOODTRANSFUSIONTRANSFUSION

TYPE OFTYPE OFSURGERYSURGERY

LOWLOW

INTERMEDIATEINTERMEDIATE

HIGHHIGH

Usually notrequired

Frequentlyrequired

Possible bleedingin a closed space

Skin, and general surgeryMinor orthopedic, ORLEndoscopyCataract, anterior eyeDental extr & surgery

Visceral surgeryCV surgeryMajor orthop, ORL, urologic

Intracranial neurosurgerySpinal canal surgeryEye post chamber surgery

Adapted Abualsaud et al, JACC Int 2010Adapted Abualsaud et al, JACC Int 2010

Perioperative Management of OATPerioperative Management of OATin Low- and High-Risk patients/proceduresin Low- and High-Risk patients/procedures

Low thromboembolic risk/low bleeding risk• Continue anticoagulant therapy with INR in therapeutic range

Low thromboembolic risk/high bleeding risk• Discontinue anticoagulant therapy 5 days before the procedure

• Start LMWH prophylaxis once daily or UFH i.v. 1 day after acenocoumarol interruption, and 2 days after warfarin interruption. Administer the last dose of LMWH at least 12 h before the procedure or give UFH i.v. up to 4 h prior to surgery

• Resume LMWH or UFH at the pre-procedural dose 1-2 days (at least 12 h) after the procedure according to the haemostatic status. Resume anticoagulant therapy 1 to 2 days after surgery at the pre-procedural dose + 50% boost dose for 2 consecutive days according to the haemostatic status. LMWH/UFH until therapeutic INR is reached

BR

IDG

ING

BR

IDG

ING

High thromboembolic risk• Discontinue anticoagulant therapy 5 days before the procedure

• Start therapeutic LMWH twice daily or UFH i.v. 1 day after acenocoumarol interruption, and 2 days after warfarin interruption. Administer the last dose of LMWH at least 12 h before the procedure or give UFH i.v. up to 4 h prior to surgery

• Resume LMWH or UFH at the pre-procedural dose 1-2 days (at least 12 h) after the procedure according to the haemostatic status. Resume anticoagulant therapy 1 to 2 days after surgery at the pre-procedural dose + 50% boost dose for 2 consecutive days according to the haemostatic status.

• LMWH or UHF is continued until the INR has returned to therapeutic levels

Perioperative Management of OATPerioperative Management of OATin Low- and High-Risk patients/procedures in Low- and High-Risk patients/procedures

(2)(2)

BR

IDG

ING

BR

IDG

ING

Circulation 2009; 119: 2920Circulation 2009; 119: 2920

Indication for OAT (n = 1,262)Indication for OAT (n = 1,262)N (%)N (%)

Pengo et al, Circulation 2009

Anticoagulation ProtocolsAnticoagulation ProtocolsAccording to Patient Thromboembolic RiskAccording to Patient Thromboembolic Risk

HIGH TE-RISK CRITERIAHIGH TE-RISK CRITERIA• Mechanical mitral valve prostheses• Monoleaflet aortic prostheses or bileaflet with AF or previous TE• AF associated with previous TE or mitral valve disease• Previous cardiogenic or unesplained systemic embolism• Venous TE < 3 m

N = 295 N = 967

Pengo et al, Circulation 2009

Types of ProceduresTypes of ProceduresAccording to the Bleeding RiskAccording to the Bleeding Risk

HIGH BLEEDING RISK (369)HIGH BLEEDING RISK (369)• Abdominal• Orthopedic• Maxillofacial• Urologic• Vascular• Gynecologic• Ocular• Mammary• Neurosurgery

LOW BLEEDING RISK (893)LOW BLEEDING RISK (893)• GI Endoscopy• Cutaneous Surgery• Cistoscopy• Biopsies• Hand surgery• Angiography• Ocular anterior• ENT procedures• Gyno procedures• PM/ICD• Hepatic procedures• Arthroscopy• Miscellaneous

Pengo et al, Circulation 2009

Thromboembolic EventsThromboembolic Events 5 TE events: 3 venous and 2 arterial 1 fatal event All 5 events in HIGH TE-risk patients 3 events : LMWH not administered according to

protocol 2 events : not “bridget” at allHemorrhagic EventsHemorrhagic Events 15 major bleedings : none fatal

11 / 15 : surgical site bleeding8 / 15 : protocol A ; 7 / 15 : protocol B

53 minor bleedings27 /53 : at the procedure siteRelated to protocol (A > B) and procedure

bleeding risk

EVENTIEVENTIISCHEMICIISCHEMICI

EVENTIEVENTIEMORRAGICIEMORRAGICI

Come gestire la terapia antiaggregante Come gestire la terapia antiaggregante nei pazienti in attesa di chirurgia non nei pazienti in attesa di chirurgia non

cardiaca?cardiaca?•Prevenzione PrimariaPrevenzione Primaria•Prevenzione Prevenzione SecondariaSecondaria

•Post-StentingPost-Stenting•BMS/DESBMS/DES

Prevenzione Prevenzione PrimariaPrimaria

Thrombosis and Haemostasis 2011;105

As the peri-operative use of aspirin is associated with increased blood loss and blood product use and as patients undergoing primary prophylaxis show no manifestation of any cardiovascular disease, this expert group suggests that aspirin given for primary prevention should be stopped 5–7 days before any type of surgery (46, 47). Further trials are required in order to confirm or refute this recommendation in the future.

Prevenzione Prevenzione SecondariaSecondaria

Thrombosis and Haemostasis 2011;105

In summary, there is likely a In summary, there is likely a favourable peri-operative favourable peri-operative benefit-to risk profile for antiplatelet monotherapybenefit-to risk profile for antiplatelet monotherapy (aspirin or (aspirin or clopidogrel) in secondary prevention with the exception of specific clopidogrel) in secondary prevention with the exception of specific types of surgery and situations where the additional bleeding types of surgery and situations where the additional bleeding implies an important risk to the patient. implies an important risk to the patient.

This expert group therefore This expert group therefore recommends the continuation recommends the continuation of aspirin (or clopidogrel) monotherapy for secondary prevention of aspirin (or clopidogrel) monotherapy for secondary prevention during most types of surgery.during most types of surgery. Only in patients undergoing surgical Only in patients undergoing surgical procedures in areas of closed space (e.g. intracranial procedures in areas of closed space (e.g. intracranial neurosurgery, posterior chamber of the eye, medullary canal etc.) neurosurgery, posterior chamber of the eye, medullary canal etc.) or when major bleeding complications are to be expected, or when major bleeding complications are to be expected, stopping monotherapy with aspirin or clopidogrel 5–7 days pre stopping monotherapy with aspirin or clopidogrel 5–7 days pre operatively should be evaluated on a case by case basis. Further operatively should be evaluated on a case by case basis. Further clinical trials are warranted.clinical trials are warranted.

Antiaggreganti PiastriniciAntiaggreganti Piastrinicidopo Angioplastica Coronaricadopo Angioplastica Coronarica

Shomig et al NEJM, 1996Shomig et al NEJM, 1996

The main complicationThe main complicationof BMS is of BMS is

In-stent-restenosisIn-stent-restenosis

……a stent with a stent with optimal deliverability optimal deliverability

and scaffolding and scaffolding which is also which is also

impervious to intimal impervious to intimal hyperplasiahyperplasia

A “KEYSTONE” ofA “KEYSTONE” ofInterventional CardiologyInterventional Cardiology

will be….. will be…..

N = 238 patientsN = 238 patients de novo, nativede novo, native coronary arterycoronary artery

N = 238 patientsN = 238 patients de novo, nativede novo, native coronary arterycoronary artery

Randomized

Sirolimus-coatedSirolimus-coated Bx VelocityBx VelocityTMTM

StentStentn = 120n = 120

Sirolimus-coatedSirolimus-coated Bx VelocityBx VelocityTMTM

StentStentn = 120n = 120

Uncoated Uncoated Bx VelocityBx VelocityTMTM

StentStentn = 118n = 118

Uncoated Uncoated Bx VelocityBx VelocityTMTM

StentStentn = 118n = 118

Primary EndpointLate Loss measured by quantitative angiographic analysis at 6 months

RAVELRAVEL trial trialNEJM 2002. 346; 23NEJM 2002. 346; 23

RAVEL – Event-Free SurvivalRAVEL – Event-Free Survival(Death, MI, CABG, Re-PTCA)(Death, MI, CABG, Re-PTCA)

94.0%94.0%

70.7%70.7%

P (FE) < 0.0001 P (FE) < 0.0001

P (LR) = 0.0001P (LR) = 0.0001

6060

6565

7070

7575

8080

8585

9090

9595

100100

6060 120120 180180 240240 300300 360360

Pat

ient

s W

ithou

t Eve

nt(%

)P

atie

nts

With

out E

vent

(%)

Time (Days)Time (Days)00

SirolimusSirolimus

ControlControl

N Engl J M 2002. 346; 23

DES use must be cautious in patients with

ASA/Clopidogrel intolerance or allergy

Surgery candidates

Haemorrhagic diseases

Lancet 2004

VLST in DESVLST in DES

Daemen et al, Lancet 2007Daemen et al, Lancet 2007

First Generation DESFirst Generation DESOccurrence and Frequency of Occurrence and Frequency of

ST over timeST over time

VLSTVLST

DES and VLSTDES and VLSTBern-Rotterdam Cohort Study @ 4 YearsBern-Rotterdam Cohort Study @ 4 Years

8,146 consecutive patients treated with 8,146 consecutive patients treated with 11stst gen DES gen DES

Wenaveser et al, JACC 2008Wenaveser et al, JACC 2008

Risk of VLSTRisk of VLST0.4 – 0.5 % per year0.4 – 0.5 % per year

00

1010

2020

3030

4040%%

Mortality in Patients with Stent ThrombosisMortality in Patients with Stent Thrombosis(38/2974 – 1.27%)(38/2974 – 1.27%)

Kuchulakanti et al, Circ 2006Kuchulakanti et al, Circ 2006

12%12%

19%19%

31%31%

00 1 M1 M 6 M6 M F-UPF-UP

AcuteAcute 55Sub-acuteSub-acute 2525 8.9 8.9 ± 8.5 d± 8.5 d

Late Late (>30d)(>30d) 88 152.7 152.7 ± 100 d± 100 d

Lack of CLOPI Rx was the strongest ST predictor p = Lack of CLOPI Rx was the strongest ST predictor p = 0.00030.0003

Iakovou et al, JAMA, 2005Iakovou et al, JAMA, 2005

PREDICTORS OF THROMBOSIS AFTERPREDICTORS OF THROMBOSIS AFTERSUCCESSFUL IMPLANTATION OF DESSUCCESSFUL IMPLANTATION OF DES

Factors identified with premature discontinuation of APTFactors identified with premature discontinuation of APT

• Not receiving discharge instructions for Not receiving discharge instructions for medication usemedication use

• Not being referred for a cardiac rehabilitation Not being referred for a cardiac rehabilitation programprogram

• Older ageOlder age• Low cultural levelLow cultural level• Not being marriedNot being married• Economical issuesEconomical issues• Pre-existing anemiaPre-existing anemia• Invasive proceduresInvasive procedures• SurgerySurgery

Berger et al JACC Int 2010Days after hospital discharge

Fre

edom

fro

m M

ajo

r Surg

ery

0.5% per month after0.5% per month afterthe first 2 monthsthe first 2 months

5%5%

EVENT RegistryMajor Non-Cardiac Surgery After DES

206/4,367

RESTENOSIRESTENOSISS

STENT THROMBOSISSTENT THROMBOSIS

Sarno G, ESC 2011Sarno G, ESC 2011

42,77342,773

12,15312,153

6,4256,425

Raber et al, ESC 2011

Bern-RotterdamBern-RotterdamCohort StudyCohort Study

EES N = 4212EES N = 4212

PES N = 4308PES N = 4308

SES N = 3819SES N = 3819

Raber et al, ESC 2011

Bern-RotterdamBern-RotterdamCohort StudyCohort Study

Valgimigli, ESC, 2011

Valgimigli, ESC, 2011

Valgimigli, ESC, 2011

Valgimigli, ESC, 2011

Kastrati, ESC, 2011Kastrati, ESC, 2011

Novel Antiplatelets

PRASUGRELOral ThienopyridinePro-drug metabolized via cit P450Selective and irreversible bindingMore rapid, potent and consistent

platelet inhibitionMore effective than Clopidogrel in

ACS but with more bleedings

Peri-operative use maight be limited because of increased risk of bleeding

Potentially useful soon after surgery

Novel Antiplatelets

TICAGRELOROral ADP P2Y12 receptor antagonistNon thienopyridine ADP analog Binds directly and reversibly to the

P2Y12 without metabolic activationAchieves greater platelet aggregation

inhibition than ClopidogrelShort half-life (6-12 h)Rapid onset of action (2-4 h)Reversibility

Patients with stents would discontinue TICAGRELOR only 1 day before surgery and resume it soon after surgery, reducing the risk of both ST and Hemorrhage

Novel Antiplatelets

CANGRELOR

Intravenous ADP P2Y12 receptor antagonistNon thienopyridine ADP analog Binds directly and reversibly to the P2Y12

without metabolic activationVery short half-life (3 min)Rapid onset of actionReversibility

Could be used as a “Bridging Therapy” in the perioperative setting: stopped minutes before surgery and resumed sooner than other APT post-operatively

The BRIDGE trialThe BRIDGE trialongoingongoing

Jaffer AK. Clev Clin J 2009

CHECKLISTCHECKLISTPreoperative evaluation of patients with stentsPreoperative evaluation of patients with stents

Determine type of stent: BMS or DES ?Determine type of stent: BMS or DES ? In case of DES: 1In case of DES: 1stst or 2 or 2° ° generation DES ?generation DES ? Determine how long ago each stent was Determine how long ago each stent was

implantedimplanted Determine location of each stent & tecnique (eg, Determine location of each stent & tecnique (eg,

crush)crush) How complicated was the revascularisation? How complicated was the revascularisation?

Were there any complications (eg, Were there any complications (eg,

underexpansion, malapposition)?underexpansion, malapposition)? Is there any prior history of stent thrombosis?Is there any prior history of stent thrombosis? What APT regimen is being used?What APT regimen is being used? Determine patient’s comorbidities to further Determine patient’s comorbidities to further

ascertain risk level (EF, diabetes, renal ascertain risk level (EF, diabetes, renal

insufficiency)insufficiency) What is the recommended duration of DAPT?What is the recommended duration of DAPT? What is the surgery bleeding risk?What is the surgery bleeding risk?

Expert

sExpert

sR

eco

mm

endati

ons

Reco

mm

endati

ons

Korte et al, Thromb Haemost, 2011

May et al, Thromb Haemost 2008

Perioperative Antiplatelet Management in Perioperative Antiplatelet Management in Patients with Recently Implanted Coronary Patients with Recently Implanted Coronary

StentsStents““BRIDGING”BRIDGING”

Prevenzione SecondariaPrevenzione Primaria

Valutazione delRischio Emorragico

ValutazioneCollegiale

delRapporto

R/B

Stop APTStop APTASA : 7 gg prima int elettTPD : 15 gg prima int elett

ASA : 75 mg/die + ASA : 75 mg/die + PPIPPIDa 7 gg prima dell’int elettivo nei pazienti trattati con ASA

Da 15 gg prima dell’int elettivo nei pazienti trattati con TPD

NONO SISI

IntermedioIntermedioElevatoElevato

Pregresso IMA, CAD, Ictus, PAOD, StentPregresso IMA, CAD, Ictus, PAOD, Stent

•Riprendere ASA asap•Profilassi TE “dopo” intervento

**

BassoBasso

**

Protocollo Peri-OperatorioProtocollo Peri-OperatorioASA o TPDASA o TPD

Protocollo Peri-OperatorioProtocollo Peri-OperatorioASA + TPDASA + TPD

Elevato Rischio TRBasso Rischio TR

ChirurgiaDifferibile?

Operare in DAPT

NONO

•Riprendere DAPT asap•Profilassi TE “dopo” intervento

**

SISI

Differire

NONO

SISI

•Continua ASAContinua ASA•Stop TPD 5 gg Stop TPD 5 gg primaprima

**

““Bridge Therapy”Bridge Therapy”

Valutazione Collegiale del Rapporto R/BValutazione Collegiale del Rapporto R/B

Rischio di sanguinamento Rischio di sanguinamento non controllabile non controllabile chirurgicamente?chirurgicamente?

STENT/APT e Chirurgia non CardiacaSTENT/APT e Chirurgia non Cardiaca

DAPT in PCIDAPT in PCI = Obiettivo da perseguire= Obiettivo da perseguireAlmeno 1 mese BMS; 6 mesi DES. In considerazione della Almeno 1 mese BMS; 6 mesi DES. In considerazione della gravità della ST e della incidenza di sanguinamenti gravità della ST e della incidenza di sanguinamenti relativamente bassarelativamente bassa

Valutazione collegialeValutazione collegiale : Chirurgo – Cardiologo – Anestesista : Chirurgo – Cardiologo – Anestesista

Controindicazioni ai DESControindicazioni ai DES: in alcune situazioni cliniche : in alcune situazioni cliniche prevenire la necessità di DAPT prolungata è preferibile rispetto prevenire la necessità di DAPT prolungata è preferibile rispetto a curare le complicanze emorragiche o trombotichea curare le complicanze emorragiche o trombotiche

Rischio emorragico elevatoRischio emorragico elevato : il trattamento con sola ASA è : il trattamento con sola ASA è gravato da una incidenza di ST relativamente bassagravato da una incidenza di ST relativamente bassa

Completa sospensione dell’ APTCompleta sospensione dell’ APT : raramente necessaria, : raramente necessaria, in tal caso è opportuno adottare terapie “bridging”in tal caso è opportuno adottare terapie “bridging”

DES di nuova generazioneDES di nuova generazione : migliore profilo di sicurezza : migliore profilo di sicurezza

Nuovi farmaci antipiastriniciNuovi farmaci antipiastrinici : posso facilitare la gestione : posso facilitare la gestione peri-operatoriaperi-operatoria

TakeTakeHomeHome

MessageMessage

Predictors of ARC Definite or ProbablePredictors of ARC Definite or Probable2-Year Stent Thrombosis : EES Stent2-Year Stent Thrombosis : EES Stent

DiscontinuationDiscontinuation Hazard RatioHazard Ratio PP

of Thienopyridineof Thienopyridine (95% CI)(95% CI) VALUEVALUE

Before 6 monthsBefore 6 monthsYES vs. NEVERYES vs. NEVER

After 6 monthsAfter 6 monthsYES vs. NEVERYES vs. NEVER

8.06 8.06 (1.79 , 36.22)(1.79 , 36.22)

SPIRIT IVSPIRIT IV

1.06 1.06 (0.24 , 4.73)(0.24 , 4.73)

0.0070.007

0.940.94

HEMORRHAGIC RISK IN NON CARDIAC SURGERYHEMORRHAGIC RISK IN NON CARDIAC SURGERY

RISKRISK BLOODBLOODTRANSFUSIONTRANSFUSION

TYPE OFTYPE OFSURGERYSURGERY

LOWLOW

INTERMEDIATEINTERMEDIATE

HIGHHIGH

Usually notrequired

Frequentlyrequired

Possible bleedingin a closed space

Skin, and general surgeryBiopsiesMinor orthopedic, ORLEndoscopyCataract, anterior eyeDental extr & surgery

Visceral surgeryCV surgeryMajor orthop, ORL, urologic

Intracranial neurosurgerySpinal canal surgeryEye post chamber surgery

Adapted Abualsaud et al, JACC Int 2010Adapted Abualsaud et al, JACC Int 2010

SURGICAL RISK ESTIMATESURGICAL RISK ESTIMATERisk of MI and Cardiac DeathRisk of MI and Cardiac Deathwithin 30 days after Surgerywithin 30 days after Surgery