Manejo Perioperatorio de los

Antiplaquetarios

José Luis Ferreiro

Hospital Universitario de Bellvitge: Área de Enfermedades del Corazón

Unidad de Cardiología Intervencionista - Laboratorio de Investigación Cardiovascular

Nuevos antiagregantes en SCA. ¿Cómo gestionar el cambio? Madrid, 15 de junio

CONFLICTOS DE INTERÉS

Honorarios por conferencias: Eli Lilly Co; Daiichi Sankyo, Inc.; AstraZeneca; Grifols

Becas: Sociedad Española de Cardiología

ÍNDICE

Recomendaciones generales

Nuevos agentes

¿Siempre hay que suspender el tto

antiagregante el tiempo recomendado?

RECOMENDACIONES

GENERALES

DURATION OF DAPT IN STENTED PATIENTS

ESC guidelines: ACS: 1 year (irrespective of type of stent)

Stable patient – BMS: 1 month

DES: 6-12 months

ACC/AHA guidelines: ACS: At least 12 months

Non-ACS BMS: 1 month and ideally up to 12 months

Non-ACS DES: at least 12 months (if not high risk of

bleeding)

MAJOR SURGERY AFTER PCI

Incidence of major surgery within 1 year after

stent implantation ≈5%

Savonitto S et al. J Thromb Haemost. 2011;9:2133-42.

INCIDENCE, PREDICTORS, AND OUTCOME OF

THROMBOSIS AFTER DES

Univariate Predictors of Cumulative Stent Thrombosis

0 10 20 30 40

Incidence of Stent Thrombosis

Premature Antiplatelet Therapy Discontinuation

Prior Brachytherapy

Renal Failure

Bifurcation with 2 Stents

Bifurcation Lesion

Unprotected Left Main Artery

Diabetes

Hazard Ratio for ATP Discontinuation = 89

What does premature really mean?

Iakovou I et al. JAMA. 2005;293:2126-30.

ASPIRIN AND CABG

After CABG (48 hours)

Preoperative aspirin (5 days)

Bybee KA et al. Circulation. 2005 Mangano D et al. N Engl J Med. 2002.

PERIOPERATIVE DISCONTINUATION OF

THIENOPYRIDINES AND MACE

Iakovou I et al. JAMA. 2005;293:2126-30.

COMMON SENSE

Knowing the patient needs surgery… No stent: CABG, medical therapy…

If completely necessary: BMS

Once the patient is stented… Elective surgery: Wait until completion of DAPT

Semi-elective / Urgent: Wait as much as possible

Emergent: Surgery

The less common of the senses...

ESC GUIDELINES: RECOMMENDATIONS

Wijns W et al. Eur Heart J. 2010;31:2501-55.

ESC WG THROMBOSIS: RECOMMENDATIONS

Korte W et al. Thromb Haemost. 2011;105:743-9.

IF YOU NEED TO STOP…

Clopidogrel: 5 days

Prasugrel: 7 days

Ticagrelor: 5 days

Bridging therapy with tirofiban Only reports of case series

?

NUEVOS FÁRMACOS

ANTIPLAQUETARIOS

Clopidogrel Prasugrel Ticagrelor Cangrelor Elinogrel

Group Thienopyridine Thienopyridine CPTP ATP analog Quinazolinedione

Administration oral oral oral IV IV and oral

Receptor

blockade irreversible irreversible reversible reversible reversible

Onset of action 2-8 h 30 min-4 h 30 min – 2 h seconds seconds

Offset of action 7-10 days 7-10 days 3-5 days 60-90 minutes 50 min (IV)

12 h (oral)

CYP drug

interactions yes no yes no no

P2Y12 INHIBITORS

Modified from Angiolillo DJ and Ferreiro JL. Rev Esp Cardiol 2010;63:60-76

More potent with less variability

16

Prasugrel Binding to P2Y12

17

Hepatic

metabolism

Clopidogrel

N

S Cl

COOCH3

CYP 3A4(5)

CYP 2C9

CYP 2C19

CYP 2B6

CYP 1A2

CYP 2B6

CYP 2C19

Inactive Metabolites

(85% clopidogrel)

Esterases

CLOPIDOGREL: METABOLISM

Active Metabolite

HOOC

* HS

N

O

Cl

OCH3

CH3

O N

S

O

Cl

O C

2-oxo compound

Hepatic

metabolism

18

N

S

O

C H3 C O

F

O

Prasugrel

Pre-hepatic metabolism Blood and intestine esterases

N

S

O

F

O

HOOC

* HS

N

O

F

2-oxo compound

Active Metabolite

Hepatic metabolism

CYP 3A4(5)

CYP 2C9

CYP 2C19

CYP 2B6

PRASUGREL: METABOLISM

Sugidachi A et al. J Thromb Haemost 2007;5:1545–51.

Concentration (mM)

*

** **

** **

**

** **

0 1 10 100 0

20

40

60

80 P

late

let

ag

gre

gati

on

(%

)

1000

Prasugrel active metabolite Clopidogrel active metabolite

Prasugrel 60 mg Clopidogrel 300 mg

Time from administration (h) 0 6 12 18 24

Pla

sm

ati

c c

on

cen

trati

on

(n

g/m

L)

0.1

1

10

100

1000

ACTIVE METABOLITE

Payne CD et al. J Cardiovasc Pharmacol 2007;50:555-562.

More efficient generation of active metabolite

PRASUGREL:

RAPID ONSET OF ACTION AND GREATER IPA

mean ± SEM

20 μM ADP

Inh

ibit

ion

of

Pla

tele

t A

gg

reg

ati

on

(%

)

0

20

40

60

80

100

Loading dose Maintenance dose

Hours Days

0.25 0.5 1 2 4 6 24 3 4 5 6 7 8 9 0

Clop 300 mg

Clop 75 mg

!

Clop 600 mg

Clop 75 mg

Pras 60 mg

Pras 10 mg

Payne CD et al. J Cardiovasc Pharmacol 2007;50:555-562

PRASUGREL: CABG

Wiviott SD et al. NEJM 2007;357:2001-15.

Smith PK et al. J Am Coll Cardiol. 2012 [Epub ahead of print]

PRASUGREL: CABG

Protection in front of ischemic events???

23

Ticagrelor Binding to P2Y12

TICAGRELOR

Direct acting: Hepatic metabolism not

required for activity

Rapid intestinal absorption

Reversible binding to P2Y12

receptor (different site than ADP): half life ~8 h

Adapted from Husted S et al. Cardiovasc Ther. 2009;27:259-274.

A non-thienopyridine, in the chemical class CPTP (CycloPentylTriazoloPyrimidine)

HO

HN

HO OH

O S

F

F

N

N N

N N

Active metabolite: AR-C124910XX (half-life ~10 hours) accounts

for ~30% to 40% of total activity

Gurbel PA et al. Circulation. 2009;120:2577-85.

TICAGRELOR:

RAPID ONSET / OFFSET & GREATER IPA

0%

20%

40%

60%

80%

100%

1 2 3 4 5 6 7 >8

Ticagrelor Clopidogrel

Major Fatal/Life-Threatening Bleeding by Days from Last Dose of

Treatment to CABG

% P

atie

nts

with

Ble

ed

ing

post-

CA

BG

Days

Bleeding differences favor ticagrelor >5 days post discontinuation

TICAGRELOR: CABG

Held C. J Am Coll Cardiol. 2011;57:672-84.

TICAGRELOR: CABG

Held C. J Am Coll Cardiol. 2011;57:672-84.

Protection in front of ischemic events???

van Giezen JJJ, Humphries RG. Semin Thromb Hemost. 2005;31:195-204.

4Na+

O

HO OH

O P

O P

O P

O–

O O O

O– O–

–O N

N N

NH2

N

ATP

P O

P P

O–

O O O

O– O–

–O

Cl

Cl O

HO OH

O N

N N

HN

N

SMe

S CF3

4Na+

Cangrelor (IV)

CANGRELOR: ATP ANALOG

HO O

OH OH

N

N

N S F

F F

N

HN

S

ATP analog

Direct-acting P2Y12 antagonist

Reversible receptor binding

No hepatic or renal metabolisation: NO interactions

Extremely short half-life: 2-5 minutes

Instant onset of action: steady-state in 30 minutes

Platelet function recovered in 60-90 minutes

Great IPA: >90%

Recovery time

~60 minutes

CANGRELOR: PHARMACODYNAMICS

dose 30ug/kg then 4ug/kg/min

Concentr

ation (

ng/m

L)

% P

late

let A

ctivity

Time (minutes)

Platelet activity

Plasma concentration

infusion bolus

Akers et al. J Clin Pharmacol. 2010;50:27-35

Primary endpoint

Percent of patients with PRU<240 for all on-treatment samples:

30

98,8%

19,0%

0%

20%

40%

60%

80%

100%

Cangrelor Placebo

p<0.0001

OR (95% CI)

353 (45.6-2728)

CANGRELOR: BRIDGE

Angiolillo DJ et al. JAMA 2012;307:265-74.

0

50

100

150

200

250

300

350

400

Baseline Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Last

on-infusion

sample

Pre-CABG

sample

Time Point

n=80 n=70

n=55 n=33 n=7

n=1

n=6

n=85

n=84

n=78

Cangrelor Placebo

Verify

Now

PR

U

N indicates number of patients with valid samples in the intention to treat population; PRU= P2Y12 reaction units; Data expressed as mean±SD

CANGRELOR PRE-CABG

n=76 n=73

n=57 n=34 n=24

n=14 n=86

n=2 n=84

n=75

11,8%

10,4%

0%

5%

10%

15%

Cangrelor Placebo

Excessive CABG-related bleeding

Angiolillo DJ et al. JAMA 2012;307:265-74.

Patients with an ACS or treated with a coronary stent (BMS or DES) on a thienopyridine awaiting CABG.

¿SIEMPRE HAY QUE SUSPENDER

LOS ANTIAGREGANTES EL

TIEMPO RECOMENDADO?

CLOPIDOGREL: OFFSET OF ACTION

Price MJ et al. Am J Cardiol. 2008;102:790-5.

CLOPIDOGREL: TIME TO CABG TARGET-CABG: Primary Endpoint: 24 hr Chest Tube Output

0

500

1000

1500

2000

2500

3000

3500

mL

Clopidogrel naïve (n=86)

On Clopidogrel (n=94)

4 hrs postop 12 hrs postop 24 hrs postop

p = NS p = NS p = NS

Clopidogrel responsiveness (ADP-induced

platelet-fibrin clot strength [MAADP]) was

determined by TEG.

CABG was done within 1 day,

3–5 days, and 5 days in patients with an

MAADP >50 mm, >35–50 mm, and >35 mm,

respectively.

Waiting times to CABG

reduced by ~50% than

recommended in guidelines.

Mahlla E, Gurbel PA et al. Circ Cardiovasc Interv 2012 [in press]

¿¿Sirve la misma talla para

todo el mundo??

Tratamiento

“individualizado”

THERAPEUTIC WINDOW

Inhibition of platelet aggregation

High risk of

ischemic events

High risk of

bleeding events “Sweet spot”

Ischemic risk Bleeding risk Ischemic risk Bleeding risk

Ferreiro JL, Sibbing D & Angiolillo DJl. Thromb Haemost 2010;103:1128-35.

The lower the bleeding risk, the higher the ischemic risk

CONCLUSIONES

CONCLUSIONES Usar el sentido común en pacientes con stent:

Cirugía electiva: Esperar hasta completar DAPT

Semi-electiva / Urgente: Esperar lo que sea posible (individualizar)

Emergente: Cirugía

Considerar mantener DAPT en cirugía de bajo riesgo

Mantener AAS excepto en situaciones de riesgo de sangrado extremedamente alto

Si hay que suspender, como regla general: Clopidogrel: 5 días

Prasugrel: 7 días

Ticagrelor: 5 días

Tests de función plaquetar pueden ayudar a individualizar

GRACIAS POR SU ATENCIÓN