Iván Núñez Gil. Cardiología Intervencionista. HSCS.

}  IBPs interfieren con el clopidogrel (?).

}  Clopidogrel, se receta con IBP por riesgo de

sangrado digestivo (+AAS).

}  Precaución con discontinuar antitrombóticos

cuando se recomiendan 12 meses.

ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use

Bhatt et al., J Amer Coll Cardiol 2008; 52: 1502

GI bleedingDual antiplatelet therapy

Concomitant anticoagulant

Riesgo GI y antitrombóticos

Assess GI risk factors

History of ulcer complication History of ulcer disease (nonbleeding)

Test for H pylori; treat if

infected

More than one risk factor: Aged 60 years or more Corticosteroid use Dyspepsia or GERD symptoms

Need for antiplatelet therapy

Yes

Yes

No PPI

Yes

Yes

5,0

3,2 2,9

8,5

4,7

7,7

0

2

4

6

8

10 Placebo+ASA Clopidogrel+ASA

CURE CHARISMA MATCH

0,7 0,6

1,3 1,4

0

1

2

CURE MATCH

Total sangrado Mayor GI

Tasas de sangrado con AAS Vs AAS+Clopi en CURE. CHARISMA y MATCH.

Paci

ente

s, %

}  Datos retrospectivos: eventos adversos CV con AAS-Clopi e IBP (1).

}  Veterans Affair´s (2) ◦  8205 tras SCA, clopi + IBP: ⇧muerte y reingresos

}  Otros post hoc (SCA, post SCA, postICP): No difs (3). }  Depende del IBP (4): ◦  Inh CYP P450 2C19: omeprazol,lansoprazol, rabeprazol. ◦  Omeprazol disminuye agregación por clopidogrel. ◦  Pantoprazol NO

1- HO, JAMA 2009;Juurlink, CMAJ 2009; O´Donoghue, Lancet 2009. 2- HO, JAMA 2009. 3- Simon, NEJM 2009. 4- Gilard, JACC 2008; Sibbing, Thromb Haemost 2009.

}  Con otros Inh P2Y12: No problema (1). ◦  Lansoprazol y prasugrel.

}  PRINCIPLE TIMI 44/ TRITON TIMI 38 (2): ◦  Prasu Vs Clopi ◦  IBP atenúan clopidogrel. Menos el prasugrel. ◦  No efecto clínico (incluye ome/pantoprazol) para ambos.

}  COGENT (3) ◦  3627. ◦  Aleatorizado. ◦  AAS + Clopi ± omeprazol. ◦  NO difs CV (HR1,02). Menos sangrados. ◦  Detenido PREMATURAMENTE .

1- Small, J Clin Pharm 2008. 2- O´Donoghue, Lancet 2009. 3- Bhat, NEJM 2010.

A.  Estudios plaquetarios INVITRO B. Datos clínicos de registros retrospectivos. C. Interacción IBP-Clopidogrel en estudios

aleatorizados D. Meta-analisis, de registros y estudios

aleatorizados. E. Agencias reguladoras.

Clopidogrel (Inactive in vitro)

Thiolactone metabolite (Inactive in vitro)

Active metabolite (Platelet inhibition)

P2Y12-Receptor

<15%

Savi et al., Thromb. Haemost. 2000; 84: 891 Clarke & Waskell, Drug Metab. Dispos. 2003; 31: 53 Hagihara et al., Drug Metab. Dispos. 2009; epub

Formación del metabolito activo de Clopidogrel

Cl

H COOCH3

N

SON

S Cl

H COOCH3

Cl

H COOCH3

NO

HO

SS

Cl

H COOCH3

NO

HO

HS

N

S Cl

H COOH

SR26334 (Inactive in vitro)

85%

Clopidogrel (Inactive in vitro)

Thiolactone metabolite (Inactive in vitro)

Active metabolite (Platelet inhibition)

P2Y12-Receptor

<15%

CYP1A2 CYP2B6 CYP2C19 CYP3A4/A5

CYP2B6 CYP2C9 CYP2C19

Savi et al., Thromb. Haemost. 2000; 84: 891 Clarke & Waskell, Drug Metab. Dispos. 2003; 31: 53 Hagihara et al., Drug Metab. Dispos. 2009; epub

Cl

H COOCH3

N

SON

S Cl

H COOCH3

Cl

H COOCH3

NO

HO

SS

Cl

H COOCH3

NO

HO

HS

Formación del metabolito activo de Clopidogrel

Efecto antiplaquetario atenuado de Clopidogrel portadores de alelo (s) de función reducida CYP2C19*2

0

20

40

60

Baseline

P<0.001 P<0.001ns

Pre PCI At discharge

Wildtype, n=552*2 Allele(s), n=245

11 748 23 1146

RPA

AD

P 5 µm

ol/L

(%)

Trenk et al., J Am Coll Cardiol 2008; 51: 1925

Meta-Analisis alelos de CYP2C19 y MACE

Carriers vs Non-Carriers

Heterozygotes vs Wildtype

Homozygotes vs Wildtype

Risk Higher with CYP2C19 Variant

Risk Lower with CYP2C19 Variant

Risk Ratio (95% CI)

P Value

1.61 (1.28-2.02)

1.50 (1.08-2.08)

1.81 (1.21-2.71)

<0.001

0.016

0.004

0.5 1.0 15.0

N=9,684 Mega et al., AHA 2009

Omeprazol atenúa el efecto de Clopidogrel: OCLA study

Gilard et al., J Am Coll Cardiol. 2008; 51:256

0

20

40

60

80

100

Baseline

p<0.0001NS

Day 7

PlaceboOmeprazole 20 mg

654 14083.2 83.9 39.8 51.4

VASP

PR

I (%

)

Sibbing et al., Thromb Haemost 2009; 101: 714

Omeprazol pero no Pantoprazol o Esomeprazol atenúa el efecto antiplaquetario de clopidogrel

No PPI n=732

Pantoprazole n=162

Esomeprazole n=42

Omeprazole n=64

200

0

400

800

600 P=0.69

P=0.88

P=0.001

AD

P-in

duce

d A

ggre

gatio

n,

AU

·min

Kein PPI

Pantop

razol

Lans

opraz

ol0

20

40

60

n=74 n=152 n=74

No PPI Pantoprazole Esomeprazole

ADP-

indu

ced

Aggr

egat

ion,

U

P=0.382

Siller-Matula et al., Am Heart J 2008; 0: e1-e5

No Impacto de Pantoprazol o Esomeprazol en agregación en pacs (ADP-inducida) con Clopidogrel

MFPA analyzer

A. Estudios plaquetarios INVITRO B.  Datos clínicos de registros retrospectivos. C. Interacción IBP-Clopidogrel en estudios

aleatorizados D. Meta-analisis, de registros y estudios

aleatorizados. E. Agencias reguladoras.

Impacto de los IBP en la incidencia de infarto en 1 año Aetna database

1,38

3,08

5,05

0

1

2

3

4

5

6

Pezalla & Day, J Amer Coll Cardiol 2008; 52: 1038

Control No PPI

Low exposure to PPI

High exposure to PPI

% Incidence of MI p<0.05

66/4800 22/712 191/3795

1 10

1

2

3

0.5 5 20Adjusted Incidence (%)

No PPI

Low PPI Exposure

High PPI Exposure

Pezalla & Day, J Amer Coll Cardiol 2008; 52: 1038 * Hypertension, diabetes, heart failure, ischemic heart disease, hyperlipidemia

p<0.05 vs. Control

PPI-supply on 1-year incidence of MI: Risk-adjusted analysis*

Riesgo de muerte de todas las causas y SCA recurrente en pacs con clopi e IBP tras un SCA

0.70

0.60

0.50

0.40

0.30

0.20

0.10

0 0

90

180

270

360

450

540

630

720

810

900

990

1080

Days Since Discharge

Prop

ortio

n of

D

eath

s or

Rec

urre

nt A

CS

Neither clopidogrel nor PPI PPI without clopidogrel Clopidogrel + PPI Clopidogrel without PPI)

Ho et al. JAMA 2009; 301: 937

1 2 3 40

10

20

30∅ PPI (n=2961)+ PPI (n=5244)

Ho et al. JAMA 2009; 301: 937

Death / Rehosp. for ACS

Revas- cularization

Total mortality

Rehospit. for ACS

20.8 29.8 6.9 14.6 11.9 15.5 16.6 19.9

Eve

rnt r

ate,

%

Outcomes Associated with Proton Pump Inhibitors and Clopidogrel in Patients after ACS

Ho et al. JAMA 2009; 301: 937

11.5848932.511886

All cause death

REvascual

Rehosp

Death or rehosp

0.5

1.25 (1.11-1.41)

1.86 (1.57-2.20)

1.49 (1.30-1.71)

0.91 (0.80-1.05)

Adjusted Odds Ratios (95% CI)

Death/ Rehospitalisation for ACS (1° Endpoint) Rehospitalisation for ACS

Revascularization

Total mortality

Pronóstico tras un SCA en pacs tratados con IBP y clopidogrel

70%

80%

90%

100%

0 30 60 90 120 150 180 210 240 270 300 330 360 Follow-up days

Event-free survival

Lansoprazole Esomeprazole

Omeprazole Pantoprazole

No proton pump inhibitor

Stanek et al. LBCT SCAI Scientific Sessions May 06, 2009

Primary end point: - Combined hospitalization for a major adverse cardiovascular event over 12 months - Cerebrovascular event (Stroke or TIA) - Acute coronary syndrome (MI or unstable angina) - Cardiovascular death (resuscitated; resulting in hospitalization) - Coronary revascularization (CABG and PCI)

Efecto de IBP en pacs recibiendo clopidogrel tras stenting

HR 1.61 (1.44-1.81 ), p<0.0001 29.2% Pantoprazole HR 1.39 (1.16-1.67 ), p=0.0004 24.3% Lansoprazole

HR 1.57 (1.40-1.76 ), p<0.0001 24.9% Esomeprazole HR 1.39 ( 1.22-1.57), p<0.0001 25.1% Omeprazole

Ref 17.9% No PPI

1653 785

3257 2307 9862

A. Estudios plaquetarios INVITRO B. Datos clínicos de registros retrospectivos. C.  Interacción IBP-Clopidogrel en estudios

aleatorizados D. Meta-analisis, de registros y estudios

aleatorizados. E. Agencias reguladoras.

PRINCIPLE-TIMI 44: Efecto de IBP en la inhibiciòn plaquetaria (IPA)

Clopidogrel

- PPI (n=71)

+ PPI (n=28)

Prasugrel

- PPI (n=77)

+ PPI (n=25)

*P<0.05 90

80

70

60

50

40

30

20

10

0 0 4 8 12 16 20 24

18-24 h Hours After Loading Dose

6 h 2 h 0.5 h

Mea

n IP

A to

20

µM A

DP

(%)

*

*

* *

O’Donoghue et al., Lancet. 2009; 374: 989

50.0

0.0

18.2

0.0 0

10 20 30 40 50 60 70 80 90

100

PRINCIPLE-TIMI 44: Proporción de no respondedores tras 6h de dosis de carga N

onre

spon

ders

* Afte

r 6 H

ours

(%)

PPI (n=22)

No PPI (n=55)

PPI (n=19)

No PPI (n=53)

Clopidogrel 600 mg Loading Dose Prasugrel 60 mg Loading Dose

P=0.009

*Nonresponders defined as <20% IPA to 20µM ADP. O’Donoghue et al., Lancet. 2009; 374: 989

Prasugrel

No PPI n=4541

PPI n=2272

0 100 200 300 400

Clopidogrel

No PPI n=4538

PPI n=2257

TRITON-TIMI 38: Endpoints Primarios estratificados según el uso de IBP

CV

Dea

th, M

I or S

trok

e (%

)

Time (Days)

Clopidogrel PPI vs no PPI: Adjusted HR 0.94, 95% CI 0.80-1.11

PPI Use at Randomization (n=4529)

Prasugrel PPI vs no PPI: Adjusted HR 1.00, 95% CI 0.84-1.20

14

10

12

8

6

4

2

0

O’Donoghue et al., Lancet. 2009; 374: 989

TRITON-TIMI 38: Analisis de sensibilidad adicionales

n  No se observa asociación entre el uso de IBP y el riesgo de eventos CV -  From 0-3 and 0-30 days and in landmark analyses

from day 3, day 30, and 6 months onwards -  For patients consistently on a PPI (from start to end of

trial) -  Regardless of type of PPI or use of an H2 receptor

antagonist

O’Donoghue et al., Lancet. 2009; 374: 989

TRITON-TIMI 38: Análisis fármacogenetico

13,0

9,9 10,2

7,4

0

2

4

6

8

10

12

14

16

No PPI PPI No PPI PPI

Clopidogrel Prasugrel

CVD

, MI,

or S

trok

e Th

roug

h Lo

ng-te

rm F

ollo

w-u

p (%

)

Adjusted HR* 0.76 (95% CI 0.39-1.48)

Adjusted HR* 0.81 (95% CI 0.35-1.85)

Restricted to Patients with A Single Reduced Function CYP2C19 Allele

O’Donoghue et al., Lancet. 2009; 374: 989 *Adjusted for propensity to be treated with a PPI

30/237 12/120 24/250 9/122

Clopidogrel and the Optimization of GI EveNts Trial: COGENT study design

Bhatt et al. NEJM 2010

Clopidogrel + aspirin anticipated for a treatment period of at least 12 months due to •  acute coronary syndrome •  undergoing placement of a coronary stent

n = 3,200 → 4,200 → 5,000 patients (3627)

Stratification based on two baseline factors: •  H. pylori serology (positive or negative), and •  concomitant use of any NSAID

Clopidogrel 75 mg + Omeprazole 20 mg Clopidogrel 75 mg

HR=0.55 95% CI=0.36;0.85 P=0.007 (preliminary)

Clopidogrel: 67 events; 1895 at risk Clop+Omep: 38 events; 1878 at risk

Time (Days)

Surv

ival

Pro

babi

lity

0 30 60 90 120 150 180 210 240 270 300 330 360 390 0.90

0.92

0.94

0.96

0.98

1.00

Clopidogrel

Clopidogrel + Omeprazole

COGENT Trial –– Efecto de IBP en eventos GI compuestos*

Bhatt et al. TCT 2009

*GI endpoint was upper GI bleeding, bleeding of presumed occult GI origin with decrease in hb of ≥ 2 g/dL or decrease in hct ≥ 10%, symptomatic gastroduodenal ulcer confirmed by endoscopy or radiography, pain of presumed GI origin with underlying multiple erosive disease confirmed by endoscopy, obstruction, or perforation.

HR=1.02 95% CI=0.70;1.51

Clopidogrel: 67 events; 1821 at risk Clop+Omep: 69 events; 1806 at risk

Time (Days)

Surv

ival

Pro

babi

lity

0 30 60 90 120 150 180 210 240 270 300 330 360 390 0.90

0.92

0.94

0.96

0.98

1.00

*Composite of cardiovascular death, non-fatal MI, CABG or PCI, or ischemic stroke Bhatt et al. TCT 2009

Clopidogrel

Clopidogrel + Omeprazole

COGENT Trial –– Efecto de IBP en eventos CV compuestos*

Tasas de rehospitalizacion por Infartos o stenting en pacs con IBP y controles apareados

*Adjusted for Charlson comorbidity index score

Events per 100 person-years, n

Outcome Clopidogrel + PPI

Clopidogrel alone

Adjusted HR* (95% CI)

p

Hospitalization for MI 9.7 4.1 1.93 (1.05–3.54) 0.03

Hospitalization for MI or coronary stenting

27.6 14.3 1.64 (1.16–2.32) 0.005

Stockl et al., Arch Intern Med 2010; 170: 704

Eventos clínicos en pacs tras ICP según recibieran IBP o no

Harjai et al., ACC 2010

End point PPI (%) n=741

No PPI (%) n=1905

MACE 6.4 6.4

Death 2.8 2.5

MI 3.3 3.0

Death/MI 5.6 5.1

TVR 2.2 3.0

Stent thrombosis 1.8 1.5 MACE=Major adverse cardiovascular events (death, MI, TVR, or stent thrombosis) TVR=Target vessel revascularization

No significant impact on any of the outcomes of PPI prescription by propensity-adjusted multivariable analysis used to adjust for baseline variables

Otros

Frelinger, JACC 2012

A. Estudios plaquetarios INVITRO B. Datos clínicos de registros retrospectivos. C. Interacción IBP-Clopidogrel en estudios

aleatorizados D.  Meta-analisis, de registros y estudios

aleatorizados. E. Agencias reguladoras.

Meta-Analisis: Efecto de IBP en eventos CV y mortalidad en pacs recibiendo clopidogrel

Kwok & Loke, Aliment Pharmacol Ther 2010; 31: 810

23 Studies covering 93 278 patients

Type of study

•  20 Retrospective studies •  2 Post hoc analyses •  1 Prospective RCT

Reported endpoints

•  19 MACE •  12 Myocardial infarction •  13 Overall Mortality

IAM o SCA en pacs recibienco IBP y clopiodogrel

Kwok & Loke, Aliment Pharmacol Ther 2010; 31: 810

Unadjusted Observational Data

Observational Data Adjusted For Confounders

Data from propensity-matched or trial participants

Subtotal (95% CI) 23.1% 1.82 (0.90, 3.70)

Subtotal (95% CI) 37.7% 1.54 (1.23, 1.92)

Subtotal (95% CI) 39.1% 1.15 (0.89, 1.48)

Total (95% CI) 100.0% 1.43 (1.15, 1.77)

Mortalidad total con IBP y clopidogrel

Kwok & Loke, Aliment Pharmacol Ther 2010; 31: 810

Unadjusted Observational Data

Observational Data Adjusted For Confounders

Data from propensity-matched or trial participants

Subtotal (95% CI) 19.1% 1.41 (0.88, 2.26)

Subtotal (95% CI) 56.5% 1.04 (0.89, 1.22)

Subtotal (95% CI) 24.4% 1.00 (0.66, 1.53)

Total (95% CI) 100.0% 1.09 (0.94, 1.26)

Kwok & Loke, Aliment Pharmacol Ther 2010; 31: 810

Unadjusted Observational Data

Observational Data Adjusted For Confounders

Data from propensity-matched or trial participants

Subtotal (95%CI) 24.8% 1.17 (0.83, 1.63)

Subtotal (95%CI) 41.3% 1.44 (1.24, 1.67)

Subtotal (95%CI) 33.9% 1.07 (0.90, 1.28)

Total (95% CI) 100.0% 1.25 (1.09, 1.42)

MACE con IBP y clopidogrel

Otros…

?

A. Estudios plaquetarios INVITRO B. Datos clínicos de registros retrospectivos. C. Interacción IBP-Clopidogrel en estudios

aleatorizados D. Meta-analisis, de registros y estudios

aleatorizados. E.  Agencias reguladoras.

Zündorf & Dingermann, Pharm uZ 2009; 38: 360

Interacción Omeprazol – Clopidogrel: Inhibición de CYP2C19 ?

• New studies submitted by Sanofi-Aventis and Bristol-Myers Squibb •  Concomitant use of omeprazole and clopidogrel should be avoided: -  Clopidogrel's active metabolite levels -45% -  Antiplatelet effect of clopidogrel -47%

•  Separating the dose of clopidogrel and omeprazole in time will not reduce this drug interaction

• Other drugs that should be avoided in combination with clopidogrel because they may have a similar interaction include: esomeprazole cimetidine, CYP3A4 inhibitors and ticlopidine (Ticlid).

• No sufficient information about drug interactions between clopidogrel and PPIs other than omeprazole and esomeprazole.

•  There is no evidence that other drugs that reduce stomach acid, such as most H2 blockers ranitidine, famotidine, nizatidine, except cimetidine (a CYP2C19 inhibitor) or antacids interfere with the anti-clotting activity of clopidogrel.

EMEA Statement May 29, 2009:

“The product information for all clopidogrel-containing medicines should be amended to discourage concomitant use of PPIs unless absolutely necessary”

EMEA = European Medicines Agency.

http://www.ema.europa.eu/docs. Accedida 25 agosto 2012

}  Safety review sobre clopidogrel (1) ◦  Reevaluar añadir IBP: omeprazol y otros.

◦  No pruebas: AntiH2, antiacs interfieran con clopi.

}  Consenso expertos IBP y clopidogrel (2).

}  Últimas Guías SCASES AHA, 2012 (3). ◦  Misma actitud 2010.

1- FDA, 2009. 2- Abraham, Circulation 2010 3- Jneid, Circulation 2012.

}  Evalúa la necesidad de IBP. En algunos vale con anti H2 o

antiácidos. }  En la mayoría probablemente no sea importante. ◦  Estudios discordantes. ◦  Grupos (ancianos, diabéticos, CYP2C19 disminuida).

}  Considerar pantoprazol.

}  Separar las tomas (inh CYP2C19 transitoria).

◦  4 horas, al menos.

}  Otros antiplaquetarios? Futuro. Hoy No.