Autor: Dr. Iván Núñez. Antiagregantes e inhibidores de la bomba de protones: ¿mito o realidad?

1. Iván Núñez Gil.
Cardiología Intervencionista. HSCS.

2. } 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.

3. 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 bleeding
Dual 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

4. 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.
Pacientes,%

7. } 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.

8. } 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.

10. 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.

11. 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
S
O
N
S Cl
H COOCH3
Cl
H COOCH3
N
O
HO
SS
Cl
H COOCH3
N
O
HO
HS
N
S Cl
H COOH
SR26334
(Inactive in vitro)
85%

12. 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
S
O
N
S Cl
H COOCH3
Cl
H COOCH3
N
O
HO
SS
Cl
H COOCH3
N
O
HO
HS
Formación del metabolito activo de Clopidogrel

13. 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
RPAADP5µmol/L(%)
Trenk et al., J Am Coll Cardiol 2008; 51: 1925

14. 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

15. 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
Placebo
Omeprazole 20 mg
654 14083.2 83.9 39.8 51.4
VASPPRI(%)

16. 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
ADP-inducedAggregation,
AU·min

17. Kein
PPI
Pantoprazol
Lansoprazol
0
20
40
60
n=74 n=152 n=74
No PPI Pantoprazole Esomeprazole
ADP-inducedAggregation,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

18. 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.

19. 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

20. 1 10
1
2
3
0.5 5 20
Adjusted 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*

21. 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
Proportionof
DeathsorRecurrentACS
Neither clopidogrel nor PPI
PPI without clopidogrel
Clopidogrel + PPI
Clopidogrel without PPI)
Ho et al. JAMA 2009; 301: 937

22. 1
2
3
4
0
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
Everntrate,%
Outcomes Associated with Proton Pump Inhibitors and Clopidogrel in Patients
after ACS

23. 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

24. 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
OmeprazolePantoprazole
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<0.000129.2%Pantoprazole
HR 1.39 (1.16-1.67 ), p=0.000424.3%Lansoprazole
HR 1.57 (1.40-1.76 ), p<0.000124.9%Esomeprazole
HR 1.39 ( 1.22-1.57), p<0.000125.1%Omeprazole
Ref17.9%No PPI
1653
785
3257
2307
9862

25. 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.

26. 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 h2 h0.5 h
MeanIPAto20µMADP(%)
*
*
**
O’Donoghue et al., Lancet. 2009; 374: 989

27. 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
Nonresponders*After6Hours(%)
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

28. 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 IBPCVDeath,MIorStroke(%)
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

29. 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

30. TRITON-TIMI 38: Análisis fármacogenetico
13,0
9,910,2
7,4
0
2
4
6
8
10
12
14
16
No PPI PPI No PPI PPI
Clopidogrel Prasugrel
CVD,MI,orStrokeThrough
Long-termFollow-up(%)
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

31. 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

32. 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)
SurvivalProbability
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.

33. HR=1.02 95% CI=0.70;1.51
Clopidogrel: 67 events; 1821 at risk
Clop+Omep: 69 events; 1806 at risk
Time (Days)
SurvivalProbability
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*

34. 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

37. 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

38. Otros
Frelinger, JACC 2012

39. 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.

40. 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

41. 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)

42. 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)

43. 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

44. Otros…

45. ?

46. 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.

47. Zündorf & Dingermann, Pharm uZ 2009; 38: 360
Interacción Omeprazol – Clopidogrel: Inhibición de
CYP2C19 ?

48. • 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.

49. 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.

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

52. } 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.

53. } 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.