Combined Use of Oral Antiplatelet Combined Use of Oral Antiplatelet Agents and Gastroprotective Agents:Agents and Gastroprotective Agents:

Focus on PPIs and ClopidogrelFocus on PPIs and Clopidogrel 

Deepak L. Bhatt MD, MPH, FACC, FAHADeepak L. Bhatt MD, MPH, FACC, FAHAChief of Cardiology, VA Boston Healthcare SystemChief of Cardiology, VA Boston Healthcare System

Director, Integrated Interventional Cardiovascular Program at Brigham and Director, Integrated Interventional Cardiovascular Program at Brigham and Women’s Hospital and the VA Boston Healthcare SystemWomen’s Hospital and the VA Boston Healthcare System

Senior Investigator, TIMI Study GroupSenior Investigator, TIMI Study GroupHarvard Medical SchoolHarvard Medical School

ADP ReceptorsADP Receptors

Bhatt DL et al. Nature Reviews Drug Discovery 2003; 2:15-28.Bhatt DL et al. Nature Reviews Drug Discovery 2003; 2:15-28.

CREDO: Long-Term (1 Year) Benefits of CREDO: Long-Term (1 Year) Benefits of Clopidogrel in PCI PatientsClopidogrel in PCI Patients

MI, stroke, or death – ITT populationMI, stroke, or death – ITT population

* Plus ASA and other standard therapies.* Plus ASA and other standard therapies.

Steinhubl S, Berger P, Tift Mann III J et al. Steinhubl S, Berger P, Tift Mann III J et al. JAMAJAMA. 2002;Vol 288,No 19:2411-2420.. 2002;Vol 288,No 19:2411-2420.

Co

mb

ined

en

dp

oin

t C

om

bin

ed e

nd

po

int

occ

urr

ence

(%

)o

ccu

rren

ce (

%)

Months from randomizationMonths from randomization

27% RRR27% RRRPP=0.02=0.02

Placebo*Placebo*Clopidogrel*Clopidogrel*

00

55

1010

1515

8.5%8.5%

11.5%11.5%

00 33 66 99 1212

Multivariable Predictors of Bleeding EventsMultivariable Predictors of Bleeding EventsDischarge to 1 Year (n=1816)Discharge to 1 Year (n=1816)

Aronow HD, et alAronow HD, et al. Am Heart J . Am Heart J 2008 (published online Nov 2008)2008 (published online Nov 2008)

VariableVariable Hazard Ratio Hazard Ratio (95% CI)(95% CI) XX22 P valueP value

ClopidogrelClopidogrel 1.04 (0.75-1.44)1.04 (0.75-1.44) 0.050.05 0.820.82

Age (per 10 Age (per 10 years)years) 1.26 (1.07-1.48)1.26 (1.07-1.48) 8.18.1 0.0050.005

CABG discharge-CABG discharge-1 year1 year

32.15 (23.10-32.15 (23.10-44.74)44.74) 423.6423.6 <0.0001<0.0001

Kaplan Meier Estimates of Bleeding RiskKaplan Meier Estimates of Bleeding RiskDischarge to 1 Year (n=1816)Discharge to 1 Year (n=1816)

Variable

Placebo (n=914) Clopidogrel (n=902) p value

Any (major + minor) 71 (8.1%) 77 (8.9%) 0.60 Non-procedural 13 (1.5%) 15(1.7%) 0.69 Procedural 59(6.7%) 62 (7.1%) 0.76

CABG* 41 (4.7%) 41 (4.8%) 1.0 Non-CABG* 18 (2.0%) 21 (2.4%) 0.60

Major 34 (3.9%) 49 (5.6%) 0.09 Non-procedural 7 (0.8%) 11 (1.3%) 0.34

ICH 0 0 - GI 3 (0.3%) 10 (1.1%) 0.049 RPB 0 0 - Access site 0 0 - Other 4 (0.4%) 1 (0.1%) 0.37

Procedural 27 (3.1%) 38 (4.4%) 0.16 CABG* 23 (2.5%) 28 (3.1%) 0.48

ICH 0 0 - GI 0 0 - RPB 0 0 - Access site 0 0 - Other 23 (2.5%) 28 (3.1%) 0.45

Non-CABG* 4 (0.5%) 10 (1.1%) 0.10 ICH 0 0 - GI 0 3 (0.3%) 0.12 RPB 1 (0.1%) 0 1.0 Access site 0 1 (0.1%) 0.50 Other 3 (0.3%) 6 (0.7%) 0.34

Minor 37 (4.2%) 29 (3.3%) 0.34 Non-procedural 6 (0.7%) 5 (0.6%) 0.78 Procedural 32 (3.6%) 24 (2.8%) 0.29

CABG* 18 (2.1%) 13 (1.5%) 0.38 Non-CABG* 14 (1.6%) 11 (1.3%) 0.57

Timing of Severe or Moderate BleedingTiming of Severe or Moderate Bleeding

Placebo + ASA

Clopidogrel + ASA

Days Since RandomizationDays Since Randomization

15 60 135 270 450 630 810

0.00008

0.00007

0.00006

0.00005

0.00004

0.00003

0.00002

0.00001

0

Haz

ard

Fun

ctio

n/d

Haz

ard

Fun

ctio

n/d

Bhatt DL, Flather MD, Hacke W, et al.Bhatt DL, Flather MD, Hacke W, et al. J Am Coll Cardiol. J Am Coll Cardiol. 2007;49:1982-1988. 2007;49:1982-1988.

Algorithm to Assess GI Risk Algorithm to Assess GI Risk With Antiplatelet TherapyWith Antiplatelet Therapy

YesYes

Yes

NoNoPPI

YesYes

YesYes

Bhatt DL, Scheiman J, Abraham NS, et al. Circulation 2008.

Need for antiplatelet therapy

Assess GI risk factors

Test for H pylori; treat if infected

History of ulcer complication History of ulcer disease (nonbleeding)

Dual antiplatelet therapyConcomitant anticoagulant

More than one risk factor:Aged 60 years or more

Corticosteroid useDyspepsia or GERD symptoms

Clopidogrel is a prodrug; requires conversion by the liver primarily Clopidogrel is a prodrug; requires conversion by the liver primarily via CYP3A4 and CYP2C19 to an active metabolitevia CYP3A4 and CYP2C19 to an active metabolite

PPIs are strong inhibitors of CYP2C19 activityPPIs are strong inhibitors of CYP2C19 activity

Clopidogrel and PPIs – The OCLA studyClopidogrel and PPIs – The OCLA study

PRI: Platelet Reactivity Index as measured by vasodilator stimulated phosphoprotein (VASP)

Gilard et al. J Am Coll Cardiol 2008;51:256-60.

p<0.0001

Intake of PPIs Not Associated With Impaired Response to Clopidogrel

Siller-Matula JM, et al. Siller-Matula JM, et al. Am Heart J. Am Heart J. 2009;157(1):148.e1-148.e5.2009;157(1):148.e1-148.e5.

Platelet reactivity index in the VASP phosphorylation Platelet reactivity index in the VASP phosphorylation assay in patients on clopidogrel with or without PPI: assay in patients on clopidogrel with or without PPI: pantoprazole or esomeprazole.pantoprazole or esomeprazole.

Adenosine diphosphateAdenosine diphosphate––induced platelet induced platelet aggregation in patients on clopidogrel with or aggregation in patients on clopidogrel with or without PPI: pantoprazole or esomeprazole.without PPI: pantoprazole or esomeprazole.

Data are presented as mean and 95% CI. PPI, proton pump inhibitor; Data are presented as mean and 95% CI. PPI, proton pump inhibitor; VASP, vasodilator-stimulated phosphoprotein.VASP, vasodilator-stimulated phosphoprotein.

Variability in Clopidogrel Responsiveness in a Diverse Population of 544

Serebruany V, Steinhubl S et al. JACC 2005.Serebruany V, Steinhubl S et al. JACC 2005.

M ADP Platelet AggregationM ADP Platelet Aggregation

Genetic Variations and Clopidogrel ResponseGenetic Variations and Clopidogrel Response

Mega JL, Close SL, Wiviott SD, et alMega JL, Close SL, Wiviott SD, et al. . N Engl J Med.N Engl J Med. 2009;360:354-362. 2009;360:354-362.

Gene

Percent Difference in

AUC0-t P Value

CYP2C19 −32.4 .001CYP2C9 −6.8 .59

CYP2B6 −15.7 .03

CYP3A5 5.6 .59CYP1A2 11.2 .45

Pharmacokinetic ResponsePharmacokinetic Response

Relative Percent DifferenceRelative Percent Difference-50 -40 -30 -20 -10 0 10 20 30

Pharmacodynamic ResponsePharmacodynamic Response

Gene

Percent Difference in

ΔMPA P ValueCYP2C19CYP2C19 −−9.09.0 .001.001

CYP2C9CYP2C9 −−0.60.6 .86.86

CYP2B6CYP2B6 −−5.75.7 .012.012

CYP3A5CYP3A5 7.57.5 .012.012

CYP1A2CYP1A2 0.50.5 .90.90

Absolute DifferenceAbsolute Difference-15 -10 -5 0 5 10 25

Risk of All-Cause Mortality and Recurrent ACS in Patients Taking Clopidogrel and PPI

Ho PM, et al. Ho PM, et al. JAMAJAMA. 2009;301(9):937-944.. 2009;301(9):937-944.

0.70

0.60

0.50

0.40

0.30

0.20

0.10

00 90 180 270 360 450 540 630 720 810 900 990 1080

Days Since DischargeDays Since Discharge

Pro

port

ion

of

Pro

port

ion

of

Dea

ths

or R

ecur

rent

AC

SD

eath

s or

Rec

urre

nt A

CS

Neither clopidogrel nor PPINeither clopidogrel nor PPIPPI without clopidogrelPPI without clopidogrelClopidogrel + PPIClopidogrel + PPIClopidogrel without PPIClopidogrel without PPI

Risk of Adverse Outcomes Following Hospital Discharge With Concomitant Use of Clopidogrel Plus PPI

Primary outcomePrimary outcome Death or rehospitalization for ACSDeath or rehospitalization for ACS

Secondary outcomesSecondary outcomes Rehospitalization for ACSRehospitalization for ACS

Revascularization proceduresRevascularization procedures

Death (all-cause)Death (all-cause)

0 1 2 3 0 1 2 3

Unadjusted OR Unadjusted OR (95% CI)(95% CI)

Adjusted OR Adjusted OR (95% CI)(95% CI)OutcomeOutcome

With PPIWith PPIWithout PPIWithout PPI With PPIWith PPIWithout PPIWithout PPI

Ho PM, et al. Ho PM, et al. JAMAJAMA. 2009;301(9):937-944.. 2009;301(9):937-944.

14.816.2

13.2

9.29.210.810.8

7.77.7

00

55

1010

1515

2020

PPI at baseline (N=374)PPI at baseline (N=374)

No PPI at baseline (N=1742)No PPI at baseline (N=1742)

Primary 1-Year Endpoint:Primary 1-Year Endpoint:Death, MI or StrokeDeath, MI or Stroke

AllAllN=2116N=2116

PlaceboPlaceboN=1063N=1063

ClopidogrelClopidogrelN=1053N=1053

Results – 1 Year Endpoint from CREDOResults – 1 Year Endpoint from CREDOUnadjusted DataUnadjusted Data

P=0.001P=0.001

P=0.45P=0.45

Dunn S.P. et al AHA 2008. Slide courtesy of Steve Steinhubl MDDunn S.P. et al AHA 2008. Slide courtesy of Steve Steinhubl MD

28 Days Death/MI/

UTVR

Adjusted OR (95% CI)

p-value*

One Year Death/MI/

Stroke

Adjusted HR (95% CI)

p-value†

Clopidogrel / PPI(n=179)

18/179 (10.2)

1.8 (0.99, 3.23)

0.051

23/179 (13.2)

1.6 (1.02, 2.63)

0.043Clopidogrel / No PPI(n=874)

47/874 (5.4)

66/874 (7.7)

* Multivariate logistic regression model: PPI vs. no PPI within treatment stratum† Multivariate Cox proportional hazard model: PPI vs. no PPI within treatment stratum

Results – Clopidogrel GroupResults – Clopidogrel GroupAdjusted DataAdjusted Data

Dunn S.P. et al AHA 2008. Slide courtesy of Steve Steinhubl MDDunn S.P. et al AHA 2008. Slide courtesy of Steve Steinhubl MD

28 Days Death/MI/

UTVR

Adjusted OR (95% CI)

p-value*

One Year Death/MI/

Stroke

Adjusted HR (95% CI)

p-value†

Placebo / PPI(n=195)

19/195 (9.8)

1.4 (0.81, 2.41)

0.221

31/195 (16.2)

1.6 (1.03, 2.34)

0.035Placebo / No PPI(n=868)

64/868 (7.4)

91/868 (10.8)

* Multivariate logistic regression model: PPI vs. no PPI within treatment stratum† Multivariate Cox proportional hazard model: PPI vs. no PPI within treatment stratum

Results – Placebo GroupResults – Placebo GroupAdjusted DataAdjusted Data

Dunn S.P. et al AHA 2008. Slide courtesy of Steve Steinhubl MDDunn S.P. et al AHA 2008. Slide courtesy of Steve Steinhubl MD

Results – 1 Year Primary Endpoint Results – 1 Year Primary Endpoint

Randomized Randomized TherapyTherapy

Death, MI Death, MI or Strokeor Stroke

Adjusted HR Adjusted HR (95% CI)(95% CI)

P-valueP-value

Placebo Placebo (N=195)(N=195) 16.2%16.2%

0.77 0.77 (0.45, 1.33)(0.45, 1.33) 0.350.35

Clopidogrel (N=179)

13.2%

Randomized Randomized TherapyTherapy

Death, MI Death, MI or Strokeor Stroke

Adjusted HR Adjusted HR (95% CI)(95% CI)

P-valueP-value

Placebo Placebo (N=868)(N=868) 10.8%10.8%

0.750.75(0.55, 1.03)(0.55, 1.03) 0.080.08

Clopidogrel (N=874)

7.7%

PPI at Baseline

No PPI at Baseline

P-value for P-value for interaction interaction between between randomized randomized therapy and therapy and baseline PPIbaseline PPIP=0.69P=0.69

Dunn S.P. et al AHA 2008. Slide courtesy of Steve Steinhubl MDDunn S.P. et al AHA 2008. Slide courtesy of Steve Steinhubl MD

THE LANCET

CV

dea

th,

MI

or s

trok

eC

V d

eath

, M

I or

str

oke

DaysDays

CLOPIDOGREL CLOPIDOGREL PPI vs no PPI: Adj HR 0.94, 95% CI 0.80-1.11PPI vs no PPI: Adj HR 0.94, 95% CI 0.80-1.11

PPI use at randomization (n= 4529)

Clopidogrel

Prasugrel

PRASUGRELPRASUGREL PPI vs no PPI: Adj HR 1.00, 95% CI 0.84-1.20PPI vs no PPI: Adj HR 1.00, 95% CI 0.84-1.20

Primary endpoint stratified by use of a PPI

Type of PPIClopidogrel

HR (95% CI)CV death, MI or stroke

PrasugrelHR (95% CI)

CV death, MI or stroke

Omeprazole

(n=1675)0.91 (0.72-1.15) 1.04 (0.81-1.34)

Pantoprazole

(n=1844)0.94 (0.74-1.18) 1.09 (0.86-1.39)

Esomeprazole

(n=613)1.07 (0.75-1.52) 0.86 (0.55-1.33)

Lansoprazole

(n=441)1.00 (0.63-1.59) 0.98 (0.61-1.57)

Risk of CV Events with Different Types of PPIsRisk of CV Events with Different Types of PPIs

Rabeprazole not included due to small sample size (n=66)

Clopidogrel and the Optimization of GI Events Trial – COGENT

Conclusions

► Dual antiplatelet therapy reduces important ischemic events Dual antiplatelet therapy reduces important ischemic events after PCI, ACSafter PCI, ACS

► GI bleeding is the most common form of major bleeding that GI bleeding is the most common form of major bleeding that occursoccurs

► Logical, though not proved, that prophylactic PPI reduces this Logical, though not proved, that prophylactic PPI reduces this GI bleeding GI bleeding

► Patients prescribed PPI are a higher risk than those who are Patients prescribed PPI are a higher risk than those who are notnot

► While pathways for an interaction exist, unclear degree of While pathways for an interaction exist, unclear degree of clinical relevanceclinical relevance