Combined Use of Oral Antiplatelet Agents and Gastroprotective Agents: Focus on PPIs and Clopidogrel...
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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