The Risk of CV Events for Patients Treated The Risk of CV Events for Patients Treated with Clopidogrel or Prasugrel in with Clopidogrel or Prasugrel in

Combination with a Proton Pump Inhibitor Combination with a Proton Pump Inhibitor

Results from the TRITON-TIMI 38 Trial Results from the TRITON-TIMI 38 Trial

M. O’Donoghue, S.D. Wiviott, E.M. Antman,

S.A. Murphy, C.F. Contant, E.R. Bates, Y. Rozenman,

J.L. Mega, M.S. Sabatine and E. Braunwald

Cardiovascular Division, Brigham and Women’s Hospital

DisclosuresDisclosures M. O’Donoghue: M. O’Donoghue: nonenone

S.D. Wiviott: S.D. Wiviott: Grants from Eli Lilly, Daiichi Sankyo, sanofi aventis, Schering Plough. Grants from Eli Lilly, Daiichi Sankyo, sanofi aventis, Schering Plough. Consulting or advisory board fees: Astra Zeneca, sanofi aventis. Honoraria from Eli Lilly, Consulting or advisory board fees: Astra Zeneca, sanofi aventis. Honoraria from Eli Lilly, Daiichi Sankyo, Astra Zeneca, Schering PloughDaiichi Sankyo, Astra Zeneca, Schering Plough

E.M. Antman: E.M. Antman: Grants from Eli Lilly, Daiichi Sankyo, sanofi aventis. Consulting or advisory Grants from Eli Lilly, Daiichi Sankyo, sanofi aventis. Consulting or advisory board feesboard fees from sanofi aventis. Lecture fees from Eli Lilly, sanofi aventisfrom sanofi aventis. Lecture fees from Eli Lilly, sanofi aventis

S.A. Murphy: S.A. Murphy: Research grants from Eli Lilly, Daiichi Sankyo. Consulting fees from Eli Lilly.Research grants from Eli Lilly, Daiichi Sankyo. Consulting fees from Eli Lilly.

E.R. Bates: E.R. Bates: Honoraria from Eli Lilly, Daiichi Sankyo, sanofi aventis, Bristol-Myers SquibbHonoraria from Eli Lilly, Daiichi Sankyo, sanofi aventis, Bristol-Myers Squibb

Y. Rozenman: Y. Rozenman: Consulting or lecture fees from Eli Lilly, sanofi aventis, Medtronic, Boston Consulting or lecture fees from Eli Lilly, sanofi aventis, Medtronic, Boston Scientific, Pfizer, Schering-PloughScientific, Pfizer, Schering-Plough

J.L. Mega: J.L. Mega: Grants from Eli Lilly, Daiichi Sankyo, Johnson & Johnson. Honoraria from Bayer Grants from Eli Lilly, Daiichi Sankyo, Johnson & Johnson. Honoraria from Bayer Healthcare.Healthcare.

M.S. Sabatine: M.S. Sabatine: Research grants from sanofi aventis and Astra Zeneca. Honoraria and/or Research grants from sanofi aventis and Astra Zeneca. Honoraria and/or consulting for sanofi aventis, Bristol-Myers Squibb, Astra Zeneca, Eli Lillyconsulting for sanofi aventis, Bristol-Myers Squibb, Astra Zeneca, Eli Lilly

E. Braunwald: E. Braunwald: Research grants and honoraria from Eli Lilly, Daiichi Sankyo. Research grants and honoraria from Eli Lilly, Daiichi Sankyo.

BackgroundBackground• PPIs are often administered with dual PPIs are often administered with dual

antiplatelet therapy for gastric protectionantiplatelet therapy for gastric protection

1 Gilard et al., J Am Coll Cardiol 2008

2 Sibbing et al., Thromb Haemost 2009

• Ex vivoEx vivo studies have shown diminished studies have shown diminished platelet inhibition in response to clopidogrel platelet inhibition in response to clopidogrel in the presence of a PPI in the presence of a PPI 1,1,2

3 Juurlink et al., CMAJ 2009

4 Ho et al., JAMA 2009

• Recent studies have raised concerns Recent studies have raised concerns that PPIs may attenuate the clinical that PPIs may attenuate the clinical benefit of clopidogrel benefit of clopidogrel 3,43,4

FDA and EMEA StatementsFDA and EMEA Statements

EMEA statement May 29, 2009EMEA statement May 29, 2009::

“The product information for all

clopidogrel-containing medicines

should be amended to discourage

concomitant use of PPIs unless

absolutely necessary”

NNSS

OO

ClCl

OO CHCH33CC

Clopidogrel

Pro-drugs

33

NNSS

OO

CCHHCC

OOFF

OO

Thienopyridines: Formation of Active MetaboliteThienopyridines: Formation of Active Metabolite

PrasugrelGutGut

Oxidation(Cytochrome P450)

Oxidation(Cytochrome P450)

ActiveMetabolite

HOOCHOOC HSHS

NN

OO

ClCl

OCHOCH33

CYPs:

1A2

2C19

2B6

CYPs:

3A

2C19

2C9

2B6

CHCH33

OONN

SS

OO

ClCl

OOCC

85% Inactive Metabolites

NNSS

OO

FFOO

HOOCHOOC HSHS

NN

OO

FF

CYPs:

3A

2B6

2C9

2C19

ActiveMetabolite

Hydrolysis(Esterases)

-

Proton pump

inhibitors

-

- ?

-

Primary AimPrimary Aim

To examine the association between

PPI use and the risk of CV events for

patients on either clopidogrel or

prasugrel

TITAN

ASAn= 13,608

Wiviott et al., NEJM 2007; 357: 2001-5

TRITON-TIMI 38TRITON-TIMI 38

0

5

10

15

0 90 180 270 360 450

HR 0.81(0.73-0.90)P=0.0004

Prasugrel

Clopidogrel

Days

En

dp

oin

t (%

)

12.1

9.9

HR 1.32(1.03-1.68)

P=0.03

Prasugrel

Clopidogrel1.82.4

1o EP: CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

TITAN

Wiviott et al., NEJM 2007; 357: 2001-5

TRITON-TIMI 38TRITON-TIMI 38

MethodsMethods PPI use was at the discretion of the treating

physician and captured on the case-report forms at each patient visit

Propensity scores were constructed to predict PPI use

Cox proportional hazards models included potential confounders and were stratified by propensity score strata

Primary and Secondary AnalysesPrimary and Secondary Analyses

PPI use at randomization

End of follow-up (median 14.5m)

TRITON-TIMI 38 Trial

3 day and 30 day follow-up

Landmark day 3

Landmark month 3

Landmark month 6

* All analyses were stratified by randomized treatment arm

Additional sensitivity analyses “Consistent” use of a PPI

(defined as patients who were taking a PPI at randomization to end of follow-up)

Use of different types of PPIs Use of a PPI or H2 receptor antagonist

PPI Use at RandomizationPPI Use at Randomizationn=4529, 33% of study populationn=4529, 33% of study population

Type of PPI Frequency

Pantoprazole 1844 (40%)

Omeprazole 1675 (37%)

Esomeprazole 613 (14%)

Lansoprazole 441 (9.7%)

Rabeprazole 66 (1.5%)

Baseline CharacteristicsBaseline CharacteristicsPPI usedPPI used

(n=4529)(n=4529)

No PPINo PPI

(n=9079)(n=9079)P valueP value

Age (median)Age (median) 61 y61 y 60 y60 y <0.001<0.001

MaleMale 72%72% 75%75% <0.001<0.001

Caucasian 94%94% 92%92% <0.001<0.001

Western Europe or North America 66%66% 54%54% <0.001<0.001

UA or NSTEMI 75%75% 73%73% 0.0070.007

Diabetes mellitusDiabetes mellitus 24% 23% 0.140.14

HypertensionHypertension 65% 64% 0.080.08

HyperlipidemiaHyperlipidemia 57% 55% 0.070.07

History peptic ulcer diseaseHistory peptic ulcer disease 9.7% 4.1% <0.001<0.001

Hemoglobin (g/dl)Hemoglobin (g/dl) 13.8 14.0 <0.001<0.001

CV

dea

th,

MI

or

stro

ke

Days

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

PPI use at randomization (n= 4529)

Clopidogrel

Primary endpoint stratified by use of a PPI

CV

dea

th,

MI

or

stro

ke

Days

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

PPI use at randomization (n= 4529)

Clopidogrel

Prasugrel

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

Primary endpoint stratified by use of a PPI

Clopidogrel Adj HR (95% CI)

Death, MI or stroke 0.94 (0.80-1.11)

CV death 0.71 (0.47-1.07)

MI 0.98 (0.82-1.17)

Stent thrombosis (ARC def/prob) 1.08 (0.75-1.55)

TIMI major or minor bleeding 1.13 (0.85-1.49)

Prasugrel

Death, MI or stroke 1.00 (0.84-1.20)

CV death 1.06 (0.70-1.62)

MI 1.02 (0.84-1.25)

Stent thrombosis (ARC def/prob) 1.03 (0.60-1.76)

TIMI major or minor bleeding 0.92 (0.71-1.18)

5.01.00.2

PPI use at randomization

Favors PPI PPI worse

Risk of CV events for patients Risk of CV events for patients “consistently” on a PPI“consistently” on a PPI

CV

dea

th,

MI

or

stro

ke

Days

Defined as: PPI used at randomization and end of f/u (n= 2814)

Patients exposed to PPI for shorter durations were censored (n=3882)

CLOPIDOGREL PPI vs no PPI: Adj HR 1.05, 95% CI 0.85-1.30

PRASUGREL PPI vs no PPI: Adj HR 1.10, 95% CI 0.88-1.39

Clopidogrel

Prasugrel

Short-term outcomes stratified by use of a PPIShort-term outcomes stratified by use of a PPIC

V d

eath

, M

I o

r st

roke

Days

Clopi - Adj HR 1.00 (0.80-1.27)

Pras - Adj HR 1.14 (0.88-1.46)

PPI use at randomization (n= 4529)

THROUGH 3 DAY FOLLOW-UP THROUGH 30 DAY FOLLOW-UP

Clopi - Adj HR 0.98 (0.80-1.21)

Pras - Adj HR 1.09 (0.87-1.37)

Clopi

Pras

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)

Additional sensitivity analysesAdditional sensitivity analyses

No association seen between PPI use and the risk of CV events for:

Use of a PPI or H2 receptor antagonist at randomization

Landmark analyses that captured PPI use at day 3, month 3 and month 6 after randomization

Landmark analyses to capture PPI use at different timepoints

LimitationsLimitations

Use of a PPI was not randomized, Use of a PPI was not randomized, thus there is the potential for thus there is the potential for residual confoundingresidual confounding

PPIs could be started or stopped PPIs could be started or stopped during the course of follow-upduring the course of follow-up

ConclusionConclusion

In TRITON-TIMI 38, PPI use was not associated with an increased risk of CV events for patients on clopidogrel or prasugrel

The current findings do not support the need to avoid concomitant use of PPIs in patients treated with thienopyridines

Available online at www.thelancet.com on September 1, 2009

THE LANCET