Proton Pump Inhibitor Use is Proton Pump Inhibitor Use is Likely a Marker for, Rather than a Likely a Marker for, Rather than a

Cause of, a Higher Risk of Cause of, a Higher Risk of Cardiovascular Events:Cardiovascular Events:

Insights from PLATOInsights from PLATOShaun G. Goodman, Robert Clare, Karen S. Pieper, Shaun G. Goodman, Robert Clare, Karen S. Pieper, Stefan K. James, José C. Nicolau, Robert F. Storey, Stefan K. James, José C. Nicolau, Robert F. Storey,

Warren J. Cantor, Dominick J. Angiolillo,Warren J. Cantor, Dominick J. Angiolillo,Steen Husted, Christopher P. Cannon,Steen Husted, Christopher P. Cannon,

Ph. Gabriel Steg, Kenneth W. Mahaffey,Ph. Gabriel Steg, Kenneth W. Mahaffey,Jan Kilhamn, Robert A. Harrington, Lars Wallentin, Jan Kilhamn, Robert A. Harrington, Lars Wallentin,

on behalf of the PLATO Trial Investigatorson behalf of the PLATO Trial Investigators

The PLATO trial was funded by AstraZenecaThe PLATO trial was funded by AstraZeneca

Shaun Goodman:Shaun Goodman:

Significant research grant support from Astra Zeneca, Bristol Significant research grant support from Astra Zeneca, Bristol Myers Squibb, Daiichi Sankyo, Lilly, Novartis, Sanofi AventisMyers Squibb, Daiichi Sankyo, Lilly, Novartis, Sanofi Aventis

Modest consultant/advisory board honoraria from Astra Modest consultant/advisory board honoraria from Astra Zeneca, Bristol Myers Squibb, Lilly, Merck, TevaZeneca, Bristol Myers Squibb, Lilly, Merck, Teva

Other Author Disclosure Information available in the Other Author Disclosure Information available in the abstract: abstract: CirculationCirculation 2010;122:A12092 2010;122:A12092

Ticagrelor is not yet approved for use Ticagrelor is not yet approved for use

Disclosures/Conflicts of InterestDisclosures/Conflicts of Interest

Conflicting data exist regarding the potential adverse Conflicting data exist regarding the potential adverse interaction between clopidogrel and proton pump interaction between clopidogrel and proton pump inhibitors (PPIs)inhibitors (PPIs)

PPIs inhibit the cytochrome P450 2C19 isoenzyme PPIs inhibit the cytochrome P450 2C19 isoenzyme and conversion of clopidogrel into its active and conversion of clopidogrel into its active metabolitemetabolite

In contrast, ticagrelor is an ADP P2YIn contrast, ticagrelor is an ADP P2Y1212 inhibitor that inhibitor that

does not require biotransformation and has no known does not require biotransformation and has no known interaction with PPIsinteraction with PPIs

ADP Receptor Antagonists and ADP Receptor Antagonists and Proton Pump InhibitorsProton Pump Inhibitors

To examine the association between proton To examine the association between proton pump inhibitor (PPI) use and clinical outcomes pump inhibitor (PPI) use and clinical outcomes for acute coronary syndrome (ACS) patients for acute coronary syndrome (ACS) patients randomized to clopidogrel or ticagrelorrandomized to clopidogrel or ticagrelor

ObjectiveObjective

PLATO Study Design

Primary endpoint: Primary endpoint: CV death + CV death + MI + StrokeMI + Stroke

Primary safety endpoint: Primary safety endpoint: Total major bleedingTotal major bleeding

6–12-month exposure6–12-month exposure

Clopidogrel (n=9291)Clopidogrel (n=9291)If pre-treated, no additional loading dose;If pre-treated, no additional loading dose;if naive, standard 300 mg loading dose,if naive, standard 300 mg loading dose,

then 75 mg qd maintenance;then 75 mg qd maintenance;(additional 300 mg allowed pre PCI)(additional 300 mg allowed pre PCI)

Ticagrelor (n=9333)Ticagrelor (n=9333)180 mg loading dose, then180 mg loading dose, then

90 mg bid maintenance;90 mg bid maintenance;(additional 90 mg pre-PCI)(additional 90 mg pre-PCI)

NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)Clopidogrel-treated or -naive;Clopidogrel-treated or -naive;

randomised within 24 hours of index event randomised within 24 hours of index event (N=18,624)(N=18,624)

James et al James et al Am Heart J Am Heart J 2009;157:599-6052009;157:599-605

PLATO Main Endpoints

No. at riskNo. at risk

ClopidogrelClopidogrel

TicagrelorTicagrelor

9,2919,291

9,3339,333

8,5218,521

8,6288,628

8,3628,362

8,4608,460

8,1248,124

MonthsMonths

6,6506,650

6,7436,743

5,0965,096

5,1615,161

4,0474,047

4,1474,1478,2198,219

00 22 44 66 88 1010 1212

1212

1111

1010

99

88

77

66

55

44

33

22

11

00

1313

K-M

est

imat

ed r

ate

(%

per

yea

r)K

-M e

stim

ated

rat

e (

% p

er y

ear)

9.89.8

11.711.7

HR 0.84 (95% CI HR 0.84 (95% CI 0.77–0.92), 0.77–0.92), p=0.0003p=0.0003

ClopidogrelClopidogrel

TicagrelorTicagrelor

00 22 44 66 88 1010 1212

1010

55

00

1515

ClopidogrelClopidogrel

TicagrelorTicagrelor

11.211.211.611.6

HR 1.04 (95% CI HR 1.04 (95% CI 0.95–1.13), 0.95–1.13),

p=0.43p=0.43

K-M

est

imat

ed r

ate

(%

per

yea

r)K

-M e

stim

ated

rat

e (

% p

er y

ear)

MonthsMonths

Major BleedingMajor BleedingCV Death, MI, StrokeCV Death, MI, Stroke

9,1869,186

9,2359,235

7,3057,305

7,2467,246

6,9306,930

6,8266,826

6,6706,670 5,2095,209

5,1295,129

3,8413,841

3,7833,783

3,4793,479

3,4333,4336,5456,545

Wallentin et al Wallentin et al N Engl J Med N Engl J Med 2009;361:1045-572009;361:1045-57

Pre-specified subgroup analysisPre-specified subgroup analysis

Proton pump inhibitor use was at the physician’s Proton pump inhibitor use was at the physician’s discretiondiscretion

Multivariable Cox model with propensity adjustment Multivariable Cox model with propensity adjustment and landmark analysisand landmark analysis

The primary endpoint was the 1-year composite of CV The primary endpoint was the 1-year composite of CV death, MI, or strokedeath, MI, or stroke

MethodsMethods

Primary and Secondary AnalysesPrimary and Secondary Analyses

PPI use at randomization

End of follow-upMedian Time to

Death/Censoring (IQR) = 358 Days (266, 369)

PLATO Trial

All analyses were stratified by randomized treatment armAll analyses were stratified by randomized treatment arm

Landmark Day 60

Landmark Day 180

Landmark Days 2, 4, 9, 30

Landmark Day 90

Any PPI vs. Non-PPI Gastric Supressive Any PPI vs. Non-PPI Gastric Supressive (e.g., H(e.g., H22 antagonist) therapy antagonist) therapyAny PPI vs. no GI therapyAny PPI vs. no GI therapy

PPI Use at Randomization

Type of PPI*Type of PPI* Frequency (%)*Frequency (%)*

OmeprazoleOmeprazole 3200 (17)3200 (17)

PantoprazolePantoprazole 1967 (11)1967 (11)

EsomeprazoleEsomeprazole 764 (4)764 (4)

LansoprazoleLansoprazole 510 (3)510 (3)

RabeprazoleRabeprazole 97 (<1)97 (<1)

18601 of 18624 (99.9%) patients had documentation 18601 of 18624 (99.9%) patients had documentation regarding PPI use prior to randomizationregarding PPI use prior to randomization

→ → 6539 (35.2%) were taking a PPI6539 (35.2%) were taking a PPI

* Type of PPI available * Type of PPI available in n=6538in n=6538

Selected Baseline and Index Event CharacteristicsSelected Baseline and Index Event Characteristics

CharacteristicNo PPI

(n=12,060) PPI

(n=6539)

Median age, years 62 63

Age ≥75 years, % 15 17

History, % Dyslipidemia Chronic renal disease Peripheral arterial disease

453.85.8

505.16.8

Peptic ulcer Percutaneous coronary intervention Coronary-artery bypass grafting Congestive heart failure Chronic obstructive pulmonary disease

0.9125.45.75.3

2.4156.94.66.8

ECG at entry, % ST-segment depression 52 49

Troponin-I positive, % Baseline hemoglobin, medianTIMI Risk Score, % ST Elevation MI, ≥3 Non-ST Elevation ACS, ≥5GRACE Risk of In-Hospital Death, median %

82141

4342

1.66

86138

4747

1.71

All p<0.05All p<0.05

Primary Outcome by Randomized Treatment and PPI UsePrimary Outcome by Randomized Treatment and PPI Use

00

22

44

66

88

1010

1212

1414

00 5050 100100 150150 200200 250250 300300 350350 400400

DaysDays

9.199.19

10.9210.9210.9610.96

13.0313.03

Clopidogrel + PPI (n=3255)Ticagrelor + PPI (n=3284)Clopidogrel + No PPI (n=6020)Ticagrelor + No PPI (n=6040)

% of Patients with CV Death/MI/Stroke% of Patients with CV Death/MI/Stroke

Unadjusted and Adjusted* Cardiovascular Outcomes by Unadjusted and Adjusted* Cardiovascular Outcomes by Randomized Treatment and PPI UseRandomized Treatment and PPI Use

Hazard Ratio & 95% CIHazard Ratio & 95% CI

0.80.8 1.21.2 1.61.6No PPI No PPI BetterBetter

PPI PPI WorseWorse

1.41.41.01.0

Cardiovascular Cardiovascular Death, MI or Death, MI or

StrokeStroke

UnadjustedUnadjustedTicagrelorTicagrelor 1.23 (1.07,1.41)1.23 (1.07,1.41)

ClopidogrelClopidogrel 1.22 (1.08,1.39)1.22 (1.08,1.39)+ + PPP2Y12 *P2Y12 * PPIPPI

0.960.96

*Propensity *Propensity AdjustedAdjusted

ClopidogrelClopidogrel 1.20 (1.04,1.38)1.20 (1.04,1.38)

TicagrelorTicagrelor 1.24 (1.06,1.45)1.24 (1.06,1.45)0.720.72

Cardiovascular Cardiovascular Death or MIDeath or MI *Propensity *Propensity

AdjustedAdjusted

ClopidogrelClopidogrel 1.20 (1.03,1.40)1.20 (1.03,1.40)

TicagrelorTicagrelor 1.26 (1.07,1.48)1.26 (1.07,1.48)

UnadjustedUnadjustedTicagrelorTicagrelor 1.24 (1.08,1.44)1.24 (1.08,1.44)

ClopidogrelClopidogrel 1.27 (1.11,1.45)1.27 (1.11,1.45)

0.840.84

0.940.94

++ P2Y12 inhibitor Treatment * PPI interaction P-value P2Y12 inhibitor Treatment * PPI interaction P-value

ClopidogrelClopidogrel

00

11

22

33

44

55

66% of Patients% of Patients

4.394.39

3.433.43

4.904.90

4.244.24

TicagrelorTicagrelor

1-Year Non-CABG PLATO Major Bleeding* 1-Year Non-CABG PLATO Major Bleeding* by Randomized Treatment and PPI Use by Randomized Treatment and PPI Use

* Kaplan-Meier estimates * Kaplan-Meier estimates + + Propensity-adjusted Propensity-adjusted

PPIPPI No PPINo PPI PPIPPI No PPINo PPI

++Hazard Ratio Hazard Ratio 1.30 (95% CI 1.30 (95% CI

1.00-1.70)1.00-1.70)

++Hazard Ratio Hazard Ratio 1.02 (95% CI 1.02 (95% CI

0.80-1.29)0.80-1.29)

PPinteraction for P2Y12 *interaction for P2Y12 * PPIPPI=0.17=0.17

Patients (n=1826) on non-PPI gastrointestinal drugs (e.g. HPatients (n=1826) on non-PPI gastrointestinal drugs (e.g. H22

receptor antagonists) prior to randomization were at similar receptor antagonists) prior to randomization were at similar risk to those on a PPIrisk to those on a PPI Clopidogrel:Clopidogrel: HR 0.98 (0.79-1.23)HR 0.98 (0.79-1.23) Ticagrelor:Ticagrelor: HR 0.89 (0.73-1.10)HR 0.89 (0.73-1.10)

Patients (n=10236) on no gastric therapy were at significantly Patients (n=10236) on no gastric therapy were at significantly lower risk of the primary endpointlower risk of the primary endpoint Clopidogrel:Clopidogrel: HR 1.29 (1.12-1.49)HR 1.29 (1.12-1.49) Ticagrelor:Ticagrelor: HR 1.30 (1.14-1.49)HR 1.30 (1.14-1.49)

Landmark analyses accounting for PPI use (at days 2, 4, 9, 30, Landmark analyses accounting for PPI use (at days 2, 4, 9, 30, 60, 90, and 180) post-randomization showed no increased risk 60, 90, and 180) post-randomization showed no increased risk of the primary endpoint in those receiving a PPIof the primary endpoint in those receiving a PPI

Except in patients who Except in patients who prematurelyprematurely discontinued study treatment discontinued study treatment (clopidogrel or ticagrelor) from day 180 post-randomization (PPI vs. no (clopidogrel or ticagrelor) from day 180 post-randomization (PPI vs. no PPI: HR 4.31 [1.70-10.95])PPI: HR 4.31 [1.70-10.95])

Additional AnalysesAdditional Analyses

PPI vs. non PPI PPI vs. non PPI GI treatmentGI treatment

PPI vs. no GI PPI vs. no GI treatmenttreatment

Pre-defined subgroup analysis with multiple comparisons Pre-defined subgroup analysis with multiple comparisons → individual subgroups may have been underpowered to → individual subgroups may have been underpowered to show an association between PPI use and clinical show an association between PPI use and clinical outcomesoutcomes

Use of a PPI was not randomized → potential for residual Use of a PPI was not randomized → potential for residual confounding despite multivariable adjustment and confounding despite multivariable adjustment and propensity score for the decision to treat with a PPIpropensity score for the decision to treat with a PPI

PPIs could be initiated or discontinued during the course PPIs could be initiated or discontinued during the course of follow-up → landmark analyses employedof follow-up → landmark analyses employed

Different types of PPIs with potentially different effects on Different types of PPIs with potentially different effects on CYP2C19 and clopidogrel metabolismCYP2C19 and clopidogrel metabolism

LimitationsLimitations

The apparent association between PPI and The apparent association between PPI and clopidogrel use and adverse events is highly clopidogrel use and adverse events is highly confoundedconfounded

PPI use may simply be a marker for, rather than a PPI use may simply be a marker for, rather than a cause of, a higher risk of CV eventscause of, a higher risk of CV events

Regardless of PPI use, ticagrelor was superior to Regardless of PPI use, ticagrelor was superior to clopidogrel in preventing ischemic eventsclopidogrel in preventing ischemic events

ConclusionsConclusions