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Proton Pump Inhibitor Use is Likely a Marker for, Rather than a Cause of, a Higher Risk of Cardiovascular Events: Insights from PLATO. Shaun G. Goodman, Robert Clare, Karen S. Pieper, Stefan K. James, José C. Nicolau, Robert F. Storey, Warren J. Cantor, Dominick J. Angiolillo,

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slide1
Proton Pump Inhibitor Use is Likely a Marker for, Rather than a Cause of, a Higher Risk of Cardiovascular Events:

Insights from PLATO

Shaun G. Goodman, Robert Clare, Karen S. Pieper, Stefan K. James, José C. Nicolau, Robert F. Storey, Warren J. Cantor, Dominick J. Angiolillo,

Steen Husted, Christopher P. Cannon,

Ph. Gabriel Steg, Kenneth W. Mahaffey,

Jan Kilhamn, Robert A. Harrington, Lars Wallentin, on behalf of the PLATO Trial Investigators

slide2
Disclosures/Conflicts of Interest
  • The PLATO trial was funded by AstraZeneca
  • Shaun Goodman:
    • Significant research grant support from Astra Zeneca, Bristol Myers Squibb, Daiichi Sankyo, Lilly, Novartis, Sanofi Aventis
    • Modest consultant/advisory board honoraria from Astra Zeneca, Bristol Myers Squibb, Lilly, Merck, Teva
  • Other Author Disclosure Information available in the abstract: Circulation 2010;122:A12092
  • Ticagrelor is not yet approved for use
slide3
ADP Receptor Antagonists and Proton Pump Inhibitors
  • Conflicting data exist regarding the potential adverse interaction between clopidogrel and proton pump inhibitors (PPIs)
  • PPIs inhibit the cytochrome P450 2C19 isoenzyme and conversion of clopidogrel into its active metabolite
  • In contrast, ticagrelor is an ADP P2Y12 inhibitor that does not require biotransformation and has no known interaction with PPIs
slide4
Objective
  • To examine the association between proton pump inhibitor (PPI) use and clinical outcomes for acute coronary syndrome (ACS) patients randomized to clopidogrel or ticagrelor
plato study design
PLATO Study Design

NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)

Clopidogrel-treated or -naive;

randomised within 24 hours of index event

(N=18,624)

Ticagrelor (n=9333)

180 mg loading dose, then

90 mg bid maintenance;

(additional 90 mg pre-PCI)

Clopidogrel (n=9291)

If pre-treated, no additional loading dose;

if naive, standard 300 mg loading dose,

then 75 mg qd maintenance;

(additional 300 mg allowed pre PCI)

6–12-month exposure

Primary endpoint: CV death + MI + Stroke

Primary safety endpoint: Total major bleeding

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

plato main endpoints
PLATO Main Endpoints

Major Bleeding

CV Death, MI, Stroke

13

15

12

11.7

Clopidogrel

11

Ticagrelor

11.6

10

9.8

11.2

9

10

Clopidogrel

Ticagrelor

8

7

K-M estimated rate (% per year)

K-M estimated rate (% per year)

6

5

HR 0.84 (95% CI 0.77–0.92), p=0.0003

HR 1.04 (95% CI 0.95–1.13), p=0.43

5

4

3

2

1

0

0

0

2

4

6

8

10

12

0

2

4

6

8

10

12

Months

Months

No. at risk

9,235

7,246

6,826

6,545

5,129

3,783

3,433

Ticagrelor

9,333

8,628

8,460

8,219

6,743

5,161

4,147

9,186

7,305

6,930

6,670

5,209

3,841

3,479

Clopidogrel

9,291

8,521

8,362

8,124

6,650

5,096

4,047

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

slide7
Methods
  • Pre-specified subgroup analysis
  • Proton pump inhibitor use was at the physician’s discretion
  • Multivariable Cox model with propensity adjustment and landmark analysis
  • The primary endpoint was the 1-year composite of CV death, MI, or stroke
slide8
Primary and Secondary Analyses

End of follow-up

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

Landmark

Days 2, 4, 9, 30

Landmark

Day 60

Landmark

Day 90

Landmark

Day 180

PLATO Trial

  • Any PPI vs. Non-PPI Gastric Supressive (e.g., H2 antagonist) therapy
  • Any PPI vs. no GI therapy

PPI use at randomization

All analyses were stratified by randomized treatment arm

ppi use at randomization
PPI Use at Randomization

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

→ 6539 (35.2%) were taking a PPI

* Type of PPI available in n=6538

slide11
Primary Outcome by Randomized Treatment and PPI Use

% of Patients with CV Death/MI/Stroke

14

13.03

12

10.96

10.92

10

9.19

8

6

Clopidogrel + PPI (n=3255)

Ticagrelor + PPI (n=3284)

Clopidogrel + No PPI (n=6020)

Ticagrelor + No PPI (n=6040)

4

2

0

0

50

100

150

200

250

300

350

400

Days

slide12
Unadjusted and Adjusted* Cardiovascular Outcomes by Randomized Treatment and PPI Use

Hazard Ratio & 95% CI

+ PP2Y12 *PPI

Clopidogrel

1.22 (1.08,1.39)

0.96

Unadjusted

Cardiovascular Death, MI or Stroke

Ticagrelor

1.23 (1.07,1.41)

Clopidogrel

1.20 (1.04,1.38)

*Propensity Adjusted

0.72

Ticagrelor

1.24 (1.06,1.45)

Clopidogrel

1.27 (1.11,1.45)

0.84

Unadjusted

Ticagrelor

1.24 (1.08,1.44)

Cardiovascular Death or MI

Clopidogrel

1.20 (1.03,1.40)

*Propensity Adjusted

0.94

Ticagrelor

1.26 (1.07,1.48)

0.8

1.0

1.2

1.4

1.6

No PPI Better

PPI Worse

+ P2Y12 inhibitor Treatment * PPI interaction P-value

slide13
1-Year Non-CABG PLATO Major Bleeding* by Randomized Treatment and PPI Use

% of Patients

6

Pinteraction for P2Y12 *PPI=0.17

5

4.90

4.39

4.24

4

3.43

3

+Hazard Ratio 1.30 (95% CI 1.00-1.70)

+Hazard Ratio 1.02 (95% CI 0.80-1.29)

2

1

0

PPI

No PPI

PPI

No PPI

Ticagrelor

Clopidogrel

* Kaplan-Meier estimates + Propensity-adjusted

slide14
Additional Analyses
  • Patients (n=1826) on non-PPI gastrointestinal drugs (e.g. H2 receptor antagonists) prior to randomization were at similar risk to those on a PPI
    • Clopidogrel: HR 0.98 (0.79-1.23)
    • Ticagrelor: HR 0.89 (0.73-1.10)
  • Patients (n=10236) on no gastric therapy were at significantly lower risk of the primary endpoint
    • Clopidogrel: HR 1.29 (1.12-1.49)
    • Ticagrelor: HR 1.30 (1.14-1.49)
  • Landmark analyses accounting for PPI use (at days 2, 4, 9, 30, 60, 90, and 180) post-randomization showed no increased risk of the primary endpoint in those receiving a PPI
    • Except in patients who prematurely discontinued study treatment (clopidogrel or ticagrelor) from day 180 post-randomization (PPI vs. no PPI: HR 4.31 [1.70-10.95])

PPI vs. non PPI GI treatment

PPI vs. no GI treatment

slide15
Limitations
  • Pre-defined subgroup analysis with multiple comparisons → individual subgroups may have been underpowered to show an association between PPI use and clinical outcomes
  • Use of a PPI was not randomized → potential for residual confounding despite multivariable adjustment and propensity score for the decision to treat with a PPI
  • PPIs could be initiated or discontinued during the course of follow-up → landmark analyses employed
  • Different types of PPIs with potentially different effects on CYP2C19 and clopidogrel metabolism
slide16
Conclusions
  • The apparent association between PPI and clopidogrel use and adverse events is highly confounded
    • PPI use may simply be a marker for, rather than a cause of, a higher risk of CV events
  • Regardless of PPI use, ticagrelor was superior to clopidogrel in preventing ischemic events
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